Phase I/II Trial of Tivantinib With FOLFOX for the Treatment of Advanced Solid Tumors and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal Junction or Stomach

• Sponsor: SCRI Development Innovations, LLC (Other)
• Overall Status: Completed
• CT.gov ID: NCT01611857
• Collaborator: Daiichi Sankyo, Inc. (Industry)
• Enrollment: 49
• Locations: 9
• Arm: 1
• Duration (Months): 37
• Patients Per Site: 5.4
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

This study is a Phase I/II trial of Tivantinib plus FOLFOX for the treatment of patients with advanced solid tumors. In Phase I the Maximum Tolerated Dose (MTD) will be determined; in Phase II patients with first-line metastatic GE cancer will be treated at the MTD. It is hypothesized that the response rate (RR) will be improved from 45% to at least 65% under this regimen.

Condition or Disease	Intervention/Treatment	Phase
Malignant Solid Tumour; Gastroesophageal Cancer	Drug: Tivantinib; Drug: FOLFOX	Phase 1/Phase 2

Detailed Description

This is a Phase I, open-label, non-randomized, dose-escalation study with a Phase II portion planned upon reaching the Maximum Tolerated Dose or recommended Phase II dose (RP2D). Phase I: The first cycle of the Phase I portion of the trial will be considered the Dose Limiting Toxicity evaluation period. Patients with advanced solid tumors will be treated with Tivantinib on Days 1 to 14 and with FOLFOX on Day 1. Following evaluation of the Dose Limiting Toxicities, doses will be escalated/reduced according to the protocol with 3 to 6 patients treated per dose level until the Maximum Tolerated Dose is determined.

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Trial of the c-Met Inhibitor, Tivantinib, in Combination With FOLFOX for the Treatment of Patients With Advanced Solid Tumors (Phase I) and Previously Untreated Metastatic Adenocarcinoma of the Distal Esophagus, Gastroesophageal (GE) Junction, or Stomach (Phase II)
• Study Start Date: Jul 1, 2012
• Actual Primary Completion Date: Jul 1, 2015
• Actual Study Completion Date: Aug 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Maximum Tolerated Dose Phase I trial of Tivantinib plus FOLFOX for the treatment of patients with advanced solid tumors followed by a Phase II portion for patients with first-line metastatic GE cancer.

Drug: Tivantinib; Patients with advanced solid tumors will be treated with oral Tivantinib (120, 240, or 360 mg BID) daily for 14 days in cycles of 14 days.; Other Names: ARQ 197 ; Drug: FOLFOX; The FOLFOX treatment regimen is started on Day 1 of each cycle and consists of 5-Fluorouracil (5-FU) 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2.; Other Names: 5-FU Leucovorin Oxaliplatin Levoleucovorin 5-Fluorouracil

Outcome Measures

Primary Outcome Measures

1. The Incidence of Dose Limiting Toxicities (DLT) in Phase I Dose Escalation [14 Days (1 cycle)]

   Using a standard 3+3 design participants were enrolled in dose-escalating cohorts to determine the maximum tolerated dose (MTD) of tivantinib when given with FOLFOX (5-FU 400 mg/m^2, continuous IV 5-FU 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2). MTD is defined as the highest dose level at which no more than 1 of 6 patients experiences a DLT, assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.

Secondary Outcome Measures

1. Progression Free Survival in Phase II Dose Expansion [every 8 weeks until treatment discontinuation, projected 18 months and then every 3 months thereafter up to 5 years from start of treatment.]

   Defined as the time from first treatment until objective tumor progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

2. Overall Survival in Phase II Dose Expansion [every 8 weeks until treatment discontinuation, an expected average of 18 months, then every 12 weeks thereafter up to 5 years from start of treatment.]

   Defined as the time from first treatment until death from any cause.

3. Time to Progression in Phase II Dose Expansion [every 8 weeks until progressive disease, expected 18 months.]

   Defined as the time from first treatment until objective tumor progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Life expectancy ≥12 weeks.

• Karnofsky performance status ≥70%

• Patients must have measurable disease per RECIST Version 1.1.

• Adequate hematologic function defined as:

• Absolute neutrophil count (ANC) ≥1500/μL

• Hemoglobin (Hgb) ≥9 g/dL (5.6 mmol/L)

• Platelets ≥100,000/uL

• Adequate liver function defined as:

• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST <2.5 x the institutional upper limit of normal (ULN) or ≤5.0 x the institutional ULN in patients with liver metastases.

• Total bilirubin within normal limits (WNL) (or ≤1.5 x the institutional ULN in patients with liver metastases; or total bilirubin ≤3.0 x ULN with direct bilirubin within normal limits in patients with well documented Gilbert Syndrome).

• Serum creatinine <1.5 X ULN or calculated 24-hour creatinine clearance >40 mL/min.

• Patients who are on coumadin should have an international normalized ratio (INR) value within the therapeutic range (i.e., 2 to 3 x ULN). Patients who are on stable, chronic doses of coumadin are eligible.

PHASE I ONLY

•Patients must have histologically confirmed solid tumor malignancy that is metastatic or unresectable and for which standard therapy would include FOLFOX or for which standard curative or palliative measures do not exist or are no longer effective.

PHASE II ONLY

• Histologic documentation of adenocarcinoma of the esophagus, GE junction, or stomach.

• Metastatic GE cancer as documented by radiologic study or surgical evidence of metastatic disease.

• No prior chemotherapy for metastatic disease. Previous combined modality therapy for locally advanced disease is allowed if completed ≥6 months prior to recurrence (acceptable chemotherapy drugs include 5-FU, capecitabine, cisplatin, carboplatin, paclitaxel, oxaliplatin, and docetaxel).

• Prior radiation therapy is allowed. At least 4 weeks must have elapsed from completion of the radiation therapy and all signs of toxicity must have resolved.

• Prior adjuvant chemotherapy is allowed if completed ≥6 months prior to the documentation of metastatic disease.

Exclusion Criteria:

• Patients with known central nervous system (CNS) metastases may be enrolled, provided the metastases have undergone treatment, the patient is asymptomatic, and the patient does not require antiepileptic drugs or steroids as treatment for the CNS metastases.

• Patients with poorly controlled or clinically significant atherosclerotic vascular disease including New York Heart Association Grade 3 or greater congestive heart failure; unstable angina ; myocardial infarction, cardiovascular accident, transient ischemic accidents, angioplasty, cardiac or vascular stenting in the past 6 months; or ventricular arrhythmia requiring medication. Patients with previously diagnosed symptomatic bradycardia will be ineligible.

• Medical history of prolonged QT syndrome (>450 ms).

• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit safety or compliance with study requirements.

• History of hypersensitivity to active or inactive excipients of any component of treatment (5-FU, leucovorin, oxaliplatin, or Tivantinib), or known dipyrimidine dehydrogenase deficiency.

• Patients with evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation).

• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair, or recent peripheral arterial thrombosis) ≤6 months prior to Day 1 of treatment.

• Any known positive test for human immunodeficiency virus, hepatitis C virus or acute or chronic hepatitis B infection.

• Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study.

• Use of any non-approved or investigational agent ≤28 days or 5 half-lives prior to administration of the first dose of study drug, whichever is shorter.

• Patients may not receive any other investigational or anti-cancer treatments while participating in this study.

• Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter drug absorption (e.g. active inflammatory bowel disease, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).

• Inability to swallow whole capsules.

PHASE I ONLY

•Patients who have had radiation therapy, hormonal therapy, biologic therapy, investigational agents, or chemotherapy for cancer within 28 days or 5 half-lives of the chemotherapy or biologic/targeted agents, whichever is shorter, prior to Day 1 of the study.

PHASE II ONLY

•Past or current history of neoplasm other than the entry diagnosis with the exception of treated non-melanoma skin cancer or carcinoma in situ of the cervix, or other cancers cured by local therapy alone and a disease free survival ≥5 years.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yale University School of Medicine	New Haven	Connecticut	United States	06520
2	Florida Cancer Specialists-South	Fort Myers	Florida	United States	33916
3	Florida Cancer Specialists-Sarasota	Sarasota	Florida	United States	34232
4	Florida Cancer Specialists-North	St. Petersburg	Florida	United States	33705
5	Oklahoma University	Oklahoma City	Oklahoma	United States	73104
6	South Carolina Oncology Associates	Columbia	South Carolina	United States	29210
7	Tennessee Oncology - Chattanooga	Chattanooga	Tennessee	United States	37404
8	Tennessee Oncology, PLLC	Nashville	Tennessee	United States	37023
9	Center for Cancer and Blood Disorders	Fort Worth	Texas	United States	76104

Sponsors and Collaborators

• SCRI Development Innovations, LLC
• Daiichi Sankyo, Inc.

Investigators

• Study Chair: Johanna C Bendell, M.D., SCRI Development Innovations, LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT01611857
• Other Study ID Numbers: SCRI GI 157
• First Posted: Jun 5, 2012
• Last Update Posted: Nov 23, 2016
• Last Verified: Oct 1, 2016

• Keywords provided by SCRI Development Innovations, LLC: Advanced solid tumors; First-Line Metastatic GE cancer; c-Met Inhibitor; Tivantinib; FOLFOX
• Additional relevant MeSH terms: Adenocarcinoma; Leucovorin; Fluorouracil; Oxaliplatin; Levoleucovorin

Study Results

Participant Flow

Recruitment Details	Between January 2012 and March 2014, 49 patients were enrolled at multiple centers in the U.S. Fifteen patients with advanced solid tumors were enrolled in the dose escalation phase, and 34 patients with first-line metastatic cancer of the esophagus, gastroesophageal (GE) junction, or stomach in the expansion phase.
Pre-assignment Detail	Forty-nine patients were enrolled; 47 were treated. Two participants withdrew prior to dosing. 15 participants were enrolled and treated in the dose escalation phase. 34 participants were enrolled in the dose expansion phase; however only 32 were treated. Patients continued treatment until disease progression or intolerable toxicity.

Arm/Group Title	Tivantinib + FOLFOX Dose Escalation	Tivantinib + FOLFOX Dose Expansion
Arm/Group Description	Tivantinib: (120 mg; 240 mg; or 360 mg) orally, twice daily (PO BID) on Days 1-14 of each 2 week cycle; FOLFOX: [5-Fluorouracil (5-FU) 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2] on Day 1 each cycle.	Tivantinib: 360 mg PO BID on Days 1-14 of each 2-week cycle. FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 of each 2-week cycle.
Period Title: Overall Study
STARTED	15	34
Tivantinib 120 mg	5	0
Tivantinib 240 mg	3	0
Tivantinib 360 mg	7	32
COMPLETED	15	32
NOT COMPLETED	0	2

Baseline Characteristics

Arm/Group Title	Tivantinib+FOLFOX Dose Escalation	Tivantinib+FOLFOX Dose Expansion	Total
Arm/Group Description	Tivantinib: (120 mg, 240 mg, or 360 mg) orally, twice daily on Days 1-14 of each 2 week cycle. FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 each cycle.	Tivantinib: 360 mg PO BID on Days 1-14 of each 2-week cycle; FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 of each 2-week cycle. Treatment continued until disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	15	34	49
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	62	65	63.5
Sex: Female, Male (Count of Participants)
Female	5 33.3%	8 23.5%	13 26.5%
Male	10 66.7%	26 76.5%	36 73.5%
Region of Enrollment (participants) [Number]
United States	15 100%	34 100%	49 100%
Tumor Type (participants) [Number]
Colorectal	7 46.7%	0 0%	7 14.3%
Esophageal	4 26.7%	14 41.2%	18 36.7%
Pancreatic	1 6.7%	0 0%	1 2%
GE Junction	1 6.7%	9 26.5%	10 20.4%
Cholangiocarcinoma	1 6.7%	0 0%	1 2%
Unknown primary	1 6.7%	0 0%	1 2%
Gastric	0 0%	11 32.4%	11 22.4%
Karnofsky Performance Score (participants) [Number]
100	2 13.3%	7 20.6%	9 18.4%
90	3 20%	18 52.9%	21 42.9%
80	10 66.7%	3 8.8%	13 26.5%
70	0 0%	5 14.7%	5 10.2%
60	0 0%	0 0%	0 0%
50	0 0%	0 0%	0 0%
40	0 0%	0 0%	0 0%
30	0 0%	0 0%	0 0%
20	0 0%	0 0%	0 0%
10	0 0%	0 0%	0 0%
0	0 0%	0 0%	0 0%
Unknown	0 0%	1 2.9%	1 2%
Number of Participants with Prior Radiation Therapy (participants) [Number]
Received Prior Radiation: Yes	5 33.3%	11 32.4%	16 32.7%
Received Prior Radiation: No	10 66.7%	23 67.6%	33 67.3%

Outcome Measures

1. Primary Outcome

Title	The Incidence of Dose Limiting Toxicities (DLT) in Phase I Dose Escalation
Description	Using a standard 3+3 design participants were enrolled in dose-escalating cohorts to determine the maximum tolerated dose (MTD) of tivantinib when given with FOLFOX (5-FU 400 mg/m^2, continuous IV 5-FU 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2). MTD is defined as the highest dose level at which no more than 1 of 6 patients experiences a DLT, assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.
Time Frame	14 Days (1 cycle)

Outcome Measure Data

Analysis Population Description

Patients were assessed for DLT if they received at least 85% of the scheduled doses of study drugs in cycle 1. In the Tivantinib 120 mg cohort two participants were replaced due to missed drug. In the Tivantinib 360 mg cohort one patient was replaced due to an allergic reaction to oxaliplatin.

Arm/Group Title	Tivantinib 120 mg (PO BID) + FOLFOX	Tivantinib 240 mg (PO BID) + FOLFOX	Tivantinib 360 mg (PO BID) + FOLFOX
Arm/Group Description	Tivantinib 120 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 each cycle.	Tivantinib 240 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle; FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 each cycle.	Tivantinib 360 mg given orally, twice daily (PO BID) on Days 1-14 of each 14-day cycle cycle; FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 each cycle.
Measure Participants	3	3	6
Number [participants]	0 0%	0 0%	1 2%

2. Secondary Outcome

Title	Progression Free Survival in Phase II Dose Expansion
Description	Defined as the time from first treatment until objective tumor progression or death from any cause. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	every 8 weeks until treatment discontinuation, projected 18 months and then every 3 months thereafter up to 5 years from start of treatment.

Outcome Measure Data

Analysis Population Description

The analysis was performed on an Intent-to-Treat basis (N = 34) for all participants in the Phase II portion of the study. Median follow-up was 15 months (3-21 months)

Arm/Group Title	Tivantinib + FOLFOX Dose Expansion
Arm/Group Description	Tivantinib: 360 mg PO BID on Days 1-14 of each 14-day cycle. FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 of each 14-day cycle. Treatment continued until disease progression or unacceptable toxicity.
Measure Participants	34
Median (95% Confidence Interval) [months]	6.1

3. Secondary Outcome

Title	Overall Survival in Phase II Dose Expansion
Description	Defined as the time from first treatment until death from any cause.
Time Frame	every 8 weeks until treatment discontinuation, an expected average of 18 months, then every 12 weeks thereafter up to 5 years from start of treatment.

Outcome Measure Data

Analysis Population Description

The analysis was performed on an Intent-to-Treat basis (N=34) for all participants in the Phase II portion of the study.

Arm/Group Title	Tivantinib + FOLFOX Dose Expansion
Arm/Group Description	Tivantinib: 360 mg PO BID on Days 1-14 of each 14-day cycle. FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 of each 14-day cycle. Treatment continued until disease progression or unacceptable toxicity.
Measure Participants	34
Median (95% Confidence Interval) [months]	9.6

4. Secondary Outcome

Title	Time to Progression in Phase II Dose Expansion
Description	Defined as the time from first treatment until objective tumor progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions.
Time Frame	every 8 weeks until progressive disease, expected 18 months.

Outcome Measure Data

Analysis Population Description

The analysis was performed on all participants (N = 34) in the Phase II portion of the study.

Arm/Group Title	Tivantinib + FOLFOX Dose Expansion
Arm/Group Description	Tivantinib: 360 mg PO BID on Days 1-14 of each 14-day cycle. FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 of each 14-day cycle. Treatment continued until disease progression or unacceptable toxicity.
Measure Participants	34
Median (95% Confidence Interval) [months]	7.0

Adverse Events

Time Frame	Collected from day of first dose to 30 days after last dose of study medication up to 18 months.
Arm/Group Title	Tivantinib+FOLFOX Dose Escalation		Tivantinib+FOLFOX Dose Expansion
Arm/Group Description	Tivantinib: orally, twice daily (PO BID) on Days 1-14 of each 2 week cycle; FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 each cycle.		Tivantinib: 360 mg PO BID on Days 1-14 of each 2-week cycle. FOLFOX: (5-FU 400 mg/m^2, 5-FU continuous IV 2400 mg/m^2 over 46 hours, leucovorin 400 mg/m^2 IV, and oxaliplatin 85 mg/m^2) on Day 1 of each 2-week cycle. Treatment continued until disease progression or unacceptable toxicity.
All Cause Mortality
	Tivantinib+FOLFOX Dose Escalation		Tivantinib+FOLFOX Dose Expansion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Tivantinib+FOLFOX Dose Escalation		Tivantinib+FOLFOX Dose Expansion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/15 (40%)		17/32 (53.1%)
Blood and lymphatic system disorders
Anemia	0/15 (0%)	0	1/32 (3.1%)	1
Neutropenia	0/15 (0%)	0	1/32 (3.1%)	1
Febrile neutropenia	1/15 (6.7%)	1	0/32 (0%)	0
Cardiac disorders
Myocardial infarction	0/15 (0%)	0	1/32 (3.1%)	1
Eye disorders
Optic nerve disorder	0/15 (0%)	0	1/32 (3.1%)	1
Gastrointestinal disorders
Vomiting	3/15 (20%)	3	1/32 (3.1%)	1
Diarhhea	1/15 (6.7%)	1	2/32 (6.3%)	2
Abdominal pain	1/15 (6.7%)	1	0/32 (0%)	0
Nausea	1/15 (6.7%)	1	0/32 (0%)	0
Ileus	0/15 (0%)	0	1/32 (3.1%)	1
General disorders
Asthenia	1/15 (6.7%)	1	0/32 (0%)	0
Non-cardiac chest pain	0/15 (0%)	0	1/32 (3.1%)	1
Infections and infestations
Sepsis	0/15 (0%)	0	1/32 (3.1%)	1
Bacteremia	0/15 (0%)	0	1/32 (3.1%)	1
Pneumonia	0/15 (0%)	0	1/32 (3.1%)	1
Septic shock	0/15 (0%)	0	1/32 (3.1%)	1
Metabolism and nutrition disorders
Hyperglycemia	0/15 (0%)	0	1/32 (3.1%)	1
Nervous system disorders
Encephalopathy	1/15 (6.7%)	1	0/32 (0%)	0
Cerebrovascular accident	0/15 (0%)	0	1/32 (3.1%)	1
Ischemic stroke	0/15 (0%)	0	1/32 (3.1%)	1
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/15 (6.7%)	1	0/32 (0%)	0
Pulmonary embolism	0/15 (0%)	0	1/32 (3.1%)	1
Respiratory arrest	0/15 (0%)	0	1/32 (3.1%)	1
Vascular disorders
Embolism	0/15 (0%)	0	1/32 (3.1%)	1
Other (Not Including Serious) Adverse Events
	Tivantinib+FOLFOX Dose Escalation		Tivantinib+FOLFOX Dose Expansion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/15 (93.3%)		31/32 (96.9%)
Blood and lymphatic system disorders
Neutropenia	4/15 (26.7%)	7	20/32 (62.5%)	20
Thrombocytopenia	6/15 (40%)	14	9/32 (28.1%)	9
Anemia	5/15 (33.3%)	14	8/32 (25%)	8
Febrile neutropenia	0/15 (0%)	0	3/32 (9.4%)	3
Leukopenia	3/15 (20%)	3	2/32 (6.3%)	2
Blood bilirubin increased	1/15 (6.7%)	1	0/32 (0%)	0
Cardiac disorders
Bradycardia	0/15 (0%)	0	3/32 (9.4%)	3
Eye disorders
Visual impairment	0/15 (0%)	0	2/32 (6.3%)	2
Gastrointestinal disorders
Nausea	7/15 (46.7%)	8	16/32 (50%)	16
Diarrhea	5/15 (33.3%)	6	16/32 (50%)	16
Constipation	5/15 (33.3%)	5	8/32 (25%)	8
Vomiting	3/15 (20%)	5	8/32 (25%)	8
Dyspepsia	0/15 (0%)	0	2/32 (6.3%)	2
Oral pain	0/15 (0%)	0	2/32 (6.3%)	2
Proctolgia	1/15 (6.7%)	1	0/32 (0%)	0
Stomatitis	1/15 (6.7%)	1	3/32 (9.4%)	4
Muscosal inflammation	1/15 (6.7%)	1	6/32 (18.8%)	7
General disorders
Fatigue	8/15 (53.3%)	10	18/32 (56.3%)	18
Temperature intolerance	1/15 (6.7%)	1	10/32 (31.3%)	10
Mucositis	0/15 (0%)	0	9/32 (28.1%)	9
Asthenia	0/15 (0%)	0	3/32 (9.4%)	3
Chills	2/15 (13.3%)	2	2/32 (6.3%)	2
Edema	1/15 (6.7%)	3	2/32 (6.3%)	2
Pyrexia	2/15 (13.3%)	2	2/32 (6.3%)	2
Peripheral edema	1/15 (6.7%)	1	0/32 (0%)	0
Infections and infestations
Candida infection	0/15 (0%)	0	2/32 (6.3%)	2
Investigations
Weight decreased	2/15 (13.3%)	2	3/32 (9.4%)	3
QT prolongation	3/15 (20%)	6	2/32 (6.3%)	5
Aspartate aminotransferase increased	1/15 (6.7%)	1	0/32 (0%)	0
Alkaline phosphatase increased	1/15 (6.7%)	1	0/32 (0%)	0
Alanine aminotransferase increased	1/15 (6.7%)	1	0/32 (0%)	0
Metabolism and nutrition disorders
Anorexia	1/15 (6.7%)	1	6/32 (18.8%)	6
Dehydration	2/15 (13.3%)	3	1/32 (3.1%)	2
Musculoskeletal and connective tissue disorders
Myalgia	1/15 (6.7%)	1	2/32 (6.3%)	2
Nervous system disorders
Peripheral neuropathy	5/15 (33.3%)	10	14/32 (43.8%)	14
Dizziness	2/15 (13.3%)	2	5/32 (15.6%)	5
Dysgeusia	2/15 (13.3%)	2	2/32 (6.3%)	2
Paresthesia	1/15 (6.7%)	2	2/32 (6.3%)	2
Headache	1/15 (6.7%)	2	1/32 (3.1%)	1
Somnolence	1/15 (6.7%)	1	0/32 (0%)	0
Psychiatric disorders
Libido decreased	1/15 (6.7%)	1	0/32 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/15 (0%)	0	4/32 (12.5%)	4
Epistaxis	0/15 (0%)	0	2/32 (6.3%)	2
Hiccups	0/15 (0%)	0	2/32 (6.3%)	2
Skin and subcutaneous tissue disorders
Alopecia	0/15 (0%)	0	3/32 (9.4%)	3
Dry skin	0/15 (0%)	0	2/32 (6.3%)	2
Erythema	2/15 (13.3%)	2	0/32 (0%)	0
Pruritus	1/15 (6.7%)	1	0/32 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	2/15 (13.3%)	2	2/32 (6.3%)	3
Maculo-papular rash	1/15 (6.7%)	1	0/32 (0%)	0
Erythematous rash	1/15 (6.7%)	1	0/32 (0%)	0
Photosensitivity	1/15 (6.7%)	1	0/32 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The sponsor can review/embargo results communications prior to public release for a period that is >60 days but ≤180 days from date submitted to sponsor, who may require changes to the communication in order to remove specifically identified confidential information (other than study data) and/or delay the proposed publication to enable the sponsor to seek patent protection for inventions. The PI may not publish its results until 18 mos. after the trial has been completed at all sites.