Trial Outcomes & Findings for Preoperative Folfirinox, Radiation Therapy for Resectable Adenocarcinoma of the Pancreas (NCT NCT01560949)

Last Updated: 2020-08-10

Results Overview

Patients with borderline resectable treated with preoperative modified FOLFIRINOX chemotherapy, followed by gemcitabine-based chemoradiation therapy. At least 4- 6 weeks after the last dose of gemcitabine if there is no local progression or distant metastasis, patients were scheduled for surgery.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

34 participants

Primary outcome timeframe

43 months

Results posted on

2020-08-10

Participant Flow

June 2012 to November 2015. All recruitment done at The University of Texas, MD Anderson Cancer Center.

A total of 34 participants enrolled in study 1 participant withdrew consent before initiating treatment.

Participant milestones

Participant milestones
Measure	Systemic Phase: mFOLFIRINOX Systemic: Oxaliplatin at 75 mg/m2 IV on day 1, Irinotecan at 150 mg/m2 IV on day 1, 5 fluorouracil at 2000 mg/m2 IV 46 hour continuous infusion on day 1 - 2, every other week for 6 cycles (12 weeks). Chemo: Gemcitabine at 350 mg/m2 IV weekly for 5 doses beginning day 1. External beam radiation therapy delivered 5 days/week, a total dose of 50.4 Gy. Surgery: At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis
Systemic Phase: mFOLFIRINOX STARTED	33
Systemic Phase: mFOLFIRINOX COMPLETED	27
Systemic Phase: mFOLFIRINOX NOT COMPLETED	6
Chemoradiation Phase: With Gemcitabine STARTED	23
Chemoradiation Phase: With Gemcitabine COMPLETED	23
Chemoradiation Phase: With Gemcitabine NOT COMPLETED	0
Surgery Phase STARTED	18
Surgery Phase COMPLETED	15
Surgery Phase NOT COMPLETED	3

Reasons for withdrawal

Reasons for withdrawal
Measure	Systemic Phase: mFOLFIRINOX Systemic: Oxaliplatin at 75 mg/m2 IV on day 1, Irinotecan at 150 mg/m2 IV on day 1, 5 fluorouracil at 2000 mg/m2 IV 46 hour continuous infusion on day 1 - 2, every other week for 6 cycles (12 weeks). Chemo: Gemcitabine at 350 mg/m2 IV weekly for 5 doses beginning day 1. External beam radiation therapy delivered 5 days/week, a total dose of 50.4 Gy. Surgery: At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis
Systemic Phase: mFOLFIRINOX Adverse Event	6
Surgery Phase Physician Decision	3

Baseline Characteristics

Preoperative Folfirinox, Radiation Therapy for Resectable Adenocarcinoma of the Pancreas

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Systemic Phase: mFOLFIRINOX n=33 Participants Oxaliplatin at 75 mg/m2 IV on day 1, Irinotecan at 150 mg/m2 IV on day 1, 5 fluorouracil at 2000 mg/m2 IV 46 hour continuous infusion on day 1 - 2, every other week for 6 cycles (12 weeks)
Age, Categorical <=18 years	0 Participants n=99 Participants
Age, Categorical Between 18 and 65 years	18 Participants n=99 Participants
Age, Categorical >=65 years	15 Participants n=99 Participants
Sex: Female, Male Female	12 Participants n=99 Participants
Sex: Female, Male Male	21 Participants n=99 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	3 Participants n=99 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	30 Participants n=99 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=99 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=99 Participants
Race (NIH/OMB) Asian	2 Participants n=99 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=99 Participants
Race (NIH/OMB) Black or African American	2 Participants n=99 Participants
Race (NIH/OMB) White	26 Participants n=99 Participants
Race (NIH/OMB) More than one race	0 Participants n=99 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=99 Participants
Region of Enrollment United States	33 participants n=99 Participants

PRIMARY outcome

Timeframe: 43 months

Outcome measures

Outcome measures
Measure	Surgery n=33 Participants At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis.
Number of Participants With Resectability Rate	15 Participants

SECONDARY outcome

Timeframe: 43 months

The specimen was designated R0 if no tumor cells were identified at any of the resection margins.

Outcome measures

Outcome measures
Measure	Surgery n=15 Participants At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis.
Number of Participants With R0 Margin Resection	10 Participants

SECONDARY outcome

Timeframe: 54 months

Disease free survival (DFS) was defined as the time interval from the date of surgery to the date of disease recurrence or death or the date of a participant was last known to be alive without disease recurrence.

Outcome measures

Outcome measures
Measure	Surgery n=33 Participants At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis.
Disease Free Survival (DFS)	11.1 months Interval 5.8 to Insufficient number of participants with events.

SECONDARY outcome

Timeframe: 43 months

Tumor tissue collected pre-therapy and post-therapy for surgically resected patients was assessed for SMAD4 status and classified as either present or absent based on immunohistochemistry evaluation.

Outcome measures

Outcome measures
Measure	Surgery n=15 Participants At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis.
Number of Participants That Were SMAD4 Positive Before and After Surgery SMAD4 positive before surgery	4 Participants
Number of Participants That Were SMAD4 Positive Before and After Surgery SMAD4 positive after surgery	4 Participants

SECONDARY outcome

Timeframe: 54 months

Overall survival (OS) was defined as the time interval from the date of diagnosis to the date of death due to any cause or the date a patient was last known to be alive. Estimated by using the Kaplan-Meier method.

Outcome measures

Outcome measures
Measure	Surgery n=33 Participants At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis.
Overall Survival	24 months Interval 16.2 to 29.6

SECONDARY outcome

Timeframe: 43 months

Outcome measures

Outcome measures
Measure	Surgery n=15 Participants At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis.
Number of Participants With Local and Distant Failure Local recurrence	0 Participants
Number of Participants With Local and Distant Failure Distant recurrence	10 Participants

SECONDARY outcome

Timeframe: 43 months

Tumor tissue collected pre-therapy and post-therapy for surgically resected patients was assessed for SMAD4 status and classified as either present or absent based on immunohistochemistry evaluation.

Outcome measures

Outcome measures
Measure	Surgery n=6 Participants At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis.
Number of Participants Correlative Studies Including DPC4 (SMAD4) Staining and Circulating Tumor Cells (CTC) Pre-Surgery Present	4 Participants
Number of Participants Correlative Studies Including DPC4 (SMAD4) Staining and Circulating Tumor Cells (CTC) Pre-Surgery Absent	2 Participants

SECONDARY outcome

Timeframe: 43 months

Tumor tissue collected pre-therapy and post-therapy for surgically resected patients was assessed for SMAD4 status and classified as either present or absent based on immunohistochemistry evaluation.

Outcome measures

Outcome measures
Measure	Surgery n=11 Participants At least 4 - 6 weeks after the last dose of Gemcitabine if there is no local progression or distant metastasis.
Number of Participants Correlative Studies Including DPC4 (SMAD4) Staining and Circulating Tumor Cells (CTC) Post-Surgery Present	4 Participants
Number of Participants Correlative Studies Including DPC4 (SMAD4) Staining and Circulating Tumor Cells (CTC) Post-Surgery Absent	7 Participants

Adverse Events

Systemin Phase: mFOLFIRINOX

Serious events: 5 serious events

Other events: 33 other events

Deaths: 0 deaths

Chemoradiation Phase: Radiation With Gemcitabine

Serious events: 2 serious events

Other events: 23 other events

Deaths: 0 deaths

Surgery

Serious events: 0 serious events

Other events: 5 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Systemin Phase: mFOLFIRINOX n=33 participants at risk Oxalipaltin 75 mg/m2 IV on day 1, irinotecan 150 mg/m2 IV on day 1, 5-fluorouracil 2,000 mg/m2 IV 46 hours continuous infusion, every other week for 6 cycles (12 weeks).	Chemoradiation Phase: Radiation With Gemcitabine n=23 participants at risk Gemcitabine 350 mg/m2 IV weekly for 5 doses beginning day 1. External beam radiation therapy 5 days/week, a total dose of 50.4 Gy.	Surgery n=18 participants at risk At least 4-6 weeks after the last dose of gemcitabine if there is no local progression or distant metastasis
Gastrointestinal disorders Duodenal hemorrhage	0.00% 0/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Gastric ulcer	0.00% 0/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Nausea	0.00% 0/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Gastro-esophageal hemorrhage	0.00% 0/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
General disorders Multi-organ failure (Septic shock)	3.0% 1/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Investigations Neutrophil count decreased	3.0% 1/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Metabolism and nutrition disorders Dehydration	3.0% 1/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Nervous system disorders Dizziness	6.1% 2/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Respiratory, thoracic and mediastinal disorders Dyspnea	3.0% 1/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Infections and infestations Divice related infection	3.0% 1/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Cardiac disorders Miocardial Infarction	3.0% 1/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Cardiac disorders Atrial fibrilation	3.0% 1/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Respiratory, thoracic and mediastinal disorders Lower respiratory infection	3.0% 1/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.

Other adverse events

Additional Information

Dr. Gauri R Varadhachary,Professor, GI Medical Oncology

UT MD Anderson Cancer Center

Phone: (713) 792-2828

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Systemin Phase: mFOLFIRINOX n=33 participants at risk Oxalipaltin 75 mg/m2 IV on day 1, irinotecan 150 mg/m2 IV on day 1, 5-fluorouracil 2,000 mg/m2 IV 46 hours continuous infusion, every other week for 6 cycles (12 weeks).	Chemoradiation Phase: Radiation With Gemcitabine n=23 participants at risk Gemcitabine 350 mg/m2 IV weekly for 5 doses beginning day 1. External beam radiation therapy 5 days/week, a total dose of 50.4 Gy.	Surgery n=18 participants at risk At least 4-6 weeks after the last dose of gemcitabine if there is no local progression or distant metastasis
Blood and lymphatic system disorders Anemia	21.2% 7/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	8.7% 2/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	5.6% 1/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Diarrhea	60.6% 20/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	21.7% 5/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Mucositis oral	24.2% 8/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	8.7% 2/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Vomiting	33.3% 11/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	34.8% 8/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
General disorders Fatigue	84.8% 28/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	78.3% 18/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	5.6% 1/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Investigations Alanine aminotransferase increased	39.4% 13/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	17.4% 4/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Investigations Aspartate aminotranferase increased	27.3% 9/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Investigations Alkaline Phosphatase increased	24.2% 8/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	17.4% 4/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Investigations Neutrophil count decreased	30.3% 10/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	43.5% 10/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Investigations Weight loss	24.2% 8/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	21.7% 5/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	16.7% 3/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Nervous system disorders Paresthesia	39.4% 13/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	8.7% 2/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Nervous system disorders Dysesthesia	54.5% 18/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Nervous system disorders Peripheral sensory neuropathy	33.3% 11/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Nausea	75.8% 25/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	65.2% 15/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Anorexia	54.5% 18/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	43.5% 10/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	5.6% 1/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Flatulence	12.1% 4/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	8.7% 2/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Abdominal cramping/pain	39.4% 13/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	30.4% 7/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Gastrointestinal disorders Constipation	18.2% 6/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	21.7% 5/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Metabolism and nutrition disorders Hypomagnesemia	27.3% 9/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	30.4% 7/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	5.6% 1/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Investigations Platelet count	33.3% 11/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	78.3% 18/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Metabolism and nutrition disorders Hypokalemia	18.2% 6/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	5.6% 1/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Skin and subcutaneous tissue disorders Alopesia	36.4% 12/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	13.0% 3/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Respiratory, thoracic and mediastinal disorders Allergic rhinitis	12.1% 4/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Nervous system disorders Dizziness	9.1% 3/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Skin and subcutaneous tissue disorders Skin hyperpigmentation	12.1% 4/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Respiratory, thoracic and mediastinal disorders Hiccups	15.2% 5/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Vascular disorders Flushing	9.1% 3/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Respiratory, thoracic and mediastinal disorders Voice alteration	9.1% 3/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	4.3% 1/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Nervous system disorders Dysguesia	15.2% 5/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Metabolism and nutrition disorders Hyponalbuminemia	15.2% 5/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	17.4% 4/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.
Musculoskeletal and connective tissue disorders Musculo-skeletal - other	9.1% 3/33 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/23 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.	0.00% 0/18 • 4 years,6 months Toxicity was continuously monitored throughout the study, which includes grade 4 hematological toxicity and grade 3 or higher non-hematological toxicity.