Study to Assess Safety and Tolerability of Oral CC-115 for Patients With Advanced Solid Tumors, and Hematologic Malignancies.

Study Overview
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Brief Summary
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The main purpose of this first human study with CC-115 is to assess the safety and action of a new class of experimental drug (dual DNA-PK and TOR kinase inhibitors) in patients with advanced tumors unresponsive to standard therapies and to determine the appropriate dose and tumor types for later-stage clinical trials. The bioavailability of tablet and capsule formulations under fasting and fed conditions will also be evaluated in some patients.

Detailed Description
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Latest amendment clarifies that Chronic Lymophocytic Leukemia (CLL) includes T-cell Prolymphocytic Leukemia (T-PLL). Prior treatment with some drugs targeting mTOR, P13K and related pathways is now permitted.

Official Title
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A Phase 1a/1b, Multicenter, Open Label, Dosefinding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the Dual Dna-pk and Tor Kinase Inhibitor, Cc-115, Administered Orally to Subjects With Advanced Solid Tumors and Hematologic Malignancies

Conditions
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Chronic Lymphocytic Leukemia, Glioblastoma Multiforme, Squamous Cell Carcinoma of Head and Neck, Prostate Cancer, Ewing's Osteosarcoma, Neoplasm Metastasis

Intervention / Treatment
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* Drug: CC-115


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically-confirmed advanced solid tumor, chronic lymphocytic leukemia, small lymphocytic lymphoma, T-cell prolymphocytic leukemia, Non-Hodgkin Lymphoma or multiple myeloma Progressed or not tolerated standard therapy, and no further standard therapy is available Archival and screening tumor biopsy Eastern Cooperative Oncology Group Performance Status: 0 or 1 Adequate organ function Exclusion Criteria: Prior cancer-directed modalities or investigational drugs within 4 wks or 5 half lives, whichever is shorter Symptomatic brain metastases (prior treatment and stable metastases are allowed) Acute or chronic renal disease or pancreatitis Diarrhea ≥ Grade 2, impaired gastrointestinal absorption Impaired cardiac function History of diabetes requiring treatment, glucose >126 mg/dL, Glycated hemoglobin (HbA1c) ≥6.5% Peripheral neuropathy ≥ Grade 2 Known Human Immunodeficiency Virus (HIV) infection, chronic hepatitis B or C (unless associated with hepatocellular cancer) Pregnant, inadequate contraception, breast feeding Most concurrent second malignancies Part B only: Prior treatment with agents targeting both mammalian target of rapamycin (mTOR) complexes (dual mammalian target of rapamycin complex 1/2 inhibitors) and/or PI3K/AKT pathways. However, prior treatment with isolated target of rapamycin complex 1 (TORC1) inhibitors (eg., rapalogs) is allowed in both parts of this study.

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-115<br> | Drug: CC-115<br>* Part A (actively recruiting): Dose level starts with 0.5mg daily by mouth in cycles of 28 days. Level increases for different patient cohorts in 100% or 50% increments until optimal dose schedule is established for further study. Treatment continues for as long as patient benefits (i.e., until disease progression or unacceptable toxicity). Part B: Optimal dose schedule is administered in 28-day cycles until disease progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose-Limiting Toxicity |  | Continuously for 28 days after starting treatment | 
| Non-Tolerated Dose |  | Continuously for 28 days after starting treatment | 
| Maximum Tolerated Dose |  | Continuously for 28 days after starting treatment | 
| Maximum Observed Concentration in Plasma of CC-115 |  | Days 1, 2, 15, 16 of treatment | 
| Area Under the Concentration-Time Curve for CC-115 |  | Days 1, 2, 15 and 16 of treatment | 
| Time to Maximum Concentration of CC-115 |  | Days 1, 2, 15, and 16 of treatment | 
| Terminal Half-Life for CC-115 |  | Days 1, 2, 15, and 16 of treatment | 
| Apparent Total Body Clearance of CC-115 |  | Days 1, 2, 15 and 16 of treatment | 
| Apparent Volume of Distribution of CC-115 |  | Days 1, 2, 15, and 16 of treatment | 
| Accumulation Index of CC-115 |  | Days 1, 2, 15 and 16 of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics | Phosphorylation inhibition determined by changes in the levels of multiple biomarkers including S6 and, 4EBP (for mTORC1), AKT (for mTORC2) and other appropriate biomarkers in circulating granulocytes and tumor tissue (when available). | Screening (within 28 days prior to first dose of study drug) and Days 1, 2, 8, 15, 22, 28, 155, and end of treatment | 
| Anti-Tumor Efficacy | Tumor response rates using appropriate objective criteria for various malignancies | Every 2-3 months until proof of tumor progression | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Neoplasm, Malignancy, Carcinoma, Lymphoma, Leukemia, Multiple myeloma, mTOR kinase inhibitor, Castration-resistant prostate cancer, Hormone-resistant prostate cancer, Diffuse Large B-cell lymphoma