Safety and Efficacy of AEB071 and EVEROLIMUS in Patients With CD79-mutant or ABC Subtype Diffuse Large B-Cell Lymphoma

Study Overview
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Brief Summary
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Study of the safety and efficacy of AEB071 and EVEROLIMUS in patients with CD79-mutant or ABC subtype Diffuse Large B-Cell Lymphoma. The trial did not progress into Phase II due to the suboptimal tolerability of the combination treatment of sotrastaurin and everolimus in the Phase Ib part of the study. There were no serious safety concerns associated with this combination.

Detailed Description
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This is a Phase Ib dose escalation and Phase II study in patients with DLBCL harboring mutations in CD79A/B or of the ABC subtype. Pre-screening for mutations in CD79A/B or the ABC subtype will be required, as it is anticipated that both patient groups may receive clinical benefit from the combination of AEB071 and EVEROLIMUS.

Official Title
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An Open-Label, Single-arm, Phase Ib/II Study of AEB071 (a Protein Kinase C Inhibitor) and Everolimus (mTOR Inhibitor) in Patients With CD79-mutant or ABC Subtype Diffuse Large B-Cell Lymphoma

Conditions
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CD79 Mutant or ABC-subtype Diffuse Large B-Cell Lymphoma

Intervention / Treatment
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* Drug: AEB071
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female ≥18 years of age. Diffuse DLBCL with activating mutations in CD79 (A or B subunits) or ABC-subtype DLBCL (CD79 wildtype or CD79 mutant). DLBCL that arose from transformed indolent lymphoma is allowed. Prior treatment and relapse following chemotherapy and autologous bone marrow or stem cell transplant. Patients who are not transplant eligible or who did not respond to chemotherapy may be considered for the study following a single regimen of chemotherapy such as R-CHOP or R-EPOCH. There is no limit to number of prior therapies allowed. May be treated with localized radiation as long as measurable or evaluable disease remains at untreated sites. WHO performance status of ≤ 2. A representative FFPE tumor sample must be available for molecular testing along with a corresponding pathology report. An archival tumor sample may be submitted. However, if not available, a new tumor biopsy obtained for the purpose of this study must be submitted instead. Exclusion Criteria: Treatment with strong inducers or inhibitors (medications and herbal supplements) of cytochrome P450 3A4/5 (CYP3A4/5), or CYP3A4/5 substrates with a QT prolongation risk that cannot be discontinued at least 7 half-lives (or if the half-life is unknown,14 days) prior to study drug treatment. Impaired cardiac function or clinically significant cardiac diseases. Impairment of GI function or GI disease that could interfere with the absorption of AEB071 or everolimus. Severe systemic infections, current or within the two weeks prior to initiation of AEB071. Kown history of HIV. Poorly controlled diabetes as defined by a fasting serum glucose > 2.0 x ULN. Evidence of current CNS involvement. Significant symptomatic deterioration of lung function.

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: AEB071 and EVEROLIMUS<br>AEB071 and EVEROLIMUS will be taken together in this open-label non-randomized study | Drug: AEB071<br>* a Protein Kinase C Inhibitor<br>* Other names: sotrastuarin;Drug: Everolimus<br>* mTOR inhibitor<br>* Other names: RAD001;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase Ib- Incidence of dose limiting toxicities (DLT) during the first cycle | Estimate the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the AEB071and EVEROLIMUS combination therapy in patients with DLBCL. | 12 months | 
| Phase II- Overall response rate (ORR) = complete response (CR) + partial response (PR) according to the non-Hodgkin's Lymphoma International Working Group criteria | Assess the preliminary evidence for anti-tumor activity at RP2D for AEB071 and EVEROLIMUS in patients with a CD79 mutation and those wild-type for the mutation but of the ABC subtype | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Occurrence of Adverse Events (AEs), Serious Adverse Events (SAEs) assessments of clinical laboratory values and vital sign measurements. | Safety and tolerability of AEB071 and EVEROLIMUS, including acute and chronic toxicities | 24 months | 
| Best Overall Response (BOR) | Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS | 24 months | 
| Duration of Response (DOR) | Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS | 24 months | 
| Progression Free survival (PFS) | Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS | 24 months | 
| Overall Survival (OS) | Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS | 24 months | 
| Concentration-time profiles of Pharmacokinetics (PK) parameters - Phase Ib | To characterize the PK profiles of AEB071 and EVEROLIMUS | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diffuse Large B-Cell Lymphoma, DBCL, AEB071, Everolimus