Trial Outcomes & Findings for Low-dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-negative Early Breast Cancer (NCT NCT00022516)

Last Updated: 2016-09-16

Results Overview

Estimated percentage of patients alive and disease-free at 5 years from randomization, where disease-free survival is defined as the time from randomization to the first appearance of one of the following: invasive breast cancer recurrence at local, regional, or distant site, invasive contralateral breast cancer, second (non-breast) invasive cancer, or death without cancer event; or censored at date of last follow-up.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1086 participants

Primary outcome timeframe

5-year estimates, reported at a median follow-up of 6.9 years

Results posted on

2016-09-16

Participant Flow

1086 patients were randomized between November 2000 and December 2012.

Participant milestones

Participant milestones
Measure	No-CM No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Overall Study STARTED	542	544
Overall Study COMPLETED	539	314
Overall Study NOT COMPLETED	3	230

Reasons for withdrawal

Reasons for withdrawal
Measure	No-CM No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Overall Study Adverse Event	0	59
Overall Study Lack of Efficacy	0	27
Overall Study Physician Decision	0	1
Overall Study Protocol Violation	1	3
Overall Study Withdrawal by Subject	2	113
Overall Study Incomplete documentation	0	27

Baseline Characteristics

Low-dose Oral Cyclophosphamide and Methotrexate Maintenance for Hormone Receptor-negative Early Breast Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	No-CM n=542 Participants No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance n=544 Participants 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year	Total n=1086 Participants Total of all reporting groups
Age, Continuous	52 years n=5 Participants	52 years n=7 Participants	52 years n=5 Participants
Sex: Female, Male Female	542 Participants n=5 Participants	544 Participants n=7 Participants	1086 Participants n=5 Participants
Sex: Female, Male Male	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: 5-year estimates, reported at a median follow-up of 6.9 years

Population: Intention to treat (N=1081 patients)

Outcome measures

Outcome measures
Measure	No-CM n=539 Participants No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance n=542 Participants 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Disease-free Survival	74.7 percentage of participants Interval 70.6 to 78.3	78.1 percentage of participants Interval 74.2 to 81.6

SECONDARY outcome

Timeframe: 5-year estimates, reported at a median follow-up of 6.9 years

Population: Intention to treat (N=1081 patients)

Estimated percentage of patients alive and disease-free at 5 years from randomization, where overall survival is defined as the time from randomization to death from any cause; or censored at date last known alive.

Outcome measures

Outcome measures
Measure	No-CM n=539 Participants No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance n=542 Participants 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Overall Survival	85.0 percentage of participants Interval 81.5 to 87.9	85 percentage of participants Interval 81.5 to 88.0

SECONDARY outcome

Timeframe: 5-year estimates, reported at a median follow-up of 6.9 years

Population: Intention-to-treat (N=1081 patients)

Estimated percentage of patients alive and disease-free at 5 years from randomization, where distant recurrence-free Interval is defined as the time from randomization to invasive breast cancer recurrence at distant site, or invasive contralateral breast cancer; or censored at date of last follow up.

Outcome measures

Outcome measures
Measure	No-CM n=539 Participants No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance n=542 Participants 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Distant Recurrence-free Interval	83.5 percentage of participants Interval 79.9 to 86.5	85.5 percentage of participants Interval 79.9 to 86.5

SECONDARY outcome

Timeframe: 5-year estimates, reported at a median follow-up of 6.9 years

Population: Intention-to-treat (N=1081 patients)

Estimated percentage of patients alive and disease-free at 5 years from randomization, where breast cancer-free interval is defined as the time from randomization to invasive breast cancer recurrence at local, regional, or distant site, or invasive contralateral breast cancer; or censored at date of last follow up.

Outcome measures

Outcome measures
Measure	No-CM n=539 Participants No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance n=542 Participants 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Breast Cancer-free Interval	77.3 percentage of participants Interval 73.3 to 80.7	81.0 percentage of participants Interval 77.2 to 84.2

Adverse Events

No-CM

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

CM-Maintenance

Serious events: 11 serious events

Other events: 58 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	No-CM No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance n=473 participants at risk 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Blood and lymphatic system disorders Leukopenia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.42% 2/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Blood and lymphatic system disorders Neutropenia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	1.1% 5/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Skin and subcutaneous tissue disorders Radiation dermatitis	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Nervous system disorders CNS hemorrhage	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Hepatobiliary disorders Elevated SGPT	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Nervous system disorders Neurologic-other	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Eye disorders Ocular-other	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Musculoskeletal and connective tissue disorders Arthralgia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)

Other adverse events

Additional Information

Rudolf Maibach, Executive Officer for International Trial Activities

IBCSG

Phone: +41 31 389 91 96

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	No-CM No further chemotherapy following standard adjuvant chemotherapy.	CM-Maintenance n=473 participants at risk 12-month CM-maintenance regimen (C, cyclophosphamide 50 mg/day orally continuously and M, methotrexate 2.5 mg twice/day orally days 1 and 2 of every week for 1 year) Cyclophosphamide: 50 mg/day orally continuously for 1 year Methotrexate: 2.5 mg twice/day orally days 1 and 2 of every week for 1 year
Blood and lymphatic system disorders Anemia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Blood and lymphatic system disorders Leukopenia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	1.7% 8/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Blood and lymphatic system disorders Lymphopenia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Blood and lymphatic system disorders Neutropenia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.42% 2/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Cardiac disorders Arrhythmia-other	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Cardiac disorders Hypertension	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Cardiac disorders Peripheral arterial ischemia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
General disorders Fatigue	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Gastrointestinal disorders Nausea	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.85% 4/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Gastrointestinal disorders Pancreatitis	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Gastrointestinal disorders Vomiting	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.63% 3/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Hepatobiliary disorders Elevated GGT	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Hepatobiliary disorders Elevated SGOT	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	1.9% 9/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Hepatobiliary disorders Elevated SGPT	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	6.8% 32/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Infections and infestations Infection w/ unknown ANC	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Infections and infestations Infection w/o neutropenia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.42% 2/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Infections and infestations Infection w/ grade 3 or 4 neutropenia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Musculoskeletal and connective tissue disorders Joint, muscle, bone-other	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Psychiatric disorders Insomnia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Nervous system disorders Neuropathy-sensory	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Nervous system disorders Seizure	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
General disorders Abdominal pain	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
General disorders Headache	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Musculoskeletal and connective tissue disorders Myalgia	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.21% 1/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)
Renal and urinary disorders Dysuria	— 0/0 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)	0.42% 2/473 • Adverse event data were collected every 3 months during the 12-month CM-maintenance chemotherapy treatment period. Only Grade 3 and higher AEs were collected among patients who initiated the experimental (CM-Maintenance) therapy (N=473) . AE data were NOT collected for patients who did not receive CM-maintenance therapy (No-CM)