Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-cell Lymphoma and Follicular Lymphoma

Study Overview
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Brief Summary
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First study, at multiple clinical centers, exploring the effects of different combinations of compounds (CC-122, CC-223 ,CC-292 and rituximab) to treat Diffuse Large B Cell Lymphoma (DLBCL) and Follicular Lymphoma

Detailed Description
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Study CC-122-DLBCL-001 is a Phase 1b dose escalation and expansion clinical study of CC 122, CC-223 and CC-292 administered orally as doublets with or without rituximab, in participants with relapsed/refractory DLBCL who have failed standard therapy. In expansion phase, selected combination will be administered to lenalidomide naïve FL participants and lenalidomide exposed FL participants in addition to relapsed/refractory DLBCL participants.

Official Title
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A Phase 1B, Multi-Center, Open-Label Study of Novel Combinations of CC-122, CC-223, CC-292, and Rituximab in Diffuse Large B-Cell Lymphoma and Follicular Lymphoma

Conditions
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Lymphoma, Large B-Cell, Diffuse

Intervention / Treatment
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* Drug: CC-122
* Drug: CC-223
* Drug: Rituximab
* Drug: CC-122
* Drug: CC-292
* Drug: Rituximab
* Drug: CC-223
* Drug: CC-292
* Drug: Rituximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men and women, 18 years or older, with histologically or cytologically-confirmed either: Chemo-refractory DLBCL (including transformed low grade lymphoma) Lenalidomide naïve; relapsed or refractory CD20-positive follicular lymphoma (Grade 1, 2, or 3a) following at least one prior standard systemic treatment regimen including systemic chemo-, immune-; or chemo-immunotherapy and at least one prior line of salvage therapy with no prior exposure to lenalidomide, or double-refractory FL participants with no prior exposure to lenalidomide (FL-1 cohort) Lenalidomide exposed: relapsed or refractory CD20-positive follicular lymphoma (Grade 1, 2, or 3a) previously treated with at least two cycles of lenalidomide-containing regimen (FL-2 cohort), either as a single agent or in combination At least one site of measurable disease Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. Participants must have the following laboratory values: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L or ≥ 1.0 x 109/L (with bone marrow involvement with DLBCL) Hemoglobin (Hgb) ≥ 8 g/dL. Potassium within normal limits Asparate Aminotransferase/Serum Glutamic Oxaloacetic Transaminase (AST/SGOT) and Alanine Aminotransferase/Serum Glutamic-Pyruvic Transaminase (ALT/SGPT) ≤ 2.5 x Upper Limit of Normal (ULN) or ≤ 5.0 X ULN if liver tumor is present. Serum bilirubin ≤ 1.5 x ULN. Estimated serum creatinine clearance of ≥ 50 mL/min Participants must have the following laboratory values: Absolute Neutrophil Count (ANC) ≥ 1.5 x 109/L without growth factor support for 7 days (14 days if participants received pegfilgrastim). Males enrolled into treatment arms receiving CC-122 must: Agree to abstain from donating sperm while taking IP and for at least 95 days following discontinuation of IP Exclusion Criteria: Symptomatic central nervous system involvement. Known symptomatic acute or chronic pancreatitis. Persistent diarrhea or malabsorption despite medical management. Peripheral neuropathy ≥ grade 2 Impaired cardiac function or clinically significant cardiac diseases Participants with diabetes on active treatment (for participants treated on CC-223 containing arms only) Prior autologous stem cell transplant (ASCT) ≤ 3 months before first dose. Prior allogeneic stem cell transplant with either standard or reduced intensity conditioning. Prior systemic cancer-directed treatments or investigational modalities ≤ 5 half lives or 4 weeks prior to starting study drugs, whichever is shorter. Participants who have undergone major surgery ≤ 2 weeks prior to starting study drugs. Women who are pregnant or breast feeding. Adults of reproductive potential not willing to employ two forms of birth control. Participants with known HIV infection, chronic active hepatitis B or C virus (HBV/HCV) infection. Participants with treatment-related myelodysplastic syndrome. History of concurrent second cancers requiring active, ongoing systemic treatment. Prior treatment with a dual mTORC1/mTORC2 inhibitor (CC-223 arms only) or BTK inhibitor (PCI-32765) (CC-292 arms only). [Prior treatment with rapamycin analogues, PI3K or AKT inhibitors, lenalidomide and rituximab are allowed].

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CC-122 + CC-223 +/- rituximab<br>CC-122 administered orally once daily at 2mg or 3 mg in combination with CC-223 administered orally once daily at 20mg or 30 mg with or without Rituximab administered by IV once every 28 days | Drug: CC-122<br>* 2mg or 3 mg administered orally once daily<br>Drug: CC-223<br>* 20mg or 30mg administered orally once daily.<br>Drug: Rituximab<br>* 375 mg/m2 administered intravenously once every 28 days<br>|
| Experimental: CC-122 + CC-292 +/- rituximab<br>CC-122 administered orally once daily at 2mg or 3 mg in combination with CC-292 administered orally twice daily at 500 mg with or without Rituximab administered by IV once every 28 days | Drug: CC-122<br>* 2mg or 3mg administered orally once daily.<br>Drug: CC-292<br>* 500 mg twice a day administered orally.<br>Drug: Rituximab<br>* 375 mg/m2 administered intravenously once every 28 days<br>|
| Experimental: CC-292 + CC-223 +/- rituximab<br>CC-292 administered twice daily at 500 mg in combination with CC-223 administered orally once daily at 20mg or 30 mg with or without Rituximab administered by IV once every 28 days | Drug: CC-223<br>* 20mg or 30mg per day administered orally daily.<br>Drug: CC-292<br>* 500 mg twice a day administered orally.<br>Drug: Rituximab<br>* 375 mg/m2 administered intravenously once every 28 days<br>|
| Experimental: CC-122 + rituximab<br>CC-122 administered orally once daily in combination with Rituximab. | Drug: CC-122<br>* 2mg or 3 mg administered orally once daily<br>Drug: Rituximab<br>* 375 mg/m2 administered intravenously once every 28 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety | To determine safety profiles and dose-limiting toxicities of study drug combinations using NCI CTCAE v4. | From the time of informed consent, throughout dosing period and for 28 days after the last dose of study drug. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Efficacy | Tumor response rates using Cheson Revised Response Criteria for Malignant Lymphoma | Every 2-3 months until proof of tumor progression | 
| Pharmacokinetics - CC-223 and CC-292 interaction | Area under the plasma concentration-time curve | Day 1, Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CC-122, CC-223, CC-292, Rituximab, Lymphoma, Diffuse Large B-Cell Lymphoma, Lenalidomide naïve Follicular Lymphoma, Lenalidomide exposed Follicular Lymphoma