RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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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
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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.

Official Title
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A Phase I/II Study of RAD001 and AV-951 in Patients With Refractory, Metastatic Colorectal Cancer

Conditions
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Gastrointestinal Cancer

Intervention / Treatment
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* Drug: Everolimus
* Drug: Tivozanib


Participation Criteria
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Eligibility Criteria
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For the Phase I component: 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 If female and of child bearing potential, documentation of negative pregnancy test prior to enrollment. 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 Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures Significant proteinuria, defined as urine dipstick protein of 3+ or greater Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past 3 years or any currently active malignancy Elevated fasting levels of the following: serum cholesterol, serum triglycerides, and serum glucose Patients who are pregnant or lactating Malabsorption, uncontrolled vomiting or diarrhea, or any disease significantly affecting gastrointestinal function that could interfere with absorption of study drugs Inability to swallow pills For the phase II component, only patients with metastatic colorectal cancer will be enrolled. For the Phase II component: Inclusion Criteria (Phase II): 18 years of age or older Histologic confirmation of colorectal cancer Stage IV disease At least one site of disease measurable by RECIST criteria Receipt of or intolerance to a fluoropyrimidine (fluorouracil or capecitabine), irinotecan, oxaliplatin, bevacizumab, and a monoclonal antibody to epidermal growth factor receptor (cetuximab or panitumumab). If a patient's tumor was K-RAS mutation positive, then previous treatment with cetuximab or panitumumab is not required. Eastern Cooperative Oncology Group (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 3 weeks is required from: (a) previous regimen of chemotherapy, (b)immunotherapy or biological therapy, (c) other investigational agents, and (d) radiotherapy. Of note, concomitant radiotherapy is NOT allowed, while a patient is on protocol. At least 3 weeks is required from prior treatment with bevacizumab At least 3 weeks is required since prior systemic hormonal therapy or treatment with strong CYP3A4 inducers or inhibitors. Negative pregnancy test for women of child bearing potential Exclusion Criteria (Phase II): Prior therapy with inhibitors of mTOR or VEGFR (prior treatment with bevacizumab is allowed) Clinically apparent CNS metastases or carcinomatous meningitis, as determined by physical examination and imaging studies Clinically significant cardiovascular disease, defined as follows: (A)Symptomatic congestive heart failure, (B)Symptomatic coronary artery disease or myocardial infarction within 3 months of enrollment, (C)Cardiac arrhythmias not controlled with medication, (D)Deep venous thrombosis or pulmonary embolus within the last 6 months, (E) Cerebrovascular accident within the last 12 months, (F)Poorly controlled hypertension, defined as systolic pressure > 150 mmHg or diastolic pressure > 100 mmHg documented on 2 consecutive measurements taken at least 24 hours apart, (G)Symptomatic peripheral vascular disease, defined as claudication on walking ≤ 1 block 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. Major surgery defined as those surgeries that require general anesthesia Active bleeding diathesis or history of grade 2 or higher clinically significant bleeding (hemoptysis, hematemesis, hematochezia, or melena) 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 less than or equal to 88% O2 saturation at rest in room air. Immunocompromise or chronic use of immunosuppressant medications (prednisone ≤ 10 mg daily or the equivalent of a comparable steroid is allowed, if deemed necessary by a study investigator) Uncontrolled serious medical or psychiatric illness Subjects with non-healing wounds, active peptic ulcers, or unhealed bone fractures Significant proteinuria, defined as urine dipstick protein 3+ or greater Concurrent malignancy (other than non-melanoma skin cancer) diagnosed within the past 3 years or any currently active malignancy. Elevated fasting levels of the following: serum cholesterol, serum triglycerides, and serum glucose. Patients who are pregnant or lactating Malabsorption, uncontrolled vomiting or diarrhea, or any disease significantly affecting gastrointestinal function that could interfere with absorption of study drugs Inability to swallow pills

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Cohort 1: Everolimus 5 mg + Tivozanib 1 mg<br>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. | Drug: Everolimus<br> <br> * Other names: Afinitor;Drug: Tivozanib<br> <br> * Other names: AV-951;|
| Experimental: Phase I Cohort 2: Everolimus 10 mg + Tivozanib 1 mg<br>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. | Drug: Everolimus<br> <br> * Other names: Afinitor;Drug: Tivozanib<br> <br> * Other names: AV-951;|
| Experimental: Phase I Cohort 3: Everolimus 10 mg + Tivozanib 1.5 mg<br>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. | Drug: Everolimus<br> <br> * Other names: Afinitor;Drug: Tivozanib<br> <br> * Other names: AV-951;|
| Experimental: Phase II: Everolimus 10 mg + Tivozanib 1 mg<br>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. | Drug: Everolimus<br> <br> * Other names: Afinitor;Drug: Tivozanib<br> <br> * Other names: AV-951;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Everolimus Maximum Tolerated Dose (MTD) [Phase I] | 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. | Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment. | 
| Tivozanib Maximum Tolerated Dose (MTD) [Phase I] | 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. | Patients were assessed continuously for toxicity while on study. The observation period for MTD evaluation was the first 28 days (cycle 1) of treatment. | 
| Dose Limiting Toxicity (DLT) [Phase I] | 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 | Patients were assessed continuously for toxicity while on study. The observation period for DLT evaluation was the first 28 days (cycle 1) of treatment. | 
| Progression-Free Survival (PFS) [Phase II] | 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. | Disease was assessed radiographically to document clinical progression every 2 cycles on treatment. Participants were followed for up to 16 months since study entry. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Control Rate (DCR) [Phase II] | Disease Control Rate is defined as the percentage of patients who achieve confirmed stable disease (SD) or better on treatment based on RECIST 1.0 criteria. Per RECIST 1.0 for target lesions, complete response (CR) is disappearance of all target lesions and partial response (PR) is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. Progressive disease (PD) is at least a 20% increase in sum LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started. SD is neither PR nor PD. For non-target lesions, PD is the appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | 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] | OS based on the Kaplan-Meier method is defined as the time from study entry to death or date last known alive. | Long-term follow-up for survival was not specified per protocol. Participants were followed for up to 20 months on this study. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal Cancer