Sorafenib in Treating Patients With Metastatic, Locally Advanced, or Recurrent Sarcoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00245102
• Collaborator: (none)
• Enrollment: 147
• Location: 1
• Arm: 1
• Duration (Months): 65.9
• Patients Per Site Per Month: 2.2

Study Details

Study Description

Brief Summary

This phase II trial is studying how well sorafenib works in treating patients with metastatic, locally advanced, or recurrent sarcoma. Sorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor.

Condition or Disease	Intervention/Treatment	Phase
Adult Angiosarcoma; Adult Epithelioid Sarcoma; Adult Leiomyosarcoma; Adult Malignant Fibrous Histiocytoma; Adult Neurofibrosarcoma; Adult Synovial Sarcoma; Ovarian Sarcoma; Recurrent Adult Soft Tissue Sarcoma; Recurrent Uterine Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage III Uterine Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Stage IV Uterine Sarcoma; Uterine Carcinosarcoma; Uterine Leiomyosarcoma	Drug: sorafenib tosylate	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. The primary endpoint is the response rate (CR+PR) for each stratum of sarcoma patients treated with sorafenib as defined by RECIST.

SECONDARY OBJECTIVES:

1. Progression-free survival (defined as CR + PR + SD, assessed at 3 months or 6 months).

2. Overall survival. III. Pharmacokinetics of sorafenib in this patient population (all sites will participate).

3. Frequency of B-raf mutations in the patients' sarcomas treated as part of this study and correlation with response or resistance to sorafenib (all sites will participate).

4. Ras-raf kinase pathway activation in pre-treatment existing tumor specimens (paraffin section immunohistochemistry; all sites will participate).

5. At MSKCC only: Pre and post treatment specimen changes in downstream events of ras signaling, specifically inhibition of ERK phosphorylation. Only patients with angiosarcoma and MPNST will undergo biopsy (up to 10 patients).

6. At MSKCC only: Circulating Endothelial Cells (CECs), VE-cadherin levels, and soluble protein levels (VEGF, bFGF, endostatin) as a measures of angiogenesis before and after starting sorafenib therapy.

OUTLINE: This is an open-label, non-randomized, multicenter study. Patients are stratified according to sarcoma histology (angiosarcoma vs malignant peripheral nerve sheath tumor vs leiomyosarcoma [closed to accrual as of 11/29/06] vs high-grade undifferentiated pleomorphic sarcoma [i.e., malignant fibrous histiocytoma (including myxofibrosarcoma)(closed to accrual as of 11/29/06)] vs synovial sarcoma (closed to accrual as of 11/29/06) vs all other types of sarcoma).

Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study, patients are followed at 4 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 147 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter Phase II Study of Sorafenib (BAY43-9006) in Non-GIST Sarcomas
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm I Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: sorafenib tosylate; Given orally; Other Names: BAY 43-9006 BAY 43-9006 Tosylate Salt BAY 54-9085 Nexavar SFN

Outcome Measures

Primary Outcome Measures

1. Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST [Up to 4 weeks]

   A 5% response rate is considered not promising, a 20% response rate is considered promising. For each stratum, the response rate will be estimated and a confidence interval will be constructed.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Histologically or cytologically confirmed sarcoma, including any of the following neoplastic subtypes:

• Giant hemangioma

• Angiosarcoma (including epithelioid hemangioendothelioma)

• Malignant peripheral nerve sheath tumor

• Leiomyosarcoma (closed to accrual as of 11/29/06)

• High-grade undifferentiated pleomorphic sarcoma (i.e., malignant fibrous histiocytoma [including myxofibrosarcoma]) (closed to accrual as of 11/29/06)

• Synovial sarcoma (closed to accrual as of 11/29/06)

• Carcinosarcoma (closed to accrual as of 11/29/06)

• Metastatic, locally advanced, or locally recurrent disease

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques OR ≥ 10 mm by spiral CT scan

• Lesions in a previously irradiated area may be considered measurable provided there is evidence of subsequent disease progression that cannot be attributed to necrosis or bleeding

• No gastrointestinal stromal tumor

• No known brain metastases

• Performance status - ECOG 0-2

• Absolute neutrophil count ≥ 1,500/mm^3

• Platelet count ≥ 100,000/mm^3

• No evidence of bleeding diathesis

• Bilirubin ≤ 1.5 mg/dL

• INR ≤ 1.5

• AST and ALT ≤ 2.5 times upper limit of normal

• Creatinine ≤ 1.5 mg/dL

• No symptomatic congestive heart failure

• No unstable angina pectoris

• No cardiac arrhythmia

• No uncontrolled hypertension

• No history of allergic reaction to compounds of similar chemical or biologic composition to sorafenib

• No known HIV positivity

• No active or ongoing infection

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No psychiatric illness or social situation that would preclude study compliance

• No swallowing dysfunction that would preclude the swallowing of tablets

• Other malignancies allowed provided sarcoma is the primary disease requiring treatment

• No other uncontrolled illness

• No more than 1 prior chemotherapy regimen for recurrent or metastatic disease (≤ 3 regimens for angiosarcoma or malignant peripheral nerve sheath tumor)

• Adjuvant chemotherapy completed > 1 year prior to study entry is not considered a line of prior treatment

• More than 3 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)

• At least 3 weeks since prior radiotherapy

• Recovered from prior antitumor therapy

• Alopecia allowed

• No prior sorafenib

• No prior small molecule inhibitors of MAPK signaling intermediates

• No concurrent therapeutic anticoagulation

• Prophylactic anticoagulation (i.e., low-dose warfarin) of venous or arterial devices allowed provided requirements for PT, INR, or PTT requirements are met

• No other concurrent investigational agents

• No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin, carbamazepine, or phenobarbital)

• No concurrent rifampin or Hypericum perforatum (St. John's wort)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Memorial Sloan-Kettering Cancer Center	New York	New York	United States	10065

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Robert Maki, Memorial Sloan Kettering Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00245102
• Other Study ID Numbers: NCI-2012-01469; NCI-2012-01469; NCI-7060; CDR0000449962; MSKCC-05081; 05-081; 7060; N01CM62206; P30CA008748; N01CM62201
• First Posted: Oct 27, 2005
• Last Update Posted: May 23, 2014
• Last Verified: Dec 1, 2012

• Additional relevant MeSH terms: Sarcoma; Leiomyosarcoma; Carcinosarcoma; Sarcoma, Synovial; Hemangiosarcoma; Histiocytoma; Histiocytoma, Benign Fibrous; Histiocytoma, Malignant Fibrous; Neurofibrosarcoma; Recurrence; Sorafenib

Study Results

Participant Flow

Recruitment Details	Protocol Open to Accrual 09/09/2005 Protocol Closed to Accrual 07/22/2008 Primary Completion Date 03/22/2011 Recruitment Location is the medical clinic

Arm/Group Title	Angiosarcoma	MPNST	Leiomyosarcoma	Undifferentiated Pleomorphic Sarcoma	Fibrosarcoma	Other Histology
Arm/Group Description	Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Patients receive oral sorafenib twice daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	44	16	46	13	5	23
COMPLETED	37	12	39	10	5	19
NOT COMPLETED	7	4	7	3	0	4

Baseline Characteristics

Arm/Group Title	Angiosarcoma	MPNST	Leiomyosarcoma	Undifferentiated Pleomorphic Sarcoma	Fibrosarcoma	Other Histology	Total
Arm/Group Description	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Total of all reporting groups
Overall Participants	44	16	46	13	5	23	147
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	20 45.5%	14 87.5%	35 76.1%	7 53.8%	5 100%	22 95.7%	103 70.1%
>=65 years	24 54.5%	2 12.5%	11 23.9%	6 46.2%	0 0%	1 4.3%	44 29.9%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54 (50.91168825)	47.5 (34.64823228)	56 (33.9411255)	62.5 (31.81980515)	43.5 (10.60660172)	44 (31.11269837)	54 (50.91168825)
Sex: Female, Male (Count of Participants)
Female	25 56.8%	9 56.3%	37 80.4%	8 61.5%	4 80%	11 47.8%	94 63.9%
Male	19 43.2%	7 43.8%	9 19.6%	5 38.5%	1 20%	12 52.2%	53 36.1%
Region of Enrollment (participants) [Number]
United States	44 100%	15 93.8%	46 100%	13 100%	5 100%	23 100%	146 99.3%
Italy	0 0%	1 6.3%	0 0%	0 0%	0 0%	0 0%	1 0.7%

Outcome Measures

1. Primary Outcome

Title	Overall Response Rate Measured by Complete Response (CR) Rate and Partial Response (PR) Rate as Determined by RECIST
Description	A 5% response rate is considered not promising, a 20% response rate is considered promising. For each stratum, the response rate will be estimated and a confidence interval will be constructed.
Time Frame	Up to 4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Angiosarcoma	MPNST	Leiomyosarcoma	Undifferentiated Pleomorphic Sarcoma	Fibrosarcoma	Other Histology
Arm/Group Description	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID	Sorafenib 400 mg PO BID
Measure Participants	37	12	39	10	5	19
Complete Response	1 2.3%	0 0%	0 0%	0 0%	0 0%	0 0%
Partial Response	4 9.1%	0 0%	1 2.2%	0 0%	0 0%	0 0%

Adverse Events

Arm/Group Title	Angiosarcoma		MPNST		Leiomyosarcoma		Undifferentiated Pleomorphic Sarcoma		Fibrosarcoma		Other Histology
Arm/Group Description	Sorafenib 400 mg PO BID		Sorafenib 400 mg PO BID		Sorafenib 400 mg PO BID		Sorafenib 400 mg PO BID		Sorafenib 400 mg PO BID		Sorafenib 400 mg PO BID
All Cause Mortality
	Angiosarcoma		MPNST		Leiomyosarcoma		Undifferentiated Pleomorphic Sarcoma		Fibrosarcoma		Other Histology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Angiosarcoma		MPNST		Leiomyosarcoma		Undifferentiated Pleomorphic Sarcoma		Fibrosarcoma		Other Histology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/44 (29.5%)		7/16 (43.8%)		7/46 (15.2%)		9/13 (69.2%)		0/5 (0%)		5/23 (21.7%)
Blood and lymphatic system disorders
Hemoglobin decreased (Anemia)	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Cardiac disorders
Cardiac disorder	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Left ventricular systolic dysfunction	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Atrial fibrillation	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Left ventricular diastolic dysfunction	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Eye disorders
Vision-flashing lights	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Gastrointestinal disorders
Upper gastrointestinal hemorrhage	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Small intestinal perforation	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Small intestinal obstruction	0/44 (0%)	0	1/16 (6.3%)	1	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Ileal perforation	0/44 (0%)	0	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Vomiting	0/44 (0%)	0	1/16 (6.3%)	1	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Constipation	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Diarrhea	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	1/23 (4.3%)	1
Abdominal pain	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Colitis	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
General disorders
Death-Disease progression	1/1 (100%)	1	1/16 (6.3%)	1	1/46 (2.2%)	1	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Non-cardiac chest pain	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	1/23 (4.3%)	1
Fatigue	0/44 (0%)	0	1/16 (6.3%)	1	1/46 (2.2%)	1	1/13 (7.7%)	1	0/5 (0%)	0	2/23 (8.7%)	2
Fever	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	1/23 (4.3%)	1
General symptom, other-Failure to thrive	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Death, NOS	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	1/23 (4.3%)	1
Infections and infestations
Bladder infection	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Investigations
Lymphocyte count decreased	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Alanine aminotransferase increased	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Aspartate aminotransferase increased	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Alkaline phosphatase increased	0/44 (0%)	0	0/16 (0%)	0	2/46 (4.3%)	2	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Blood Bilirubin increased	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Cardiac troponin T increased	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Metabolism and nutrition disorders
Hyponatremia	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Dehydration	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Anorexia	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Myalgia	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Neck pain	0/44 (0%)	0	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Nervous system disorders
Ischemia cerebrovascular	1/44 (2.3%)	1	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Peripheral motor neuropathy	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Peripheral sensory neuropathy	0/44 (0%)	0	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Intracranial hemorrhage	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Psychiatric disorders
Confusion	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Cough	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Dyspnea	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Pneumonitis	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Pneumothorax	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Bronchopulmonary hemorrhage	0/44 (0%)	0	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Hemorrhage, Respiratory tract (NOS)	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	2/23 (8.7%)	2
Hemorrhage, bleeding other-Chest wall	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Palmar-plantar erythrodysesthesia syndrome	1/44 (2.3%)	1	0/16 (0%)	0	1/46 (2.2%)	1	0/13 (0%)	0	0/5 (0%)	0	1/23 (4.3%)	1
Vascular disorders
Hypertension	1/44 (2.3%)	1	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Thrombosis	0/44 (0%)	0	0/16 (0%)	0	1/46 (2.2%)	1	2/13 (15.4%)	2	0/5 (0%)	0	0/23 (0%)	0
Other (Not Including Serious) Adverse Events
	Angiosarcoma		MPNST		Leiomyosarcoma		Undifferentiated Pleomorphic Sarcoma		Fibrosarcoma		Other Histology
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	36/44 (81.8%)		12/16 (75%)		40/46 (87%)		10/13 (76.9%)		4/5 (80%)		21/23 (91.3%)
Blood and lymphatic system disorders
Anemia	10/44 (22.7%)	10	3/16 (18.8%)	3	2/46 (4.3%)	24	3/13 (23.1%)	3	1/5 (20%)	1	4/23 (17.4%)	4
Eye disorders
Eyelid function disorder	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Gastrointestinal disorders
Constipation	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Diarrhea	3/44 (6.8%)	3	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	1/5 (20%)	1	3/23 (13%)	3
Nausea	2/44 (4.5%)	2	2/16 (12.5%)	2	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Vomiting	3/44 (6.8%)	3	0/16 (0%)	0	2/46 (4.3%)	2	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Abdominal pain	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Abdominal distension	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Flatulence	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Gingival pain	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
General disorders
Fatigue	11/44 (25%)	11	0/16 (0%)	0	4/46 (8.7%)	4	0/13 (0%)	0	1/5 (20%)	1	4/23 (17.4%)	4
Fever	0/44 (0%)	0	0/16 (0%)	0	3/46 (6.5%)	3	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Edema limbs	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Injury, poisoning and procedural complications
Wound complication, non-infectious	0/44 (0%)	0	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Investigations
Alanine aminotransferase increased	3/44 (6.8%)	3	1/16 (6.3%)	1	5/46 (10.9%)	5	2/13 (15.4%)	2	1/5 (20%)	1	1/23 (4.3%)	1
Aspartate aminotransferase increased	3/44 (6.8%)	3	1/16 (6.3%)	1	4/46 (8.7%)	4	0/13 (0%)	0	1/5 (20%)	1	1/23 (4.3%)	1
Blood bilirubin increased	2/44 (4.5%)	2	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	2/23 (8.7%)	2
INR increased	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
White blood cell decreased	2/44 (4.5%)	2	1/16 (6.3%)	1	6/46 (13%)	6	2/13 (15.4%)	2	1/5 (20%)	1	4/23 (17.4%)	4
Lymphocyte count decreased	7/44 (15.9%)	7	2/16 (12.5%)	2	7/46 (15.2%)	7	4/13 (30.8%)	4	1/5 (20%)	1	3/23 (13%)	3
Neutrophil count decreased	0/44 (0%)	0	1/16 (6.3%)	1	2/46 (4.3%)	2	0/13 (0%)	0	1/5 (20%)	1	2/23 (8.7%)	2
Weight loss	0/44 (0%)	0	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Platelet count decreased	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Metabolism and nutrition disorders
Hypoalbuminemia	5/44 (11.4%)	5	5/16 (31.3%)	5	2/46 (4.3%)	2	3/13 (23.1%)	3	1/5 (20%)	1	3/23 (13%)	3
Hyperglycemia	2/44 (4.5%)	2	3/16 (18.8%)	3	7/46 (15.2%)	7	3/13 (23.1%)	3	0/5 (0%)	0	2/23 (8.7%)	2
Hypophosphatemia	12/44 (27.3%)	12	1/16 (6.3%)	1	7/46 (15.2%)	7	2/13 (15.4%)	2	0/5 (0%)	0	9/23 (39.1%)	9
Hyperkalemia	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Hypokalemia	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Hypocalcemia	0/44 (0%)	0	3/16 (18.8%)	3	3/46 (6.5%)	3	2/13 (15.4%)	2	1/5 (20%)	1	1/23 (4.3%)	1
Hypomagnesemia	0/44 (0%)	0	1/16 (6.3%)	1	0/46 (0%)	0	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Anorexia	0/44 (0%)	0	0/16 (0%)	0	3/46 (6.5%)	3	1/13 (7.7%)	1	1/5 (20%)	1	0/23 (0%)	0
Hypoglycemia	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	2/13 (15.4%)	2	0/5 (0%)	0	0/23 (0%)	0
Hyponatremia	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Musculoskeletal and connective tissue disorders
Pain in extremity	3/44 (6.8%)	3	0/16 (0%)	0	4/46 (8.7%)	4	2/13 (15.4%)	2	2/5 (40%)	2	0/23 (0%)	0
Joint range of motion decrease	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Arthralgia	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Nervous system disorders
Peripheral sensory neuropathy	2/44 (4.5%)	2	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Psychiatric disorders
Anxiety	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Insomnia	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Renal and urinary disorders
Renal/Genitourinary-Other	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	1/13 (7.7%)	1	0/5 (0%)	0	0/23 (0%)	0
Skin and subcutaneous tissue disorders
Pruritus	3/44 (6.8%)	3	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Rash	10/44 (22.7%)	10	0/16 (0%)	0	12/46 (26.1%)	12	2/13 (15.4%)	2	3/5 (60%)	3	3/23 (13%)	3
Palmar-plantar erythrodysesthesia syndrome	15/44 (34.1%)	15	5/16 (31.3%)	5	17/46 (37%)	17	2/13 (15.4%)	2	3/5 (60%)	3	6/23 (26.1%)	6
Alopecia	0/44 (0%)	0	1/16 (6.3%)	1	2/46 (4.3%)	2	0/13 (0%)	0	0/5 (0%)	0	0/23 (0%)	0
Scalp pain	0/44 (0%)	0	0/16 (0%)	0	0/46 (0%)	0	0/13 (0%)	0	1/5 (20%)	1	0/23 (0%)	0
Vascular disorders
Hypertension	8/44 (18.2%)	8	0/16 (0%)	0	4/46 (8.7%)	4	1/13 (7.7%)	1	0/5 (0%)	0	2/23 (8.7%)	2

Limitations/Caveats

[Not Specified]

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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.