A Phase I/II Study of RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer
Overview
- Phase
- Phase 1
- Intervention
- Tivozanib
- Conditions
- Gastrointestinal Cancer
- Sponsor
- Dana-Farber Cancer Institute
- Enrollment
- 56
- Locations
- 3
- Primary Endpoint
- Everolimus Maximum Tolerated Dose (MTD) [Phase I]
- Status
- Completed
- Last Updated
- 9 years ago
Overview
Brief Summary
Research has shown that anti-angiogenic agents can be effective therapies to treat cancer. Anti-angiogenic agents target the blood vessels required for tumors to grow. Vascular endothelial growth factor (VEGF) is one of the cell pathways used for this blood vessel growth. When the investigators interfere with the VEGF pathway, the investigators inhibit this blood vessel growth which is required by tumors. One of the study drugs being used, tivozanib (AV-951), selectively interferes with the VEGF pathway. The second study drug being used, everolimus (RAD001) interferes with the mTOR pathway. The mTOR pathway is another pathway involved in blood vessel and tumor cell growth. By combining these two drugs the investigators hope to slow or reverse tumor cell growth in patients whose tumors have become resistant to other therapies for their disease.
Detailed Description
Primary Objective Phase I * To determine the safety, tolerability, and maximally tolerated dose (MTD) of everolimus and tivozanib administered in combination to patients with advanced gastrointestinal tumors. Phase II * At the MTD, to assess progression-free survival associated with everolimus and tivozanib in patients with refractory, metastatic colorectal cancer. Secondary Objectives Phase II * To assess tumor response rate. * To assess overall survival.
Investigators
Brian Wolpin, MD, MPH
Principal Investigator
Dana-Farber Cancer Institute
Eligibility Criteria
Inclusion Criteria
- •18 years of age or older
- •Histologic confirmation of a gastrointestinal malignancy, limited to cancer of the esophagus, stomach, small bowel, liver, biliary tract, gallbladder, pancreas, large bowel, appendix, rectum and anus.
- •Locally advanced or metastatic disease
- •Disease that: a) has recurred or progressed following standard therapy, b) for which no standard therapy currently exists, or c) for which the subject is not a candidate for or unwilling to undergo standard therapy. There is no limit to the number of prior regimens received by the patient.
- •ECOG Performance Status of 0, 1 or 2
- •Life expectancy of at least 12 weeks
- •Adequate organ function as outlined in the protocol
- •At least 4 weeks is required from : a) previous regimen of chemotherapy, b) immunotherapy or biological therapy, c) other investigational agents, and d) radiotherapy.
- •At least 4 weeks is required from treatment of bevacizumab
- •At least 4 weeks is required from prior systemic hormonal therapy or treatment with strong CYP3A4 inducers or inhibitors
Exclusion Criteria
- •Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is allowed).
- •Clinically apparent CNS metastases or carcinomatous meningitis
- •Clinically significant cardiovascular disease
- •Major surgery within 4 weeks of the start of study treatment or patients who have not recovered from the side effects of any major surgery.
- •Active bleeding diathesis or history of Grade 2 or greater clinically significant bleeding within 3 months of enrollment
- •Active infection requiring antibiotics
- •Participants with a known positive history of chronic Hepatitis B viral infection or known positive HBV-DNA test are excluded.
- •History of interstitial pneumonitis or severely impaired lung function defined as 88% or less O2 saturation at rest in room air
- •Immunocompromise or chronic use of immunosuppressant medications
- •Uncontrolled serious medical or psychiatric illness
Arms & Interventions
Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg
Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Intervention: Tivozanib
Phase II: Everolimus 10 mg + Tivozanib 1 mg
Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Intervention: Everolimus
Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg
Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Intervention: Everolimus
Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg
Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Intervention: Tivozanib
Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg
Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Intervention: Everolimus
Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg
Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Intervention: Tivozanib
Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg
Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Intervention: Everolimus
Phase II: Everolimus 10 mg + Tivozanib 1 mg
Patients received oral everolimus daily continuously and oral tivozanib daily for 3 of a 4 weeks cycle. Patients are treated until disease progression, unacceptable toxicity or withdrawal of consent.
Intervention: Tivozanib
Outcomes
Primary Outcomes
Everolimus Maximum Tolerated Dose (MTD) [Phase I]
Time Frame: Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment.
The everolimus MTD in combination with tivozanib is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.
Tivozanib Maximum Tolerated Dose (MTD) [Phase I]
Time Frame: Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment.
The tivozanib MTD in combination with everolimus is determined by the number of patients who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached.
Dose Limiting Toxicity (DLT) [Phase I]
Time Frame: Patients were assessed continuously for toxicity while on study. The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment.
A DLT was defined as a treatment-related (attribution possible, probable, definite) adverse event that meets any of the following criteria: Grade 3 (G3) or higher non-hematologic toxicity (excluding, nausea, vomiting, diarrhea, alopecia, hypertension, hypercholesterolemia, or hypertriglyceridemia); G3 diarrhea, nausea or vomiting lasting \> 48 hours or leading to hospitalization, despite aggressive anti-diarrheal or anti-emetic medications; G4 diarrhea, despite aggressive anti-diarrheal medications; G4 vomiting, despite aggressive anti-emetic medications; G3 hypertension, for which blood pressure cannot be reduced to \<150/100 with anti-hypertensive therapies; G4 hypertension or severe hypertension, as defined by systolic blood pressure \>180 mmHg or diastolic blood pressure \> 110 mmHg; G4 hypercholesterolemia or hypertriglyceridemia lasting \> 7 days, despite appropriate use of anti-hyperlipidemic medications; G4 hematologic toxicity lasting for \>5 days, including leukopenia, neutropen
Progression-Free Survival (PFS) [Phase II]
Time Frame: Disease was assessed radiographically to document clinical progression every 2 cycles on treatment. Participants were followed for up to 16 months since study entry.
PFS based on the Kaplan-Meier method is defined as the time from study entry to the earliest documentation of disease progression (PD) or death. Participants alive without evidence of PD were censored at the earliest date of last disease assessment. Per RECIST 1.0 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
Secondary Outcomes
- Disease Control Rate (DCR) [Phase II](Disease was assessed every 2 cycles on treatment. Median treatment duration on this study cohort was 2 months (range 1-16).)
- Overall Survival (OS) [Phase II](Long-term follow-up for survival was not specified per protocol. Participants were followed for up to 20 months on this study.)