Gastroesophageal Cancer, Malignant Solid Tumour
Conditions
Keywords
Advanced solid tumors, First-Line Metastatic GE cancer, c-Met Inhibitor, Tivantinib, FOLFOX
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.
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.
Interventions
DRUGTivantinib
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.
DRUGFOLFOX
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.
Sponsors
Daiichi Sankyo
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
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 details
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.
Participants by arm
| Arm | Count |
|---|---|
| Tivantinib+FOLFOX Dose Escalation 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. | 15 |
| Tivantinib+FOLFOX Dose Expansion 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. | 34 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 2 |
Baseline characteristics
| Characteristic | Tivantinib+FOLFOX Dose Escalation | Tivantinib+FOLFOX Dose Expansion | Total |
|---|---|---|---|
| Age, Continuous | 62 years | 65 years | 63.5 years |
| Karnofsky Performance Score 0 | 0 participants | 0 participants | 0 participants |
| Karnofsky Performance Score 10 | 0 participants | 0 participants | 0 participants |
| Karnofsky Performance Score 100 | 2 participants | 7 participants | 9 participants |
| Karnofsky Performance Score 20 | 0 participants | 0 participants | 0 participants |
| Karnofsky Performance Score 30 | 0 participants | 0 participants | 0 participants |
| Karnofsky Performance Score 40 | 0 participants | 0 participants | 0 participants |
| Karnofsky Performance Score 50 | 0 participants | 0 participants | 0 participants |
| Karnofsky Performance Score 60 | 0 participants | 0 participants | 0 participants |
| Karnofsky Performance Score 70 | 0 participants | 5 participants | 5 participants |
| Karnofsky Performance Score 80 | 10 participants | 3 participants | 13 participants |
| Karnofsky Performance Score 90 | 3 participants | 18 participants | 21 participants |
| Karnofsky Performance Score Unknown | 0 participants | 1 participants | 1 participants |
| Number of Participants with Prior Radiation Therapy Received Prior Radiation: No | 10 participants | 23 participants | 33 participants |
| Number of Participants with Prior Radiation Therapy Received Prior Radiation: Yes | 5 participants | 11 participants | 16 participants |
| Region of Enrollment United States | 15 participants | 34 participants | 49 participants |
| Sex: Female, Male Female | 5 Participants | 8 Participants | 13 Participants |
| Sex: Female, Male Male | 10 Participants | 26 Participants | 36 Participants |
| Tumor Type Cholangiocarcinoma | 1 participants | 0 participants | 1 participants |
| Tumor Type Colorectal | 7 participants | 0 participants | 7 participants |
| Tumor Type Esophageal | 4 participants | 14 participants | 18 participants |
| Tumor Type Gastric | 0 participants | 11 participants | 11 participants |
| Tumor Type GE Junction | 1 participants | 9 participants | 10 participants |
| Tumor Type Pancreatic | 1 participants | 0 participants | 1 participants |
| Tumor Type Unknown primary | 1 participants | 0 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 14 / 15 | 31 / 32 |
| serious Total, serious adverse events | 6 / 15 | 17 / 32 |
Outcome results
Primary
The Incidence of Dose Limiting Toxicities (DLT) in Phase I Dose Escalation
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)
Population: 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 | Measure | Value (NUMBER) |
|---|---|---|
| Tivantinib 120 mg (PO BID) + FOLFOX | The Incidence of Dose Limiting Toxicities (DLT) in Phase I Dose Escalation | 0 participants |
| Tivantinib 240 mg (PO BID) + FOLFOX | The Incidence of Dose Limiting Toxicities (DLT) in Phase I Dose Escalation | 0 participants |
| Tivantinib 360 mg (PO BID) + FOLFOX | The Incidence of Dose Limiting Toxicities (DLT) in Phase I Dose Escalation | 1 participants |
Secondary
Overall Survival in Phase II Dose Expansion
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.
Population: The analysis was performed on an Intent-to-Treat basis (N=34) for all participants in the Phase II portion of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivantinib 120 mg (PO BID) + FOLFOX | Overall Survival in Phase II Dose Expansion | 9.6 months |
Secondary
Progression Free Survival in Phase II Dose Expansion
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.
Population: 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 | Measure | Value (MEDIAN) |
|---|---|---|
| Tivantinib 120 mg (PO BID) + FOLFOX | Progression Free Survival in Phase II Dose Expansion | 6.1 months |
Secondary
Time to Progression in Phase II Dose Expansion
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.
Population: The analysis was performed on all participants (N = 34) in the Phase II portion of the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Tivantinib 120 mg (PO BID) + FOLFOX | Time to Progression in Phase II Dose Expansion | 7.0 months |