Ph II of Capecitabine, Carboplatin & Bevacizumab for Gastroesophageal Junction & Gastric Carcinoma

• Sponsor: Pamela L. Kunz (Other)
• Overall Status: Completed
• CT.gov ID: NCT00780494
• Collaborator: Genentech, Inc. (Industry)
• Enrollment: 35
• Location: 1
• Arm: 1
• Duration (Months): 106.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To investigate bevacizumab in combination with carboplatin and capecitabine for patients with unresectable or metastatic GEJ or gastric cancers. We hope that by adding bevacizumab to standard chemotherapy for this patient population we will improve Progression Free Survival by 90% over historical controls.

Condition or Disease	Intervention/Treatment	Phase
Stomach Cancer; Gastric (Stomach) Cancer; Neoplasm of Cardioesophageal Junction; Gastrointestinal Stromal Tumor (GIST)	Drug: bevacizumab; Drug: carboplatin; Drug: capecitabine	Phase 2

Detailed Description

Primary Objectives:

To investigate if the addition of Bevacizumab to standard chemotherapy for metastatic or unresectable GEJ and gastric adenocarcinoma will improve PFS by 90% over historical controls.

Secondary Objectives:

• Assess toxicities using CTCAE v3.0

• Evaluate overall survival (OS) using Kaplan-Meier analysis

• Evaluate objective response rate (RR) by RECIST criteria

• Explore biomarkers of tumor response: CEA, CA 19.9, and serum VEGF

• Bank serum and tissue for future correlative studies

• Evaluate CT Perfusion to predict early therapeutic response to combination chemotherapy and anti-angiogenic therapy (OPTIONAL).

Study Design

• Study Type: Interventional
• Actual Enrollment: 35 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of Capecitabine, Carboplatin, and Bevacizumab for Metastatic or Unresectable Gastroesophageal Junction and Gastric Adenocarcinoma
• Study Start Date: Feb 1, 2009
• Actual Primary Completion Date: Dec 31, 2017
• Actual Study Completion Date: Dec 31, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: bevacizumab+ carboplatin +capecitabine Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.	Drug: bevacizumab; Intravenous 15 mg/kg; Other Names: Avastin ; Drug: carboplatin; AUC 6, Intravenously Day 1 every 21 days; Other Names: Paraplatin ; Drug: capecitabine; 850mg/m2, Orally twice daily days 1-14 every 21 days.; Other Names: Xeloda

Outcome Measures

Primary Outcome Measures

1. Progression-Free Survival (PFS) [12 months]

   Tumor progression was assessed according to the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), presented below. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Objective Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria. Progression-Free Survival is assessed as the number of evaluable participants who were alive without disease progression at 1 year. Participants without out assessment at 12 months will not be included.

Secondary Outcome Measures

1. Adverse Events ≥ Grade 3 and Related to Bevacizumab [12 months]

   Toxicity was assessed as the number of adverse events ≥ Grade 3 and also possibly, probably, or definitely related to bevacizumab. The outcome is reported as the total number of applicable events, and as the number of events that were a hematologic toxicity; a non-hematologic toxicity; which are numbers without dispersion.

2. Overall Survival (OS) [7.5 years]

   Overall survival (OS) will be assessed from time from the date of enrollment to the date of death due to any cause or the last date the patient was known to be alive (censored observation) at the date of data cutoff for the final analysis. The outcome is presented as the median survival in days with standard deviation.

3. Objective (Overall) Therapeutic Response [12 months]

   Tumor response was assessed per the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions, and assessed by physical measurement; magnetic resonance imaging (MRI); computed tomography (CT), positron emission tomography (PET)-CT; and/or X-rays/radiologic scan. Response was determined based on the criteria below. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Objective Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria The outcome is provided as the number of participants who achieved each of the defined responses, with objective (overall) response defined as the sum of CR and PR. The outcome is reported as values without dispersion.

4. CEA and CA 19.9 Tumor Response Biomarkers [9 weeks]

   The detected blood levels for tumor biomarkers CEA and CA 19.9 were to be correlated to the results for progression-fee survival (PFS), with the outcome presented as the median with standard deviation.

5. Vascular Endothelial Growth Factor Tumor Response Biomarker [9 weeks]

   The detected blood levels for tumor biomarker vascular endothelial growth factor (VEGF) were to be correlated to the results for progression-fee survival (PFS), with the outcome presented as the median with standard deviation.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

Subjects must be treated at Stanford University Medical Center for the entire length of study participation.

1. Patients with histologically or cytologically confirmed adenocarcinoma of the GEJ or stomach.

2. Patients must be deemed unresectable due to involvement of critical vasculature or adjacent organ invasion. If unresectable, patients must show evidence of disease progression prior to enrollment.

3. Patients with prior surgical resection who develop radiological or clinical evidence of metastatic cancer do not require separate histological or cytological confirmation of metastatic disease unless an interval of > 5 years has elapsed between the primary surgery and the development of metastatic disease. Clinicians should consider biopsy of lesions to establish diagnosis of metastatic disease if there is substantial clinical ambiguity regarding the nature or source of apparent metastases.

4. Prior carboplatin as neoadjuvant or adjuvant therapy will be allowed if >= 6 months from the time of study entry.

5. If patients use aspirin (>325mg/day) or NSAIDS at the time of enrollment, they must have a 10 day washout period prior to beginning protocol treatment.

6. Low molecular weight heparin (or its equivalent, excluding warfarin) will be allowed for treatment of venous thromboembolic events if patients have no evidence of bleeding on full-dose anticoagulation.

7. Patients must have a primary or metastatic lesion measurable in at least one dimension by Modified RECIST criteria (see Section 11.2.3) within 4 weeks prior to entry of study

8. Patients must have ECOG performance status of 0-1

9. Patients must be >= 18 years of age

10. Laboratory values <= 2 weeks prior to randomization:

• Absolute Neutrophil Count (ANC) >= 1.5 x 109/L (>= 1500/mm3)

• Platelets (PLT) >= 100 x 109/L (>= 100,000/mm3)

• Hemoglobin (Hgb) >= 9 g/dL

• Serum creatinine <= 1.5 x ULN

• Serum bilirubin <= 1.5 x ULN (<= 3.0 x ULN if liver metastases present)

• Aspartate aminotransferase (AST/SGOT), alanine aminotransferase (ALT/SGPT) <= 3.0 x ULN (<= 5.0 x ULN if liver metastases present). Note: ERCP or percutaneous stenting may be used to normalize the liver function tests.

1. Life expectancy >= 12 weeks

2. Inclusion and exclusion criteria for DCE-MRI and DWI imaging will be determined by CT scan as part of routine post-chemotherapy imaging. Subjects will be eligible if one liver metastasis is greater than 1 cm in size. Participation in the DCE-MRI and DWI correlate is not required for eligibility.

3. Ability to give written informed consent according to local guidelines

Exclusion Criteria:

1. Disease-Specific Exclusions

2. Prior chemotherapy for metastatic disease

3. Prior full field radiotherapy <= 4 weeks or limited field radiotherapy <= 2 weeks prior to enrollment. Patients must have recovered from all therapy-related toxicities. The site of previous radiotherapy should have evidence of progressive disease if this is the only site of disease.

4. Prior biologic or immunotherapy <= 2 weeks prior to registration. Patients must have recovered from all therapy-related toxicities

5. Prior therapy with anti-VEGF agents

6. If history of other primary cancer, subject eligible only if she or he has:

• Curatively resected non-melanomatous skin cancer

• Curatively treated cervical carcinoma in situ

• Other primary solid tumor curatively treated with no known active disease present and no treatment administered for the last 3 years

1. Concurrent use of other investigational agents and patients who have received investigational drugs <= 4 weeks prior to enrollment.

2. Hypersensitivity to capecitabine, fluorouracil, or any component of the formulation and or a known deficiency of dihydropyrimidine dehydrogenase.

3. General Medical Exclusions

4. Subjects known to have chronic or active hepatitis B or C infection

5. History of any medical or psychiatric condition or laboratory abnormality that in the opinion of the investigator may increase the risks associated with study participation or study drug administration or may interfere with the conduct of the study or interpretation of study results

6. Male subject who is not willing to use adequate contraception upon enrollment into this study and for 6 months following the last dose of second-line treatment

7. Female subject (of childbearing potential, post-menopausal for less than 6 months, not surgically sterilized, or not abstinent) who is not willing to use an oral, patch or implanted contraceptive, double-barrier birth control, or an IUD during the course of the study and for 6 months following the last dose of second-line treatment

8. Female subject who is breast-feeding or who has positive serum pregnancy test 72 hours prior to randomization

9. Pleural effusion or ascites that causes respiratory compromise (>= CTCAE grade 2 dyspnea)

10. Any of the following concurrent severe and/or uncontrolled medical conditions within 24 weeks of enrollment which could compromise participation in the study:

• Unstable angina pectoris

• Symptomatic congestive heart failure

• Myocardial infarction <= 6 months prior to registration and/or randomization

• Serious uncontrolled cardiac arrhythmia

• Uncontrolled diabetes

• Active or uncontrolled infection

• Interstitial pneumonia or extensive and symptomatic interstitial fibrosis of the lung.

• Chronic renal disease

• Acute or chronic liver disease (e.g., hepatitis, cirrhosis)

1. Patients unwilling to or unable to comply with the protocol

2. Life expectancy of less than 12 weeks

3. Current, recent (within 4 weeks of the first infusion of this study), or planned participation in an experimental drug study other than a Genentech-sponsored bevacizumab cancer study

4. Bevacizumab-Specific Exclusions

5. Inadequately controlled hypertension (defined as systolic blood pressure >150 and/or diastolic blood pressure > 100 mmHg on antihypertensive medications)

6. Any prior history of hypertensive crisis or hypertensive encephalopathy

7. New York Heart Association (NYHA) Grade II or greater congestive heart failure (see Appendix A)

8. History of myocardial infarction or unstable angina within 6 months prior to study enrollment

9. History of stroke or transient ischemic attack within 6 months prior to study enrollment

10. Known CNS disease, brain metastases.

11. Significant vascular disease (e.g., aortic aneurysm, aortic dissection)

12. Symptomatic peripheral vascular disease

13. Evidence of bleeding diathesis or coagulopathy

14. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study enrollment or anticipation of need for major surgical procedure during the course of the study

15. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to study enrollment

16. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 6 months prior to study enrollment

17. Serious, non-healing wound, ulcer, or bone fracture

18. Urine protein >= 2+ on urinalysis dipstick and >= 1.0 gram on 24-hour urine collection

19. Known hypersensitivity to any component of bevacizumab

20. History of hemoptysis (bright red blood of ½ teaspoon or more per episode) within 3 months prior to study enrollment.

21. Current, ongoing treatment with full-dose warfarin.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Pamela L. Kunz
• Genentech, Inc.

Investigators

• Principal Investigator: Pamela Kunz, MD, Stanford University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 7, 2013
• Informed Consent Form - Mar 19, 2013

More Information

Publications

None provided.

• Responsible Party: Pamela L. Kunz, Asst Prof-Med Ctr Line, Stanford University
• ClinicalTrials.gov Identifier: NCT00780494
• Other Study ID Numbers: IRB-11911; 98587; SU-07082008-1238; GI0002; IRB-11911
• First Posted: Oct 27, 2008
• Last Update Posted: Jul 1, 2021
• Last Verified: Jun 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Gastrointestinal Stromal Tumors; Stomach Neoplasms; Bevacizumab; Carboplatin; Capecitabine

Study Results

Participant Flow

Recruitment Details	Indicated participant number is accurate for the number of subjects who started study treatment and completed treatment.

Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Period Title: Overall Study
STARTED	35
COMPLETED	35
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Overall Participants	35
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	10 28.6%
>=65 years	25 71.4%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56.7 (14.4)
Sex: Female, Male (Count of Participants)
Female	10 28.6%
Male	25 71.4%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	6 17.1%
Not Hispanic or Latino	29 82.9%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	5 14.3%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	27 77.1%
More than one race	0 0%
Unknown or Not Reported	3 8.6%
Region of Enrollment (participants) [Number]
United States	35 100%

Outcome Measures

1. Primary Outcome

Title	Progression-Free Survival (PFS)
Description	Tumor progression was assessed according to the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1), presented below. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Objective Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria. Progression-Free Survival is assessed as the number of evaluable participants who were alive without disease progression at 1 year. Participants without out assessment at 12 months will not be included.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Those participants who did not receive follow-up at 12 months were considered lost-to-follow-up and not evaluable for progression, and were censored from the analysis.

Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Measure Participants	28
Count of Participants [Participants]	9 25.7%

2. Secondary Outcome

Title	Adverse Events ≥ Grade 3 and Related to Bevacizumab
Description	Toxicity was assessed as the number of adverse events ≥ Grade 3 and also possibly, probably, or definitely related to bevacizumab. The outcome is reported as the total number of applicable events, and as the number of events that were a hematologic toxicity; a non-hematologic toxicity; which are numbers without dispersion.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All participants were included in this analysis.

Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Measure Participants	35
Total Toxicity Events	18
Total Hematologic Toxicities	3
Total Non-hematologic Toxicities	15

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) will be assessed from time from the date of enrollment to the date of death due to any cause or the last date the patient was known to be alive (censored observation) at the date of data cutoff for the final analysis. The outcome is presented as the median survival in days with standard deviation.
Time Frame	7.5 years

Outcome Measure Data

Analysis Population Description

Data were available for all participants. Participants remaining alive were censored at last date assessed.

Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Measure Participants	35
Median (Standard Deviation) [Days]	458 (738)

4. Secondary Outcome

Title	Objective (Overall) Therapeutic Response
Description	Tumor response was assessed per the Response Evaluation Criteria in Solid Tumors Criteria (RECIST v1.1) for target lesions, and assessed by physical measurement; magnetic resonance imaging (MRI); computed tomography (CT), positron emission tomography (PET)-CT; and/or X-rays/radiologic scan. Response was determined based on the criteria below. Complete Response (CR) = Disappearance of all target lesions Partial Response (PR) = ≥ 30% decrease in the sum of the longest diameter of target lesions Objective Response (OR) = CR + PR Progressive disease (PD) = 20% increase in the sum of the longest diameter of target lesions, and/or the appearance of one or more new lesion(s) Stable disease (SD) = Small changes that do not meet any of the above criteria The outcome is provided as the number of participants who achieved each of the defined responses, with objective (overall) response defined as the sum of CR and PR. The outcome is reported as values without dispersion.
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

Data for clinical response was not available for all participants. Response data are only reported for participants for whom response is known.

Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Measure Participants	29
Partial Response	18 51.4%
Complete Response (CR)	0 0%
Objective Response (OR) = CR + PR	18 51.4%
Stable Disease	6 17.1%
Progressive Disease	5 14.3%

5. Secondary Outcome

Title	CEA and CA 19.9 Tumor Response Biomarkers
Description	The detected blood levels for tumor biomarkers CEA and CA 19.9 were to be correlated to the results for progression-fee survival (PFS), with the outcome presented as the median with standard deviation.
Time Frame	9 weeks

Outcome Measure Data

Analysis Population Description

Based on the objective results, it was determined that the any results from tumor biomarker analyses would be of little value, and the measurement for tumor biomarkers in the collected samples were not conducted. Accordingly, there is no data to be analyzed.

Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Measure Participants	0

6. Secondary Outcome

Title	Vascular Endothelial Growth Factor Tumor Response Biomarker
Description	The detected blood levels for tumor biomarker vascular endothelial growth factor (VEGF) were to be correlated to the results for progression-fee survival (PFS), with the outcome presented as the median with standard deviation.
Time Frame	9 weeks

Outcome Measure Data

Analysis Population Description

Studies published during the conduct of this study demonstrated that this assessment was not useful, and the samples were not collected. Accordingly, there is no data to be analyzed.

Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
Measure Participants	0

Adverse Events

Time Frame	7.5 years
Arm/Group Title	Bevacizumab+ Carboplatin +Capecitabine
Arm/Group Description	Participants receive bevacizumab 15 mg/kg intravenously followed by carboplatin AUC 6 intravenously on Day 1 of a 21-day cycle, concurrently with capecitabine 850 mg/m2 twice-daily by mouth on Cycle Days 1-to-14, followed by a 1-week break.
All Cause Mortality
	Bevacizumab+ Carboplatin +Capecitabine
	Affected / at Risk (%)	# Events
Total	31/35 (88.6%)
Serious Adverse Events
	Bevacizumab+ Carboplatin +Capecitabine
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
Anemia	1/35 (2.9%)	1
Cardiac disorders
Cardiac arrest	1/35 (2.9%)	1
Gastrointestinal disorders
Nausea	1/35 (2.9%)	1
Vomiting	2/35 (5.7%)	2
Abdominal pain	3/35 (8.6%)	3
Obstruction gastric	3/35 (8.6%)	3
Diarrhea	1/35 (2.9%)	2
Pancreatitis	1/35 (2.9%)	1
General disorders
Death NOS	4/35 (11.4%)	4
Multi-organ failure	1/35 (2.9%)	1
Chills	1/35 (2.9%)	1
Hepatobiliary disorders
Hepatic failure	1/35 (2.9%)	1
Infections and infestations
Sepsis	1/35 (2.9%)	1
Urinary tract infection	1/35 (2.9%)	1
Investigations
Platelet count decreased	2/35 (5.7%)	2
Metabolism and nutrition disorders
Dehydration	3/35 (8.6%)	3
Hypokalemia	1/35 (2.9%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/35 (2.9%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Other, disease progression	27/35 (77.1%)	27
Nervous system disorders
Intracranial hemorrhage	1/35 (2.9%)	1
Encephalopathy	1/35 (2.9%)	1
Psychiatric disorders
Confusion	1/35 (2.9%)	1
Renal and urinary disorders
Chronic kidney disease	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Plural effusion	1/35 (2.9%)	1
Respiratory Failure	1/35 (2.9%)	1
Vascular disorders
Other, pulmonary embolism	2/35 (5.7%)	2
Other (Not Including Serious) Adverse Events
	Bevacizumab+ Carboplatin +Capecitabine
	Affected / at Risk (%)	# Events
Total	35/35 (100%)
Blood and lymphatic system disorders
Anemia	26/35 (74.3%)	42
Leukocytosis	23/35 (65.7%)	32
Neutrophil count decreased	23/35 (65.7%)	36
Platelet count decreased	30/35 (85.7%)	45
Lymphocyte count decreased	11/35 (31.4%)	14
Cardiac disorders
Ventricular arrhythmia	1/35 (2.9%)	1
Palpitations	1/35 (2.9%)	1
Ear and labyrinth disorders
Tinnitus	1/35 (2.9%)	1
External ear pain	1/35 (2.9%)	1
Eye disorders
Watering eyes	3/35 (8.6%)	3
Gastrointestinal disorders
Nausea	25/35 (71.4%)	31
Vomiting	15/35 (42.9%)	16
Diarrhea	18/35 (51.4%)	22
Mucositis	11/35 (31.4%)	11
Constipation	11/35 (31.4%)	11
Gastrointestinal disorders -Other, specify Enteritis	1/35 (2.9%)	1
Dyspepsia	5/35 (14.3%)	5
Dysphagia	1/35 (2.9%)	1
Dry mouth	3/35 (8.6%)	3
Flatulence	2/35 (5.7%)	2
Hemorrhoids	1/35 (2.9%)	2
Bloating	1/35 (2.9%)	1
Colitis	1/35 (2.9%)	1
Gastric hemorrhage	7/35 (20%)	7
Abdominal pain	5/35 (14.3%)	6
General disorders
Fatigue	29/35 (82.9%)	46
Chills	1/35 (2.9%)	1
Fever	1/35 (2.9%)	1
Edema limbs	1/35 (2.9%)	1
Pain	1/35 (2.9%)	1
Infections and infestations
Rash	17/35 (48.6%)	29
Soft tissue infection	2/35 (5.7%)	2
Periodontal disease	1/35 (2.9%)	1
Investigations
INR increased	1/35 (2.9%)	1
Weight loss	5/35 (14.3%)	5
Aspartate aminotransferase increased	15/35 (42.9%)	16
Alkaline phosphatase	10/35 (28.6%)	12
Alanine aminotransferase increased	9/35 (25.7%)	10
Creatinine increased	6/35 (17.1%)	6
Blood bilirubin increased	4/35 (11.4%)	5
Lipase increased	1/35 (2.9%)	1
Metabolism and nutrition disorders
Anorexia	15/35 (42.9%)	17
Dehydration	6/35 (17.1%)	7
Hypokalemia	5/35 (14.3%)	7
hypoalbuminemia	10/35 (28.6%)	13
Hyponatremia)	5/35 (14.3%)	6
Hyperkalemia	1/35 (2.9%)	2
Hyperglycemia	4/35 (11.4%)	4
Hypoglycemia	1/35 (2.9%)	1
Hypocalcemia	4/35 (11.4%)	4
Musculoskeletal and connective tissue disorders
Joint range of motion decreased, upper extremity	1/35 (2.9%)	1
Arthritis	1/35 (2.9%)	1
Pain- Joint	4/35 (11.4%)	5
Pain in extremity	6/35 (17.1%)	6
Back pain	4/35 (11.4%)	4
Chest pain	1/35 (2.9%)	2
Buttock pain	1/35 (2.9%)	1
Neck pain	1/35 (2.9%)	1
Myalgia	1/35 (2.9%)	1
Nervous system disorders
Dysgeusia	6/35 (17.1%)	6
Intracranial hemorrhage	1/35 (2.9%)	1
Neuropathy: sensory	4/35 (11.4%)	4
Cognitive disturbance	1/35 (2.9%)	1
Dizziness	9/35 (25.7%)	9
Ataxia	1/35 (2.9%)	1
Altered mental status	1/35 (2.9%)	1
Headache	7/35 (20%)	8
Psychiatric disorders
Insomnia	1/35 (2.9%)	1
Libido	1/35 (2.9%)	1
Renal and urinary disorders
Renal and urinary disorders - Other, specify Hemorrhage Urinary	6/35 (17.1%)	6
Proteinuria	10/35 (28.6%)	15
Renal and urinary disorders -Other, specify Urethera pain	1/35 (2.9%)	1
Reproductive system and breast disorders
Pelvic pain	1/35 (2.9%)	1
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/35 (5.7%)	2
Epistaxis	19/35 (54.3%)	19
Bronchopulmonary hemorrhage	2/35 (5.7%)	2
Pharyngeal hemorrhage	1/35 (2.9%)	1
Pharyngolaryngeal pain	1/35 (2.9%)	1
Respiratory, thoracic andmediastinal disorders - Other, specify paranasal sinus reactions	13/35 (37.1%)	13
Dyspnea	5/35 (14.3%)	6
Cough	2/35 (5.7%)	2
Hoarseness	9/35 (25.7%)	9
Skin and subcutaneous tissue disorders
Sweating (hyperhidrosis, diaphoresis)	2/35 (5.7%)	2
Skin hyperpigmentation	15/35 (42.9%)	22
Dry skin	4/35 (11.4%)	4
Erythema multiforme	1/35 (2.9%)	1
Urticaria	1/35 (2.9%)	1
Pruritus	1/35 (2.9%)	1
Infections and infestations -Other, specify desquamation	1/35 (2.9%)	1
Nail discoloration	1/35 (2.9%)	1
Purpura	1/35 (2.9%)	1
Vascular disorders
Hypertension	7/35 (20%)	9
Hypotension	1/35 (2.9%)	1
Thromboembolic event	4/35 (11.4%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.