Trial Outcomes & Findings for Fulvestrant With or Without Lapatinib in Treating Postmenopausal Women With Stage III or Stage IV Breast Cancer That is Hormone Receptor-Positive (NCT NCT00390455)

Last Updated: 2019-12-20

Results Overview

PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first. Progression is defined as a 20% increase in the sum of longest diameter of target lesions (per RECIST criteria).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

295 participants

Primary outcome timeframe

Interval from randomization until disease progression or death, whichever occurs first, assessed up to 5 years

Results posted on

2019-12-20

Participant Flow

Between September 2006 and July 2010, 295 participants were recruited.

Participant milestones

Participant milestones
Measure	Arm I (Lapatinib) Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Overall Study STARTED	148	147
Overall Study COMPLETED	116	124
Overall Study NOT COMPLETED	32	23

Reasons for withdrawal

Reasons for withdrawal
Measure	Arm I (Lapatinib) Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Overall Study Adverse Event	17	3
Overall Study Withdrawal by Subject	8	8
Overall Study Alternate Treatment	0	1
Overall Study Other Medical Reasons	7	11

Baseline Characteristics

Fulvestrant With or Without Lapatinib in Treating Postmenopausal Women With Stage III or Stage IV Breast Cancer That is Hormone Receptor-Positive

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Arm I (Lapatinib) n=146 Participants Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=145 Participants Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.	Total n=291 Participants Total of all reporting groups
Age, Customized <40	8 participants n=5 Participants	7 participants n=7 Participants	15 participants n=5 Participants
Age, Customized 40-49	21 participants n=5 Participants	17 participants n=7 Participants	38 participants n=5 Participants
Age, Customized 50-59	49 participants n=5 Participants	54 participants n=7 Participants	103 participants n=5 Participants
Age, Customized 60-69	41 participants n=5 Participants	47 participants n=7 Participants	88 participants n=5 Participants
Age, Customized 70+	27 participants n=5 Participants	20 participants n=7 Participants	47 participants n=5 Participants
Sex: Female, Male Female	146 Participants n=5 Participants	145 Participants n=7 Participants	291 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	7 Participants n=5 Participants	7 Participants n=7 Participants	14 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	130 Participants n=5 Participants	129 Participants n=7 Participants	259 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	9 Participants n=5 Participants	9 Participants n=7 Participants	18 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race (NIH/OMB) Asian	4 Participants n=5 Participants	2 Participants n=7 Participants	6 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	11 Participants n=5 Participants	8 Participants n=7 Participants	19 Participants n=5 Participants
Race (NIH/OMB) White	127 Participants n=5 Participants	132 Participants n=7 Participants	259 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	2 Participants n=7 Participants	2 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	1 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment United States	146 participants n=5 Participants	145 participants n=7 Participants	291 participants n=5 Participants
Prior tamoxifen therapy Yes	83 participants n=5 Participants	82 participants n=7 Participants	165 participants n=5 Participants
Prior tamoxifen therapy No	63 participants n=5 Participants	63 participants n=7 Participants	126 participants n=5 Participants
Bond disease only Yes	45 participants n=5 Participants	43 participants n=7 Participants	88 participants n=5 Participants
Bond disease only No	101 participants n=5 Participants	102 participants n=7 Participants	203 participants n=5 Participants

PRIMARY outcome

Timeframe: Interval from randomization until disease progression or death, whichever occurs first, assessed up to 5 years

Population: 4 participants who never received protocol therapy were excluded.

Outcome measures

Outcome measures
Measure	Arm I (Lapatinib) n=146 Participants Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=145 Participants Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Progression-free Survival (PFS)	4.7 months Interval 3.7 to 5.7	3.8 months Interval 3.8 to 5.6

SECONDARY outcome

Timeframe: Up to 5 years

Population: Participants who started protocol therapy and had measurable disease were evaluated.

Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm.

Outcome measures

Outcome measures
Measure	Arm I (Lapatinib) n=101 Participants Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=103 Participants Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Objective Tumor Response Rate	20 percentage of participants Interval 13.0 to 29.0	9 percentage of participants Interval 5.0 to 17.0

SECONDARY outcome

Timeframe: Study entry to death or last follow-up, up to 5 years

Population: 4 participants who never started protocol therapy were excluded.

Overall survival was measured as the interval from study entry until death, from any cause, or last contact.

Outcome measures

Outcome measures
Measure	Arm I (Lapatinib) n=146 Participants Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=145 Participants Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Overall Survival (OS)	29.9 months Interval 24.8 to 34.8	26.4 months Interval 23.9 to 39.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 5 years

Population: Participants who began protocol therapy with HER-2 negative tumors were analyzed.

PFS was defined as the interval from study entry until disease progression or death resulting from any cause, which ever occurred first.

Outcome measures

Outcome measures
Measure	Arm I (Lapatinib) n=122 Participants Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=113 Participants Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Progression-free Survival for Participants With HER2-negative Tumors	4.1 months Interval 3.4 to 5.6	3.8 months Interval 3.1 to 5.7

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 5 years

Population: Participants who started protocol therapy and had HER2-positive disease were analyzed.

PFS was defined as the interval from study entry until disease progression or death resulting from any cause, whichever occurred first.

Outcome measures

Outcome measures
Measure	Arm I (Lapatinib) n=24 Participants Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=30 Participants Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Progression-free Survival for Participants With HER2-positive Tumors	5.9 months Interval 3.7 to 9.3	3.3 months Interval 2.1 to 7.5

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 5 years

Population: Participants who started protocol therapy, had measurable disease and HER-2 negative disease were analyzed.

Response was defined by the RECIST. A responding participant had either a Complete Response (disappearance of all target lesions) or Partial Response (30% decrease in sum of longest diameter of target lesions). The response rate of measurable tumors will be estimated with its 95% confidence interval according to treatment arm.

Outcome measures

Outcome measures
Measure	Arm I (Lapatinib) n=32 Participants Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=32 Participants Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Objective Tumor Response Rate for Participants With HER2-negative Tumors	13 percentage of participants Interval 5.0 to 29.0	23 percentage of participants Interval 12.0 to 41.0

OTHER_PRE_SPECIFIED outcome

Timeframe: Up to 5 years

Population: Participants who started protocol therapy, had measurable disease and HER-2 positive disease were analyzed.

Outcome measures

Outcome measures
Measure	Arm I (Lapatinib) n=8 Participants Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=13 Participants Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Objective Tumor Response Rate for Participants With HER2-positive Tumors	38 percentage of participants Interval 14.0 to 70.0	17 percentage of participants Interval 5.0 to 45.0

Adverse Events

Arm I (Lapatinib)

Serious events: 12 serious events

Other events: 128 other events

Deaths: 0 deaths

Arm II (Placebo)

Serious events: 14 serious events

Other events: 114 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Harold Burstein, M.D.

Dana-Farber Cancer Institue

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Arm I (Lapatinib) n=141 participants at risk Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=137 participants at risk Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Respiratory, thoracic and mediastinal disorders Dyspnea	2.1% 3/141 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Psychiatric disorders Insomnia	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Fatigue	5.7% 8/141 • Number of events 8 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	3.6% 5/137 • Number of events 5 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Gait abnormal	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Cardiac disorders Cardiac pain	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Constipation	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Diarrhea	5.0% 7/141 • Number of events 7 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	2.9% 4/137 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Gastrointestinal disorder	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Nausea	3.5% 5/141 • Number of events 5 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	2.2% 3/137 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Vomiting	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Chest pain	0.71% 1/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Disease progression	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Injection site reaction	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Pain	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Infections and infestations Sepsis	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Infections and infestations Urinary tract infection	2.1% 3/141 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Injury, poisoning and procedural complications Fracture	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Alanine aminotransferase increased	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Alkaline phosphatase increased	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Aspartate aminotransferase increased	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Blood bilirubin increased	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Metabolism and nutrition disorders Anorexia	2.8% 4/141 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Metabolism and nutrition disorders Blood glucose increased	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Metabolism and nutrition disorders Dehydration	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Metabolism and nutrition disorders Serum sodium decreased	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Arthralgia	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Bone pain	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor flare	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Nervous system disorders Dizziness	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Nervous system disorders Headache	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Nervous system disorders Ischemia cerebrovascular	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Nervous system disorders Peripheral motor neuropathy	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Respiratory, thoracic and mediastinal disorders Pneumonitis	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Rash acneiform	2.8% 4/141 • Number of events 5 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Rash desquamating	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Skin ulceration	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Vascular disorders Hot flashes	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	2.2% 3/137 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Vascular disorders Thrombosis	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)

Measure	Arm I (Lapatinib) n=141 participants at risk Patients receive 1500 mg lapatinib ditosylate PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg)of each subsequent course.	Arm II (Placebo) n=137 participants at risk Patients receive placebo PO QD on days 1-28 and fulvestrant IM on days 1 (500 mg) and 15 (250 mg) of course 1 and on day 1 (250 mg) of each subsequent course.
Blood and lymphatic system disorders Hemoglobin decreased	3.5% 5/141 • Number of events 5 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	3.6% 5/137 • Number of events 12 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Cardiac disorders Left ventricular failure	2.1% 3/141 • Number of events 6 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	2.2% 3/137 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Eye disorders Diplopia	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Eye disorders Eye pain	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Eye disorders Vision blurred	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Abdominal pain	0.71% 1/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Ascites	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Constipation	14.2% 20/141 • Number of events 25 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	18.2% 25/137 • Number of events 29 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Diarrhea	62.4% 88/141 • Number of events 206 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	21.9% 30/137 • Number of events 54 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Dyspepsia	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Flatulence	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Gastrointestinal disorder	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Mucositis oral	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Nausea	34.8% 49/141 • Number of events 76 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	29.9% 41/137 • Number of events 51 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Gastrointestinal disorders Vomiting	15.6% 22/141 • Number of events 26 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	6.6% 9/137 • Number of events 12 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Chest pain	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Edema limbs	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Fatigue	55.3% 78/141 • Number of events 205 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	53.3% 73/137 • Number of events 145 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Gait abnormal	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Ill-defined disorder	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Injection site reaction	2.8% 4/141 • Number of events 7 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	7.3% 10/137 • Number of events 17 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
General disorders Pain	0.71% 1/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Infections and infestations Bronchitis	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Infections and infestations Nail infection	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Infections and infestations Upper respiratory infection	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Infections and infestations Urinary tract infection	3.5% 5/141 • Number of events 6 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	2.9% 4/137 • Number of events 5 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Activated partial thromboplastin time prolonged	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Alanine aminotransferase increased	2.8% 4/141 • Number of events 6 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Alkaline phosphatase increased	2.1% 3/141 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Aspartate aminotransferase increased	5.7% 8/141 • Number of events 10 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Blood bilirubin increased	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Creatinine increased	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Leukocyte count decreased	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Investigations Weight loss	1.4% 2/141 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Metabolism and nutrition disorders Anorexia	13.5% 19/141 • Number of events 27 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	15.3% 21/137 • Number of events 25 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Metabolism and nutrition disorders Blood glucose increased	2.8% 4/141 • Number of events 6 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Metabolism and nutrition disorders Serum potassium decreased	1.4% 2/141 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Metabolism and nutrition disorders Serum potassium increased	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Arthralgia	2.1% 3/141 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	4.4% 6/137 • Number of events 15 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Back pain	3.5% 5/141 • Number of events 9 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Bone pain	2.1% 3/141 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Chest wall pain	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Developmental disturbance	0.71% 1/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Muscle weakness lower limb	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Myalgia	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Neck pain	0.71% 1/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 5 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Osteoporosis	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Musculoskeletal and connective tissue disorders Pain in extremity	0.71% 1/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	2.9% 4/137 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Nervous system disorders Dizziness	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Nervous system disorders Headache	13.5% 19/141 • Number of events 24 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	11.7% 16/137 • Number of events 19 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Nervous system disorders Peripheral sensory neuropathy	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	1.5% 2/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Psychiatric disorders Anxiety	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Psychiatric disorders Depression	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Psychiatric disorders Insomnia	0.71% 1/141 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Renal and urinary disorders Cystitis	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Renal and urinary disorders Ureteric obstruction	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Renal and urinary disorders Urinary frequency	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Respiratory, thoracic and mediastinal disorders Cough	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	2.2% 3/137 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Respiratory, thoracic and mediastinal disorders Dyspnea	3.5% 5/141 • Number of events 5 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	2.9% 4/137 • Number of events 6 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Respiratory, thoracic and mediastinal disorders Dyspnea (shortness of breath)	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Respiratory, thoracic and mediastinal disorders Hypoxia	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Respiratory, thoracic and mediastinal disorders Pleural effusion	0.00% 0/141 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Respiratory, thoracic and mediastinal disorders Pneumonitis	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Respiratory, thoracic and mediastinal disorders Respiratory disorder	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Alopecia	1.4% 2/141 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Dry skin	1.4% 2/141 • Number of events 11 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 4 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Nail disorder	0.71% 1/141 • Number of events 3 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Pain of skin	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Pruritus	1.4% 2/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.73% 1/137 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Rash acneiform	41.1% 58/141 • Number of events 160 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	4.4% 6/137 • Number of events 16 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Rash desquamating	11.3% 16/141 • Number of events 23 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	8.0% 11/137 • Number of events 13 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Skin disorder	0.71% 1/141 • Number of events 2 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Skin and subcutaneous tissue disorders Sweating	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Vascular disorders Hot flashes	27.0% 38/141 • Number of events 78 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	36.5% 50/137 • Number of events 104 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Vascular disorders Hypertension	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)
Vascular disorders Thrombosis	0.71% 1/141 • Number of events 1 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)	0.00% 0/137 Adverse event was available on 278 participants (Arm I: 141, Arm II: 137)