Clinical Trial 17682

Cancer Type: Malignant Hematology
Interventions:CC-122; CC-223; CC-292; Rituxan (rituximab); rituximab

Study Type: Treatment
Phase of Study: Phase I
Investigators:

  • Julio Chavez

Overview

Study Title

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

Summary

The primary purpose of this study is to evaluate the safety and tolerability of combinations of three new compounds (CC-122, CC-223, and CC-292) being developed to treat DLBCL and to identify the highest doses tolerated by participants to help guide the selection of doses to be studied as the compounds are further developed. Certain dose levels will also include the drug rituximab, which is currently part of the standard therapy for DLCBL. The secondary purpose is to look for early signals that the treatment is working (for example, tumor shrinkage) and compare drug levels in the body when CC-223 and CC-292 are given together.

Objective

The primary objectives of the study are to: - Determine the safety and tolerability of CC-122, CC-223 and CC-292 when administered orally as doublets, and as triplets in combination with rituximab. - Define the non-tolerated dose (NTD), the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of each combination. The secondary objectives of the study are to: - Provide information on the preliminary efficacy of each drug combination. - Characterize the steady-state pharmacokinetics (PK) of CC-223 and CC-292 following combination oral administration. The exploratory objectives of the study are to: - Characterize the steady-state pharmacokinetics of the M1 metabolite of CC-223 after oral administration of CC-223 in combination with CC-292. - Evaluate blood pharmacodynamic (PD) markers of CC-122 including modulation of cereblon (CRBN) and its substrates in B and T cells. - Evaluate blood PD markers of CC-223 including mammalian target of rapamycin (mTOR) signaling pathway biomarkers (p4E-BP1 and pAKT). - Evaluate blood PD markers of CC-292 including B-cell receptor signaling pathway biomarkers (pBTK and pERK). - Evaluate baseline tumor biomarkers including genetic abnormalities (eg, Myc, Bcl-2, mTOR pathway and other relevant genes), RNA expression profiling (GCB vs non-GCB and other genes of interest), protein expression (eg, CRBN, substrates of CRBN, CD10, BCL-6, MUM1, BCL-2, MYC) and other biomarkers of interest ( eg epigenetic markers). - Explore the effect of study treatments on tumor biomarkers, including CRBN and substrates of CRBN, B-cell receptor and mTOR signaling pathways, RNA expression, apoptosis, and cellular proliferation. - Explore the relationship between systemic exposure of CC-122, CC-223, CC-292 and relevant metabolites and PD biomarkers. - Explore the relationship between PD biomarkers and clinical activity. - Explore [18F]- whole body fluorodeoxyglucose-positron emission tomography (FDG)- PET imaging as a measure of PD and clinical activity.

Inclusion Criteria

  • Biopsy proven Diffuse large B-cell lymphoma (DLBCL) (including transformed low grade lymphoma)
  • Relapsed or refractory to prior standard treatment regimens
  • At least one site of measurable disease
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1
  • Adequate laboratory values
  • Women of childbearing potential and males must agree to follow specific contraceptive and pregnancy test guidelines
  • Additional criteria may also apply

  • Exclusion Criteria

  • Symptomatic central nervous system (CNS) involvement
  • Known symptomatic acute or chronic pancreatitis
  • Persistent diarrhea or malabsorption despite medical management
  • Peripheral neuropathy ≥ NCI CTCAE grade 2
  • Impaired cardiac function or clinically significant cardiac diseases
  • Participants with diabetes on active treatment (for treatment 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
  • 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].
  • 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.
  • Known HIV infection
  • Known chronic active hepatitis B or C virus (HBV/HCV) infection
  • Treatment-related myelodysplastic syndrome (MDS)
  • History of concurrent second cancers requiring active, ongoing systemic treatment
  • Additional criteria may also apply