Sorafenib Tosylate With or Without Recombinant Interferon Alfa-2b in Treating Patients With Metastatic Kidney Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00126594
• Collaborator: M.D. Anderson Cancer Center (Other)
• Enrollment: 80
• Location: 1
• Arms: 2
• Duration (Months): 98
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

This randomized phase II trial is studying sorafenib and interferon alfa-2b to see how well they work compared to sorafenib alone in treating patients with metastatic kidney cancer. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Interferon alfa-2b may interfere with the growth of tumor cells. Sorafenib and interferon alfa-2b may also block blood flow to the tumor. Giving sorafenib together with interferon alfa-2b may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Clear Cell Renal Cell Carcinoma; Recurrent Renal Cell Carcinoma; Stage IV Renal Cell Cancer	Drug: Sorafenib Tosylate; Biological: Recombinant Interferon Alfa-2b; Other: Laboratory Biomarker Analysis	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. Efficacy of Bay 43-9006 with or without low dose interferon by evaluating response rate in MRCC.

2. Toxicities of Bay 43-9006 with or without low dose interferon in MRCC.

SECONDARY OBJECTIVES:

1. Progression free survival. II. Duration of response. III. Overall Survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

Arm I: Patients receive oral sorafenib twice daily on days 1-28.

Arm II: Patients receive sorafenib as in arm I and low-dose interferon alfa-2b subcutaneously twice daily on days 1-28.

In both arms, courses repeat every 28 days in the absence of progressive disease or unacceptable toxicity.

Tissue samples are analyzed for single nucleotide polymorphisms (SNP) patterns via genotyping.

After completion of study treatment, patients are followed every 3 months.

Study Design

• Study Type: Interventional
• Actual Enrollment: 80 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Clinical Trial to Evaluate the Efficacy of BAY 43-9006 With or Without Low Dose Interferon in Metastatic Renal Cell Carcinoma
• Study Start Date: Jun 1, 2005
• Actual Primary Completion Date: Aug 1, 2013
• Actual Study Completion Date: Aug 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Sorafenib Tosylate Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.	Drug: Sorafenib Tosylate; Given orally 400 mg orally (PO) every 12 hours; Other Names: BAY 54-9085 Nexavar SFN BAY 43-9006 ; Other: Laboratory Biomarker Analysis; Correlative studies
Experimental: Sorafenib Tosylate, Recombinant interferon alfa-2b Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.	Drug: Sorafenib Tosylate; Given orally 400 mg orally (PO) every 12 hours; Other Names: BAY 54-9085 Nexavar SFN BAY 43-9006 ; Biological: Recombinant Interferon Alfa-2b; Given subcutaneously (SC) 0.5 million with +/- 5 % variance (0.475 MU - 0.525 MU); Dose level 0: 0.5 X 10^6 international units twice daily; Other Names: Alfatronol Glucoferon Heberon Alfa Sch 30500 Urifron IFN ; Other: Laboratory Biomarker Analysis; Correlative studies

Outcome Measures

Primary Outcome Measures

1. Objective Response Rate (ORR) Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST) [Tumor restaging performed at 8 weeks following baseline, responding or stable participants restaged at 8 week intervals, up to 12 months.]

   ORR defined as participants with Complete Response (CR) and Partial Response (PR) as defined by RECIST criteria: Complete Response (CR): Disappearance all target lesions. Partial Response (PR): >30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD. Progressive Disease (PD): >20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum LD since treatment started. Radiologic testing for progressive disease repeated every 8 weeks.

Secondary Outcome Measures

1. Selected Grade 3-4 Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 [Up to 12 months of treatment]

   Adverse events graded using the CTCAE version 4.0 tabulated by treatment arm within either toxicity grade for the treatment period. Treatment-related toxicity (acute and cumulative) performed every 8 weeks during the first year.

2. Progression-free Survival [From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months]

   Progression free survival (PFS) is defined as the time interval from the start of protocol therapy to death or disease progression.

3. Median Overall Survival (OS) [From the start of protocol therapy to death or date of last follow-up, up to 36 months]

   Overall survival defined as the time interval from the start of protocol therapy to death or date of last follow-up if alive.

4. Duration of Response for Participants With Stable Disease (N=37) Following Treatment [From the date response is confirmed to the date of disease progression, up to 12 months]

   Duration of response for participants with disease stabilization following treatment as measured from the date response is confirmed to the date of disease progression, first assessed up to 8 weeks (2 cycles) following start of treatment. The duration of a Stable Disease (SD) response is measured from the time measurement criteria are met for that specific SD response until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Repeat radiologic studies (CT, MRI, Chest x-ray and bone scan as indicated) to evaluate disease progression or response every 8 weeks.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients with histologically or cytologically confirmed metastatic clear cell RCC

• Patients must have measurable disease, defined as a lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) and measures >= 20 mm with conventional techniques or >= 10 mm with spiral CT scan

• ECOG performance status =< 1

• Absolute neutrophil count >= 1,500/μL

• Platelets >= 100,000/μL

• Hgb > 9.0 g/dL (may be transfused or receive epoetin alfa [e.g., Epogen®] to maintain or exceed this level)

• Total bilirubin =< 2.0 mg/dl

• Albumin > 3.0 g/dL

• Serum creatinine =< 2.0 mg/dl

• AST(SGOT) and/or ALT (SGPT) =< 2.5 X institutional upper limit of normal for subjects without evidence of liver metastases

• AST(SGOT) and/or ALT (SGPT) =< 5 X institutional upper limit of normal for subjects with documented liver metastases

• Female patients of childbearing potential must have a normal plasma beta human chorionic gonadotropin (βHCG) within 24 hours prior to enrolling in the study due to the possible teratogenic effect; however, patients will be eligible if their βHCG elevation is consistent with malignancy rather than pregnancy

• Patients of child fathering or childbearing potential must agree to practice a form of medically acceptable birth control while on study

• Patients must give written informed consent prior to initiation of therapy, in keeping with the policies of the institution; patients with a history of major psychiatric illness must be judged able to fully understand the investigational nature of the study and the risks associated with the therapy; the only approved consent is attached to this protocol

• Patients must have ability to comply with study and/or follow-up procedures

• Patients must be able to swallow pills

Exclusion Criteria:

• No prior malignancy is allowed, except for non-melanoma skin cancer, in situ carcinoma of any site, or other cancers for which the patient has been adequately treated and disease free for 5 years

• Patients must not have received any systemic anticancer therapy for renal cell carcinoma; patients must not have received any radiotherapy for renal cell carcinoma within 4 weeks prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier

• Patients must not be scheduled to receive another experimental drug while on this study; patients are permitted to be on concomitant bisphosphonates

• Patients must not have a primary brain tumor, any brain metastases, leptomeningeal disease, seizure disorders not controlled with standard medical therapy, or history of stroke

• Patients must not have active acute infections that could be worsened by anticancer therapy or interfere with this study

• Patients must not have clinically significant cardiovascular disease, myocardial infarction within the past year (unstable angina), New York Heart Association (NYHA) Grade II or greater congestive heart failure, serious cardiac dysrhythmia refractory to medical management, or peripheral vascular disease (Grade II or greater)

• Patients must not have uncontrolled hypertension

• Patients must not have history of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications

• Pregnant women are excluded from this study because BAY 43-9006 is a kinase inhibitor agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with BAY 43-9006, breastfeeding should be discontinued if the mother is treated with BAY 43-9006

• Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy; therefore, HIV-positive patients receiving combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with BAY 43-9006; appropriate studies will be undertaken in patients receiving combination anti-retroviral therapy when indicated

• Patients must not have a clinical history of coagulopathy, bleeding diathesis or thrombosis; patients must not be on therapeutic anticoagulation; prophylactic anticoagulation (ie low dose warfarin) of venous access devices is allowed provided that INR >= 1.5 is due to warfarin therapy; other patients with an INR >= 1.5 are excluded

• Patients must not have a history of severe depression

• Concomitant treatment with rifampin, St. John's wort, and the cytochrome p450 enzyme-inducin antiepileptic drugs (phenytoin, carbamazepine or Phenobarbital)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	M D Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• National Cancer Institute (NCI)
• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Eric Jonasch, M.D. Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00126594
• Other Study ID Numbers: NCI-2012-02910; NCI-2012-02910; CDR0000437796; 2004-0526; 6629; N01CM62202; P30CA016672
• First Posted: Aug 4, 2005
• Last Update Posted: Sep 16, 2016
• Last Verified: Jul 1, 2016

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Renal Cell; Interferons; Interferon-alpha; Interferon alpha-2; Sorafenib

Study Results

Participant Flow

Recruitment Details	Recruitment Period: June 23, 2005 to June 28, 2007. All recruitment done at The University of Texas (UT) MD Anderson Cancer Center.

Arm/Group Title	Sorafenib Tosylate	Sorafenib Tosylate, Recombinant Interferon Alfa-2b
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.	Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.
Period Title: Overall Study
STARTED	40	40
COMPLETED	1	3
NOT COMPLETED	39	37

Baseline Characteristics

Arm/Group Title	Sorafenib Tosylate	Sorafenib Tosylate, Recombinant Interferon Alfa-2b	Total
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.	Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.	Total of all reporting groups
Overall Participants	40	40	80
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	62.4	60.7	62.0
Sex: Female, Male (Count of Participants)
Female	8 20%	11 27.5%	19 23.8%
Male	32 80%	29 72.5%	61 76.3%
Region of Enrollment (participants) [Number]
United States	40 100%	40 100%	80 100%
ECOG (Performance Status) (participants) [Number]
0	25 62.5%	25 62.5%	50 62.5%
1	15 37.5%	15 37.5%	30 37.5%
Nephrectomy (participants) [Number]
Yes	40 100%	39 97.5%	79 98.8%
No	0 0%	1 2.5%	1 1.3%
Memorial Sloan-Kettering Cancer Center (MSKCC) Prognostic Risk (participants) [Number]
Low	21 52.5%	20 50%	41 51.3%
Intermediate	19 47.5%	18 45%	37 46.3%
Poor	0 0%	2 5%	2 2.5%
Number of Metastatic Sites (participants) [Number]
One	13 32.5%	14 35%	27 33.8%
Two	17 42.5%	20 50%	37 46.3%
Three or More	10 25%	6 15%	16 20%
Sites of Metastatic Disease (participants) [Number]
Lung	33 82.5%	30 75%	63 78.8%
Lymph Nodes	20 50%	15 37.5%	35 43.8%
Liver	3 7.5%	5 12.5%	8 10%
Bone	5 12.5%	6 15%	11 13.8%
Other	19 47.5%	19 47.5%	38 47.5%

Outcome Measures

1. Primary Outcome

Title	Objective Response Rate (ORR) Evaluated Using Response Evaluation Criteria in Solid Tumors (RECIST)
Description	ORR defined as participants with Complete Response (CR) and Partial Response (PR) as defined by RECIST criteria: Complete Response (CR): Disappearance all target lesions. Partial Response (PR): >30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD. Progressive Disease (PD): >20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum LD since treatment started. Radiologic testing for progressive disease repeated every 8 weeks.
Time Frame	Tumor restaging performed at 8 weeks following baseline, responding or stable participants restaged at 8 week intervals, up to 12 months.

Outcome Measure Data

Analysis Population Description

Analysis performed for the intent-to-treat population.

Arm/Group Title	Sorafenib Tosylate	Sorafenib Tosylate, Recombinant Interferon Alfa-2b
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.	Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.
Measure Participants	40	40
Number (95% Confidence Interval) [percentage of participants]	30 75%	25 62.5%

2. Secondary Outcome

Title	Selected Grade 3-4 Adverse Events Using NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Description	Adverse events graded using the CTCAE version 4.0 tabulated by treatment arm within either toxicity grade for the treatment period. Treatment-related toxicity (acute and cumulative) performed every 8 weeks during the first year.
Time Frame	Up to 12 months of treatment

Outcome Measure Data

Analysis Population Description

All participants were included in adverse event reporting per intent to treat analysis.

Arm/Group Title	Sorafenib Tosylate	Sorafenib Tosylate, Recombinant Interferon Alfa-2b
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.	Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.
Measure Participants	40	40
Fatigue	10 25%	13 32.5%
Diarrhea	13 32.5%	8 20%
Hand-Foot Syndrome	10 25%	7 17.5%
Hyperuricemia	12 30%	3 7.5%
Hyperamylasemia or Lipasemia	5 12.5%	4 10%
Dyspnea	4 10%	4 10%
Hypophosphatemia	3 7.5%	5 12.5%
Neutropenia	0 0%	6 15%
Hypertension	2 5%	3 7.5%
Nausea and vomiting	1 2.5%	3 7.5%
Rash/Desquamation	2 5%	2 5%
Proteinuria	1 2.5%	2 5%
Syncope (Fainting)	0 0%	3 7.5%
Weight Loss	0 0%	3 7.5%
Transaminitis	0 0%	3 7.5%
Hyponatremia	2 5%	1 2.5%
Nonneutropenic Infection	2 5%	0 0%
Sensory Neuropathy	1 2.5%	1 2.5%
Cardiac Ischemia/Infarction	1 2.5%	0 0%
Appendicitis	1 2.5%	0 0%
Pancreatitis	1 2.5%	0 0%
Adrenal Insufficiency	0 0%	1 2.5%
Reversible Posterior Leukonencephalopathy	0 0%	1 2.5%
Small Bowel Obstruction	1 2.5%	0 0%
Pneumonitis	1 2.5%	0 0%

3. Secondary Outcome

Title	Progression-free Survival
Description	Progression free survival (PFS) is defined as the time interval from the start of protocol therapy to death or disease progression.
Time Frame	From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 36 months

Outcome Measure Data

Analysis Population Description

All participants were included per intent to treat analysis.

Arm/Group Title	Sorafenib Tosylate	Sorafenib Tosylate, Recombinant Interferon Alfa-2b
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.	Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.
Measure Participants	40	40
Median (95% Confidence Interval) [Months]	7.39	7.56

4. Secondary Outcome

Title	Median Overall Survival (OS)
Description	Overall survival defined as the time interval from the start of protocol therapy to death or date of last follow-up if alive.
Time Frame	From the start of protocol therapy to death or date of last follow-up, up to 36 months

Outcome Measure Data

Analysis Population Description

Participants who die of unrelated cause during therapy or are lost to follow-up were censored. Median OS was not reached in Arm 1: Sorafenib as subjects experienced different events that made further follow-up impossible i.e. disease complications, death or lost to follow-up so overall survival data was not attainable.

Arm/Group Title	Sorafenib Tosylate	Sorafenib Tosylate, Recombinant Interferon Alfa-2b
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.	Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.
Measure Participants	40	40
Median (95% Confidence Interval) [Months]	NA	27.04

5. Secondary Outcome

Title	Duration of Response for Participants With Stable Disease (N=37) Following Treatment
Description	Duration of response for participants with disease stabilization following treatment as measured from the date response is confirmed to the date of disease progression, first assessed up to 8 weeks (2 cycles) following start of treatment. The duration of a Stable Disease (SD) response is measured from the time measurement criteria are met for that specific SD response until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded since the treatment started). Repeat radiologic studies (CT, MRI, Chest x-ray and bone scan as indicated) to evaluate disease progression or response every 8 weeks.
Time Frame	From the date response is confirmed to the date of disease progression, up to 12 months

Outcome Measure Data

Analysis Population Description

Combined analysis reflects overall stable disease duration e.g. duration of benefit for stable disease cases without being affected by the median duration not attainable for the separate arms; 37 participants in the two arms met "Stable Disease" criteria: 17 in Sorafenib alone (Arm I) and 20 in the Sorafenib Plus Interferon group (Arm II).

Arm/Group Title	Sorafenib Tosylate or Sorafenib Plus Interferon
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28 and Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.
Measure Participants	37
Median (95% Confidence Interval) [Months]	5.7

6. Post-Hoc Outcome

Title	Best Overall Response for Participants
Description	Best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The participant's best response assignment will depend on the achievement of both measurement and confirmation criteria as defined by RECIST: Complete Response (CR): Disappearance all target lesions. Partial Response (PR): >30% decrease in sum of longest diameter (LD) of target lesions, reference baseline sum LD. Progressive Disease (PD): >20% increase in sum of LD of target lesions, reference smallest sum LD recorded since treatment started or appearance of one or more new lesions. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, reference smallest sum LD since treatment started. Radiologic testing for progressive disease repeated every 8 weeks.
Time Frame	From the date response is confirmed to the date of disease progression, first assessed 2 months (8 weeks) following start of treatment and reassessed up to 36 months (on average reassessed 12 months or less).

Outcome Measure Data

Analysis Population Description

All participants were included per intent to treat analysis.

Arm/Group Title	Sorafenib Tosylate	Sorafenib Tosylate, Recombinant Interferon Alfa-2b
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.	Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.
Measure Participants	40	40
Complete Response (CR)	1 2.5%	0 0%
Partial Response (PR)	11 27.5%	10 25%
Stable Disease (SD)	17 42.5%	20 50%
Progressive Disease (PD)	6 15%	7 17.5%
Inevaluable	5 12.5%	3 7.5%

Adverse Events

Time Frame	Adverse event reporting from time of first intervention to follow up 30 days beyond last intervention. Overall study period: June 2005 to August 2013.
Adverse Event Reporting Description	Revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 utilized for AE reporting until September 30, 2010. CTCAE version 4.0 utilized beginning October 1, 2010.
Arm/Group Title	Sorafenib Tosylate		Sorafenib Tosylate, Recombinant Interferon Alfa-2b
Arm/Group Description	Arm I: Oral Sorafenib 400 mg twice daily on days 1-28.		Arm II: Sorafenib as in Arm I and low-dose Interferon alfa-2b 0.5 million units subcutaneously twice daily on days 1-28.
All Cause Mortality
	Sorafenib Tosylate		Sorafenib Tosylate, Recombinant Interferon Alfa-2b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Sorafenib Tosylate		Sorafenib Tosylate, Recombinant Interferon Alfa-2b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	29/40 (72.5%)		30/40 (75%)
General disorders
Death	27/40 (67.5%)	27	29/40 (72.5%)	29
Hepatobiliary disorders
Pancreatitis	1/40 (2.5%)	1	0/40 (0%)	0
Infections and infestations
Appendicitis	1/40 (2.5%)	1	0/40 (0%)	0
Metabolism and nutrition disorders
Hyperuricemia	6/40 (15%)	12	2/40 (5%)	2
Serum amylase increased	1/40 (2.5%)	1	0/40 (0%)	0
Lipase Increased	0/40 (0%)	0	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	Sorafenib Tosylate		Sorafenib Tosylate, Recombinant Interferon Alfa-2b
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/40 (100%)		40/40 (100%)
Blood and lymphatic system disorders
Anemia	19/40 (47.5%)	30	30/40 (75%)	60
Blood bilirubin increased	9/40 (22.5%)	17	11/40 (27.5%)	17
Lymphocyte count decreased	4/40 (10%)	9	12/40 (30%)	51
Platelet count decreased	2/40 (5%)	2	21/40 (52.5%)	39
Cardiac disorders
Conduction disorder	1/40 (2.5%)	1	0/40 (0%)	0
Hypertension	16/40 (40%)	26	10/40 (25%)	14
Hypotension	1/40 (2.5%)	1	2/40 (5%)	3
Myocardial infarction	1/40 (2.5%)	1	0/40 (0%)	0
Palpitations	1/40 (2.5%)	1	0/40 (0%)	0
Sinus tachycardia	0/40 (0%)	0	1/40 (2.5%)	1
Supraventricular tachycardia	1/40 (2.5%)	1	0/40 (0%)	0
Vascular disorders - (Other)	0/40 (0%)	0	2/40 (5%)	5
Ear and labyrinth disorders
Otitis media	1/40 (2.5%)	1	0/40 (0%)	0
Tinnitus	1/40 (2.5%)	1	0/40 (0%)	0
Endocrine disorders
Adrenal insufficiency	0/40 (0%)	0	1/40 (2.5%)	1
Eye disorders
Blurred vision	3/40 (7.5%)	3	5/40 (12.5%)	9
Extraocular muscle paresis	1/40 (2.5%)	1	0/40 (0%)	0
Eye disorders	1/40 (2.5%)	1	1/40 (2.5%)	4
Eye pain	1/40 (2.5%)	1	1/40 (2.5%)	1
Glaucoma	1/40 (2.5%)	1	1/40 (2.5%)	1
Watering eyes	2/40 (5%)	2	0/40 (0%)	0
Gastrointestinal disorders
Abdominal distension	4/40 (10%)	4	4/40 (10%)	5
Abdominal pain	7/40 (17.5%)	15	10/40 (25%)	12
Anorexia	9/40 (22.5%)	10	10/40 (25%)	17
Constipation	4/40 (10%)	9	5/40 (12.5%)	11
Diarrhea	33/40 (82.5%)	375	32/40 (80%)	382
Dysgeusia	4/40 (10%)	5	7/40 (17.5%)	7
Dyspepsia	3/40 (7.5%)	4	2/40 (5%)	2
Flatulence	7/40 (17.5%)	13	7/40 (17.5%)	14
Gastritis	2/40 (5%)	2	0/40 (0%)	0
Gastrointestinal disorders	1/40 (2.5%)	1	2/40 (5%)	2
Gastrointestinal pain	1/40 (2.5%)	1	0/40 (0%)	0
Hemorrhoids	0/40 (0%)	0	3/40 (7.5%)	14
Mucositis oral	14/40 (35%)	77	18/40 (45%)	39
Nausea	18/40 (45%)	57	24/40 (60%)	60
Oral pain	1/40 (2.5%)	1	0/40 (0%)	0
Rectal pain	0/40 (0%)	0	1/40 (2.5%)	1
Small intestinal obstruction	1/40 (2.5%)	1	1/40 (2.5%)	1
Sore throat	0/40 (0%)	0	1/40 (2.5%)	1
Stomach pain	1/40 (2.5%)	5	1/40 (2.5%)	1
Toothache	1/40 (2.5%)	2	1/40 (2.5%)	1
Vomiting	11/40 (27.5%)	42	14/40 (35%)	34
General disorders
Chills	0/40 (0%)	0	2/40 (5%)	2
Edema limbs	4/40 (10%)	4	2/40 (5%)	2
Edema trunk	1/40 (2.5%)	1	0/40 (0%)	0
Fatigue	33/40 (82.5%)	184	36/40 (90%)	247
Insomnia	0/40 (0%)	0	1/40 (2.5%)	1
Non-cardiac chest pain	3/40 (7.5%)	7	3/40 (7.5%)	4
Pain	7/40 (17.5%)	17	5/40 (12.5%)	13
Pelvic pain	0/40 (0%)	0	1/40 (2.5%)	3
Weight loss	15/40 (37.5%)	27	21/40 (52.5%)	42
Hepatobiliary disorders
Pancreatitis	0/40 (0%)	0	0/40 (0%)	0
Immune system disorders
Allergic reaction	0/40 (0%)	0	1/40 (2.5%)	1
Allergic rhinitis	2/40 (5%)	3	3/40 (7.5%)	5
Infections and infestations
Appendicitis	1/40 (2.5%)	1	0/40 (0%)	0
Infections and infestations - (Other)	5/40 (12.5%)	6	3/40 (7.5%)	3
Pneumonitis	1/40 (2.5%)	1	0/40 (0%)	0
Injury, poisoning and procedural complications
Injection site reaction	0/40 (0%)	0	5/40 (12.5%)	8
Investigations
Carbon monoxide diffusing capacity decreased	0/40 (0%)	0	1/40 (2.5%)	1
Fever	7/40 (17.5%)	17	10/40 (25%)	20
Flu like symptoms	0/40 (0%)	0	3/40 (7.5%)	6
Metabolism and nutrition disorders
Acidosis	0/40 (0%)	0	1/40 (2.5%)	1
Alanine aminotransferase increased	7/40 (17.5%)	10	23/40 (57.5%)	41
Alkaline phosphatase increased	13/40 (32.5%)	19	11/40 (27.5%)	14
Aspartate aminotransferase increased	22/40 (55%)	33	29/40 (72.5%)	55
Cholesterol high	15/40 (37.5%)	25	7/40 (17.5%)	12
Creatinine increased	10/40 (25%)	18	8/40 (20%)	15
Dehydration	0/40 (0%)	0	1/40 (2.5%)	1
Gait disturbance	0/40 (0%)	0	1/40 (2.5%)	1
Hemoglobinuria	2/40 (5%)	2	1/40 (2.5%)	1
Hypercalcemia	2/40 (5%)	2	2/40 (5%)	2
Hyperglycemia	22/40 (55%)	42	17/40 (42.5%)	47
Hyperkalemia	10/40 (25%)	16	8/40 (20%)	12
Hypertriglyceridemia	20/40 (50%)	20	21/40 (52.5%)	49
Hyperuricemia	24/40 (60%)	66	19/40 (47.5%)	37
Hypoalbuminemia	4/40 (10%)	5	6/40 (15%)	9
Hypocalcemia	2/40 (5%)	2	14/40 (35%)	37
Hypoglycemia	22/40 (55%)	42	3/40 (7.5%)	8
Hypokalemia	10/40 (25%)	16	6/40 (15%)	9
Hypomagnesemia	17/40 (42.5%)	37	21/40 (52.5%)	42
Hyponatremia	5/40 (12.5%)	8	4/40 (10%)	7
Hypophosphatemia	20/40 (50%)	36	20/40 (50%)	49
Lipase increased	5/40 (12.5%)	9	5/40 (12.5%)	5
Neutrophil count decreased	0/40 (0%)	0	18/40 (45%)	47
Serum amylase increased	3/40 (7.5%)	3	4/40 (10%)	4
White blood cell decreased	3/40 (7.5%)	4	27/40 (67.5%)	63
Musculoskeletal and connective tissue disorders
Arthralgia	8/40 (20%)	21	7/40 (17.5%)	23
Arthritis	2/40 (5%)	3	2/40 (5%)	2
Back pain	11/40 (27.5%)	20	13/40 (32.5%)	42
Bone pain	6/40 (15%)	16	6/40 (15%)	20
Chest wall pain	0/40 (0%)	0	1/40 (2.5%)	2
Fracture	0/40 (0%)	0	1/40 (2.5%)	1
Joint range of motion decreased	0/40 (0%)	0	1/40 (2.5%)	2
Myalgia	10/40 (25%)	20	8/40 (20%)	15
Neck pain	2/40 (5%)	6	1/40 (2.5%)	1
Pain in extremity	12/40 (30%)	35	14/40 (35%)	39
Tremor	0/40 (0%)	0	1/40 (2.5%)	2
Nervous system disorders
Dizziness	2/40 (5%)	3	0/40 (0%)	0
Headache	3/40 (7.5%)	8	5/40 (12.5%)	6
Memory impairment	0/40 (0%)	0	1/40 (2.5%)	1
Nervous system disorders - (Other)	0/40 (0%)	0	1/40 (2.5%)	1
Peripheral motor neuropathy	1/40 (2.5%)	1	0/40 (0%)	0
Peripheral sensory neuropathy	10/40 (25%)	20	14/40 (35%)	42
Syncope	0/40 (0%)	0	3/40 (7.5%)	3
Psychiatric disorders
Agitation	0/40 (0%)	0	1/40 (2.5%)	1
Depression	3/40 (7.5%)	4	7/40 (17.5%)	7
Renal and urinary disorders
Bladder infection	2/40 (5%)	2	0/40 (0%)	0
Bladder spasm	1/40 (2.5%)	1	0/40 (0%)	0
Proteinuria	16/40 (40%)	31	24/40 (60%)	48
Renal and urinary disorders - (Other)	1/40 (2.5%)	1	1/40 (2.5%)	2
Urinary frequency	0/40 (0%)	0	1/40 (2.5%)	2
Reproductive system and breast disorders
Erectile dysfunction	3/40 (7.5%)	3	1/40 (2.5%)	1
Reproductive system and breast disorders - (Other)	1/40 (2.5%)	1	0/40 (0%)	0
Scrotal pain	1/40 (2.5%)	2	0/40 (0%)	0
Testicular pain	0/40 (0%)	0	1/40 (2.5%)	2
Respiratory, thoracic and mediastinal disorders
Bronchospasm	0/40 (0%)	0	1/40 (2.5%)	1
Cough	7/40 (17.5%)	18	11/40 (27.5%)	19
Dyspnea	16/40 (40%)	33	20/40 (50%)	64
Epistaxis	1/40 (2.5%)	8	0/40 (0%)	0
Hiccups	1/40 (2.5%)	1	0/40 (0%)	0
Hypoxia	0/40 (0%)	0	1/40 (2.5%)	1
Lung infection	1/40 (2.5%)	1	0/40 (0%)	0
Pharyngolaryngeal pain	1/40 (2.5%)	1	1/40 (2.5%)	2
Pleural effusion	1/40 (2.5%)	1	0/40 (0%)	0
Respiratory, thoracic and mediastinal disorders - (Other)	2/40 (5%)	3	1/40 (2.5%)	1
Sinus pain	1/40 (2.5%)	1	0/40 (0%)	0
Upper respiratory infection	1/40 (2.5%)	1	0/40 (0%)	0
Voice alteration	1/40 (2.5%)	1	3/40 (7.5%)	3
Skin and subcutaneous tissue disorders
Alopecia	22/40 (55%)	22	20/40 (50%)	20
Dry skin	27/40 (67.5%)	50	22/40 (55%)	50
Flushing	1/40 (2.5%)	1	1/40 (2.5%)	1
Hyperhidrosis	4/40 (10%)	6	1/40 (2.5%)	1
Pain of skin	0/40 (0%)	0	1/40 (2.5%)	2
Palmar-plantar erythrodysesthesia syndrome	32/40 (80%)	77	31/40 (77.5%)	109
Pruritus	8/40 (20%)	8	4/40 (10%)	6
Rash acneiform	1/40 (2.5%)	1	0/40 (0%)	0
Rash maculo-papular	30/40 (75%)	63	26/40 (65%)	62
Skin and subcutaneous tissue disorders - (Other)	11/40 (27.5%)	18	12/40 (30%)	25
Skin infection	0/40 (0%)	0	1/40 (2.5%)	1
Skin ulceration	0/40 (0%)	0	3/40 (7.5%)	3
Urticaria	1/40 (2.5%)	1	0/40 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.