Trial Outcomes & Findings for Exemestane With or Without Entinostat in Treating Patients With Recurrent Hormone Receptor-Positive Breast Cancer That is Locally Advanced or Metastatic (NCT NCT02115282)

NCT ID: NCT02115282

Last Updated: 2025-12-18

Results Overview

Progression-free survival (PFS) was defined to be time from randomization to the earliest documented disease progression as defined by the RECIST criteria, new primary breast cancer, or death without progression. Disease assessment was to continue until disease progression, even after non-protocol anti-cancer therapy was started. Cases with incomplete follow up or without adequate disease evaluations were censored at the date last documented to be free of progression, regardless of whether non-protocol anti-cancer therapy was started or not. Disease progression was based on central review, and defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. In addition, the appearance of one or more new lesions was also considered progression. Kaplan-Meier method was used to estimate PFS rate.

• Recruitment status: ACTIVE_NOT_RECRUITING
• Study phase: PHASE3
• Target enrollment: 608 participants
• Primary outcome timeframe: Assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression
• Results posted on: 2025-12-18

Participant Flow

This study was activated on March 19, 2014 and terminated on October 17, 2018 with a total accrual of 608 patients.

Participant milestones

Measure	Arm A (Exemestane, Entinostat) Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Overall Study STARTED	305	303
Overall Study Eligible	265	257
Overall Study Treated	296	293
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	305	303

Reasons for withdrawal

Measure	Arm A (Exemestane, Entinostat) Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Overall Study Disease progression during treatment	216	229
Overall Study Adverse Event	49	23
Overall Study Death	1	3
Overall Study Alternative therapy	1	1
Overall Study Complicating disease	0	3
Overall Study Withdrawal by Subject	12	10
Overall Study Symptomatic progression/deterioration	7	18
Overall Study Non-compliance	5	1
Overall Study Protocol Violation	2	2
Overall Study Study termination (stop treatment due to the release of the results)	3	3
Overall Study Not start protocol therapy	9	10

Baseline Characteristics

Exemestane With or Without Entinostat in Treating Patients With Recurrent Hormone Receptor-Positive Breast Cancer That is Locally Advanced or Metastatic

Baseline characteristics by cohort

Measure	Arm A (Exemestane, Entinostat) n=305 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=303 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO	Total n=608 Participants Total of all reporting groups
Age, Continuous	63 years n=47 Participants	63 years n=41 Participants	63 years n=88 Participants
Sex: Female, Male Female	302 Participants n=47 Participants	300 Participants n=41 Participants	602 Participants n=88 Participants
Sex: Female, Male Male	3 Participants n=47 Participants	3 Participants n=41 Participants	6 Participants n=88 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	18 Participants n=47 Participants	18 Participants n=41 Participants	36 Participants n=88 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	284 Participants n=47 Participants	278 Participants n=41 Participants	562 Participants n=88 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	3 Participants n=47 Participants	7 Participants n=41 Participants	10 Participants n=88 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=47 Participants	0 Participants n=41 Participants	3 Participants n=88 Participants
Race (NIH/OMB) Asian	5 Participants n=47 Participants	2 Participants n=41 Participants	7 Participants n=88 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	1 Participants n=47 Participants	0 Participants n=41 Participants	1 Participants n=88 Participants
Race (NIH/OMB) Black or African American	42 Participants n=47 Participants	49 Participants n=41 Participants	91 Participants n=88 Participants
Race (NIH/OMB) White	246 Participants n=47 Participants	244 Participants n=41 Participants	490 Participants n=88 Participants
Race (NIH/OMB) More than one race	0 Participants n=47 Participants	0 Participants n=41 Participants	0 Participants n=88 Participants
Race (NIH/OMB) Unknown or Not Reported	8 Participants n=47 Participants	8 Participants n=41 Participants	16 Participants n=88 Participants

PRIMARY outcome

Timeframe: Assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression

Population: The first 360 patients randomized to the trial (primary analysis population for the PFS endpoint)

Progression-free survival (PFS) was defined to be time from randomization to the earliest documented disease progression as defined by the RECIST criteria, new primary breast cancer, or death without progression. Disease assessment was to continue until disease progression, even after non-protocol anti-cancer therapy was started. Cases with incomplete follow up or without adequate disease evaluations were censored at the date last documented to be free of progression, regardless of whether non-protocol anti-cancer therapy was started or not. Disease progression was based on central review, and defined as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. In addition, the appearance of one or more new lesions was also considered progression. Kaplan-Meier method was used to estimate PFS rate.

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=180 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=180 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Progression-free Survival (PFS)	3.3 months Interval 3.1 to 5.3	3.1 months Interval 3.0 to 3.3

PRIMARY outcome

Timeframe: Assessed every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until death

Population: All randomized patients (ie, intent-to-treat patients, primary analysis population for the OS endpoint)

Overall survival (OS) was defined to be time from randomization to death from any cause. Cases who were still alive were censored at the date last known alive.

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=305 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=303 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Overall Survival (OS)	23.4 months Interval 21.2 to 25.6	21.7 months Interval 19.3 to 27.1

SECONDARY outcome

Timeframe: Assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression

Population: All randomized patients (ie, the intent-to-treat population)

Objective response rate was defined as number of patients with complete response (CR) or partial response (PR) divided by all randomized patients. Responses were evaluated using the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline. CR was defined as disappearance of all target and non-target lesions. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameters), and/or persistence of one or more non-target lesion(s).

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=305 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=303 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Objective Response Rate (ORR)	4.6 percentage of participants Interval 2.5 to 7.6	4.3 percentage of participants Interval 2.3 to 7.2

SECONDARY outcome

Timeframe: Disease assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression

Population: The first 360 patients randomized to the trial who received at least one dose of protocol therapy

Time-to-treatment deterioration (TTD) was defined as time from randomization to disease progression or death or worsening of symptoms, whichever occurred first. Disease progression was assessed per RECIST v1.1. Symptoms deterioration was measured by 6 items (GP1, GP2, GP4, GF7, B1, P2, scored 0-24) from the 8-item FACT-Breast Symptom Index (FBSI). Symptom deterioration was defined as two consecutive available decreases of at least 3 points from baseline using the 6-item FBSI in this trial, and the second visit time was used as the time of symptom deterioration in this case, unless it was the final score, for which one decrease was sufficient. Kaplan-Meier method was used to estimate the median TTD and TTD rate at a certain time point. Symptoms were assessed every cycle for the first six months after randomization, every two cycles between 6 months and 1 year. It then were assessed based on the same schedule for tumor assessments until disease progression as specified below.

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=175 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=176 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Time-to-treatment Deterioration (TTD)	2.9 months Interval 2.8 to 3.1	2.9 months Interval 2.8 to 3.0

SECONDARY outcome

Timeframe: Disease assessed at baseline, then every 12 weeks until treatment discontinuation, then every 3 months within 2 years from study entry, every 6 months between 2-5 years and annually between 6-10 years from study entry, until first disease progression

Population: All patients who were randomized to arm A (exemestane +entinostat) and had lysine acetylation test results at both C1D1 and C1D15

Peripheral blood samples (PBMCs) were collected prior to therapy and on Days 8 and 15 of cycle 1, for assessment of lysine acetylation, using an assay developed by the Trepel Laboratory, NCI/NIH. CD45 blood mononuclear cells were measured. Patients with lysine acetylation change of 1.5 folds or higher were compared to patients with lysine acetylation change of less than 1.5 folds.

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=43 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=146 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Lysine Acetylation Change in CD45 Blood Mononuclear Cells Between C1D1 and C1D15 and PFS in Patients on Arm A	2.8 months Interval 2.5 to 5.1	2.7 months Interval 2.5 to 5.2

SECONDARY outcome

Timeframe: Assessed at baseline and end of cycle 3

Population: All randomized patients who reported health-related quality of life data at end of cycle 3 assessment

Health-related quality of life (HRQL) was measured using Functional Assessment of Cancer Therapy - General (FACT-G). The primary endpoint for HRQL was the FACT-G Trial Outcome Index (TOI) which was an aggregate score of 5 items from the FACT-G-Physical subscale (GP2, GP3, GP4, GP6, and GP7) and 6 items from the FACT-G-Functional subscale (GF1, GF2, GF3, GF4, GF6, and GF7). All items were rated on a 5-point Likert scale from 0 to 4. FACT-G TOI subscale score was calculated based on the scoring manual, subscale score ranges from 0 to 44, and higher scores indicate better quality of life. The primary comparison of HRQL between treatment arms was based on the end of cycle 3 assessment.

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=203 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=205 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Patient-reported Health-related Quality of Life	20.5 units on a scale Standard Deviation 5.0	20.9 units on a scale Standard Deviation 4.7

SECONDARY outcome

Timeframe: Assessed at baseline and end of cycle 3

Population: All randomized patients who reported FACIT-Diarrhea data at end of cycle 3 assessment

Diarrhea was measured by Functional Assessment of Chronic Illness Therapy for Patients With Diarrhea (FACIT-Diarrhea) subscale form, which had 11 items, all items were rated on a 5-point Likert scale from 0 to 4. FACIT-Diarrhea subscale score was calculated based on the scoring manual, subscale score ranges from 0 to 44, and higher score indicates less diarrhea. The primary comparison of patient-reported diarrhea between treatment arms was based on the end of cycle 3 assessment.

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=208 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=209 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Patient-reported Diarrhea	38.8 units on a scale Standard Deviation 7.2	41.5 units on a scale Standard Deviation 4.3

SECONDARY outcome

Timeframe: Assessed at baseline and end of cycle 3

Population: All randomized patients who reported PROMIS fatigue data at end of cycle 3 assessment

Fatigue was measured by PROMIS Fatigue short form, it had 7 items and all items were rated on a 5-point Likert scale from 1 to 5. The PROMIS Fatigue total score and T score were calculated based on the scoring manual. The total score ranges from 7 to 35, the T score ranges from 29.4 to 83.2, higher scores indicate more fatigue. The PROMIS Fatigue T score was used for arm comparison. The primary comparison of patient-reported fatigue between treatment arms was based on the end of cycle 3 assessment.

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=201 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=207 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Patient-reported Fatigue	55.5 T-score Standard Deviation 8.2	54.1 T-score Standard Deviation 8.9

SECONDARY outcome

Timeframe: Assessed at baseline and end of cycle 3

Population: All randomized patients who reported FAACT nausea and anorexia data at end of cycle 3 assessment

Nausea and anorexia were measured by The Functional Assessment of Anorexia/Cachexia Treatment (FAACT)-additional concerns, which had 12 items, all items were rated on a 5-point Likert scale from 0 to 4. FAACT-additional concerns subscale score was calculated based on scoring manual. Subscale score ranges from 0 to 48, and higher scores indicate less nausea and anorexia. The primary comparison of patient-reported nausea and anorexia between treatment arms was based on the end of cycle 3 assessment.

Outcome measures

Measure	Arm A (Exemestane, Entinostat) n=208 Participants Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm B (Exemestane, Placebo) n=203 Participants Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Patient-reported Nausea and Anorexia	35.8 units on a scale Standard Deviation 7.8	37.0 units on a scale Standard Deviation 7.9

Adverse Events

Arm A (Exemestance, Entinostat)

Serious events: 151 serious events

Other events: 280 other events

Deaths: 209 deaths

Arm A (Exemestance, Placebo)

Serious events: 47 serious events

Other events: 228 other events

Deaths: 203 deaths

Serious adverse events

Measure	Arm A (Exemestance, Entinostat) n=296 participants at risk Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm A (Exemestance, Placebo) n=293 participants at risk Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Blood and lymphatic system disorders Anemia	7.4% 22/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.7% 5/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Blood and lymphatic system disorders Febrile neutropenia	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Cardiac disorders Atrial fibrillation	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Cardiac disorders Heart failure	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Cardiac disorders Myocardial infarction	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Cardiac disorders Pericardial effusion	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Cardiac disorders Right ventricular dysfunction	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
General disorders Edema limbs	1.0% 3/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
General disorders Edema trunk	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
General disorders Fatigue	4.1% 12/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.0% 3/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
General disorders Non-cardiac chest pain	1.0% 3/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Skin and subcutaneous tissue disorders Hyperhidrosis	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Skin and subcutaneous tissue disorders Rash maculo-papular	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Skin and subcutaneous tissue disorders Urticaria	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Endocrine disorders Endocrine disorders - Other, specify	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Abdominal pain	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Colitis	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Colonic perforation	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.68% 2/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Diarrhea	4.1% 12/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Enterocolitis	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Gastric ulcer	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Gastroesophageal reflux disease	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Nausea	1.7% 5/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Vomiting	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.0% 3/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Hepatobiliary disorders Hepatic failure	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Immune system disorders Anaphylaxis	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Infections and infestations Abdominal infection	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Infections and infestations Bone infection	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Infections and infestations Lung infection	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Infections and infestations Sepsis	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.68% 2/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Infections and infestations Urinary tract infection	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Alanine aminotransferase increased	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.68% 2/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Alkaline phosphatase increased	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.68% 2/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Aspartate aminotransferase increased	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.7% 5/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Blood bilirubin increased	1.0% 3/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations GGT increased	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations INR increased	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Lymphocyte count decreased	3.4% 10/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.0% 3/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Neutrophil count decreased	19.6% 58/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Platelet count decreased	3.4% 10/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.68% 2/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Weight loss	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations White blood cell decreased	6.1% 18/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.68% 2/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Anorexia	1.7% 5/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Dehydration	1.0% 3/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypercalcemia	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hyperglycemia	1.4% 4/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.68% 2/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypoalbuminemia	1.0% 3/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypocalcemia	1.7% 5/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypokalemia	2.4% 7/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.68% 2/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hyponatremia	2.7% 8/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypophosphatemia	13.2% 39/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.4% 4/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Metabolism and nutrition disorders - Other, specify	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Arthralgia	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.0% 3/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Back pain	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Generalized muscle weakness	1.0% 3/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Muscle weakness right-sided	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Nervous system disorders Encephalopathy	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Nervous system disorders Headache	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Nervous system disorders Stroke	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Nervous system disorders Syncope	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Dyspnea	2.0% 6/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Hypoxia	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Pneumonitis	0.68% 2/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Pulmonary edema	0.34% 1/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.34% 1/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Vascular disorders Hypertension	0.00% 0/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.7% 5/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Vascular disorders Thromboembolic event	1.4% 4/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	0.00% 0/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.

Other adverse events

Measure	Arm A (Exemestance, Entinostat) n=296 participants at risk Patients receive exemestane PO QD on days 1-28 and entinostat PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Entinostat: Given PO Exemestane: Given PO Goserelin Acetate: Given SC	Arm A (Exemestance, Placebo) n=293 participants at risk Patients receive exemestane as in Arm A and placebo PO on days 1, 8, 15, and 22. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Pre/perimenopausal female patients and all male patients also receive goserelin acetate SC on day 1. Exemestane: Given PO Goserelin Acetate: Given SC Placebo Administration: Given PO
Blood and lymphatic system disorders Anemia	37.2% 110/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	18.8% 55/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
General disorders Edema limbs	18.2% 54/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	5.5% 16/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
General disorders Fatigue	56.4% 167/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	36.9% 108/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Abdominal pain	12.5% 37/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	7.2% 21/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Constipation	12.2% 36/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	12.3% 36/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Diarrhea	35.8% 106/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	16.0% 47/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Dyspepsia	13.9% 41/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	5.1% 15/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Nausea	40.5% 120/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	25.9% 76/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Gastrointestinal disorders Vomiting	18.9% 56/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	11.3% 33/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Injury, poisoning and procedural complications Bruising	6.1% 18/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	1.0% 3/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Alanine aminotransferase increased	12.8% 38/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	11.9% 35/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Alkaline phosphatase increased	28.7% 85/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	16.0% 47/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Aspartate aminotransferase increased	18.9% 56/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	18.4% 54/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Creatinine increased	11.1% 33/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	6.5% 19/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Lymphocyte count decreased	17.6% 52/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	7.8% 23/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Neutrophil count decreased	46.6% 138/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	4.1% 12/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Platelet count decreased	63.5% 188/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	6.5% 19/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations Weight loss	9.8% 29/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	4.1% 12/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Investigations White blood cell decreased	55.1% 163/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	13.3% 39/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Anorexia	20.9% 62/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	10.2% 30/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hyperglycemia	9.8% 29/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	4.1% 12/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypoalbuminemia	22.3% 66/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	3.4% 10/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypocalcemia	27.4% 81/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	4.8% 14/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypokalemia	7.4% 22/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	3.8% 11/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hyponatremia	12.5% 37/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	5.1% 15/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Metabolism and nutrition disorders Hypophosphatemia	22.6% 67/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	4.1% 12/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Arthralgia	8.8% 26/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	8.9% 26/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Musculoskeletal and connective tissue disorders Myalgia	6.1% 18/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	8.2% 24/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Nervous system disorders Dizziness	7.1% 21/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	4.8% 14/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Nervous system disorders Dysgeusia	6.8% 20/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	2.7% 8/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Nervous system disorders Headache	13.2% 39/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	5.5% 16/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Psychiatric disorders Insomnia	6.1% 18/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	3.4% 10/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Cough	5.1% 15/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	2.7% 8/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Respiratory, thoracic and mediastinal disorders Dyspnea	11.1% 33/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	6.5% 19/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.
Vascular disorders Hot flashes	7.8% 23/296 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.	12.3% 36/293 • Assessed every cycle (1 cycle=28 days) while on treatment and for 30 days after the end of treatment, up to 10 years from study entry Only patients who received protocol therapy were included in the analysis of adverse events. All randomized patients were included in the analysis of all-cause mortality.

Additional Information

Study Statistician

ECOG-ACRIN Cancer Research Group

Phone: 6176323012

Email: eatrials@jimmy.harvard.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: LTE60