Everolimus and OSI-906 for Patients With Refractory Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose (MTD) of the combination of OSI-906 and everolimus for the treatment of patients with refractory metastatic colorectal cancer.

Official Title
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A Phase I Study of Everolimus (mTOR Inhibitor) and OSI-906 (Dual IGFR and IR Tyrosine Kinase Inhibitor) for the Treatment of Patients With Refractory Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: OSI-906
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic cancer of the colon or rectum that has progressed on or for which the patient is intolerant to or not a candidate for: fluoropyrimidines, oxaliplatin, irinotecan, bevacizumab, and cetuximab or panitumumab. Testing for Kras mutation performed;Patients with mutated or wild type Kras are eligible. ECOG PS of 0-1 Life expectancy of ≥ 3 months Adequate hematological function with ANC 1500, Platelets of 100,000, and hemoglobin of 9.0 AST, ALT and Alk. Phos. ≤2.5 x ULN or ≤5 x ULN if known hepatic metastases and a total bilirubin ≤1.5 ULN Serum creatinine of ≤1.5 x ULN Fasting blood glucose <150 mg/dL Measurable disease according to RECIST 1.1 Able to swallow whole pills INR ≤1.5 - Anticoagulation is allowed with LMW heparin Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤2.5 x ULN;If these thresholds are exceeded, the patient can be included after initiation of lipid lowering medication Exclusion Criteria: Patients who have received any cancer therapies <4 weeks or 5 half lives (whichever is shorter) of initiating study therapy Treatment with any investigational drug ≤ 4 weeks, or 5 half-lives of the drug, whichever is shorter Patients who require coumadin for anticoagulation Patients who have had major surgery or significant traumatic injury ≤4 weeks of the of study treatment Minor surgery (with the exception of port placement) must be completed ≤ 7days prior to study therapy Previous treatment with an IGFR inhibitor or MTOR Inhibitor Chronic, systemic treatment with corticosteroids or another immunosuppressive agent Patients with QTc interval >450ms Patients who require drugs that can prolong QTc. Patients with congenital long QT syndrome, history of ventricular tachycardia, or ventricular fibrillation, or Torsades de Pointes with bradycardia. Immunization with attenuated live vaccines within 1 week of beginning study therapy or during study period;Close contact to anyone that has received live virus vaccine should be avoided Meningeal or brain metastasis Other malignancies < 3 years, with the exception of adequately treated basal or squamous cell carcinomas of the skin, or carcinoma in situ of the cervix Patients with known HIV Patients with positive testing for hepatitis B or C Patients with risk factors for hepatitis must be tested for hepatitis viral loadHepatitis risk factors include the following: Lived in Asia, Africa, Central and South America, Eastern Europe, Spain, Portugal, and Greece Any blood transfusions before 1990 Any IV drug use Any dialysis Household contact with a Hep B infected patient Mother had Hep B High-risk sexual activity Body piercing/tattoos History suggestive of hepatitis B Any severe or uncontrolled conditions that could affect their study participation such as:Severely impaired lung function;DCLO ≤ 50% of normal predicted value;O² Sat <88% at rest on room air Congestive Heart Failure of NYHA Class III or IV Unstable angina, symptomatic CHF, MI ≤ 6 months, serious uncontrolled cardiac arrhythmia or any other clinically significant heart disease CVA, TIA, angioplasty, or cardiac stenting <12 months Ventricular arrhythmia requiring medication Known history of diabetes and/or patients who require ongoing use of insulin or oral anti-hyperglycemic therapy Known liver disease Impairment of GI function or gastrointestinal disease that in may significantly alter the absorption of study drugs Concurrent treatment with drugs that are strong CYP3A4 inducers or moderate/strong CYP3A4 inhibitors Concurrent treatment with drugs that are strong CYP1A2 inhibitors or inducers Women who are pregnant or breastfeeding. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements

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: Dose Level 1<br>combination of OSI-906 and everolimus OSI-906: 50 mg Twice a Day, cycle-28 days Everolimus: 5mg Daily, cycle-28 days | Drug: OSI-906<br>* Dose Level 1: 50 mg Twice a Day, cycle-28 days Dose Level 2: 100 mg Twice a Day, cycle-28 days Dose Level 2a: 100 mg Twice a Day, cycle-28 days<br>Drug: Everolimus<br>* Dose Level 1: 5mg Daily, cycle-28 days Dose Level 2: 10mg Daily, cycle-28 days Dose Level 2a: 5mg Daily, cycle-28 days<br>|
| Experimental: Dose Level 2<br>combination of OSI-906 and everolimus OSI-906: 100 mg Twice a Day, cycle-28 days Everolimus: 10mg Daily, cycle-28 days | Drug: OSI-906<br>* Dose Level 1: 50 mg Twice a Day, cycle-28 days Dose Level 2: 100 mg Twice a Day, cycle-28 days Dose Level 2a: 100 mg Twice a Day, cycle-28 days<br>Drug: Everolimus<br>* Dose Level 1: 5mg Daily, cycle-28 days Dose Level 2: 10mg Daily, cycle-28 days Dose Level 2a: 5mg Daily, cycle-28 days<br>|
| Experimental: Dose Level 2a<br>combination of OSI-906 and everolimus OSI-906: 100 mg Twice a Day, cycle-28 days Everolimus: 5mg Daily, cycle-28 days | Drug: OSI-906<br>* Dose Level 1: 50 mg Twice a Day, cycle-28 days Dose Level 2: 100 mg Twice a Day, cycle-28 days Dose Level 2a: 100 mg Twice a Day, cycle-28 days<br>Drug: Everolimus<br>* Dose Level 1: 5mg Daily, cycle-28 days Dose Level 2: 10mg Daily, cycle-28 days Dose Level 2a: 5mg Daily, cycle-28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To Determine the Maximum Tolerated Dose (MTD) of the Combination of OSI-906 and Everolimus for the Treatment of Patients With Refractory Metastatic Colorectal Cancer. | The MTD of the drug combination will be determined as the highest dose at which ≤1 of 6 subjects experiences a Grade 3 or Grade 4 DLT according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0 | 18 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival (PFS) | Progression-free survival (PFS) is defined as the time between Day 1 Cycle 1 and date of first documented recurrence or death. Patients who do not exhibit progression while on trial will be censored at their last known assessment. Progression is defined per RECIST criteria as either 1) at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest (nadir) sum since the treatment started, or the appearance of one or more new lesions. Requires not only 20% increase, but absolute increase of a minimum of 5 mm over sum. OR 2) Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. | 18 Months | 
| Overall Survival (OS) | Overall survival (OS) is defined as the time between Day 1 Cycle 1 to the date of death from any cause. Those remaining alive will be censored at their last known assessment or follow-up. | 18 months | 
| Response Rate | Response rate (RR) will be estimated as the proportion of patients exhibiting complete response or partial response out of all evaluable cases. Complete Response is defined per RECIST as disappearance of all target/non-target lesions and normalization of tumor markers. Partial Response is defined per RECIST as At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD. | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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refractory metastatic colorectal cancer