Safety and Efficacy of AEB071 and EVEROLIMUS in Patients With CD79-mutant or ABC Subtype Diffuse Large B-Cell Lymphoma (COEB071X2103)

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

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.

Study Overview

• Status: Completed
• Conditions: CD79 Mutant or ABC-subtype Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: AEB071; Drug: Everolimus

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Rouen Cedex 1, France, 76038
    • Novartis Investigative Site
• Germany
  • Mainz, Germany, 55131
    • Novartis Investigative Site
  • Muenchen, Germany, 81377
    • Novartis Investigative Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Novartis Investigative Site
  • New Territories, Hong Kong
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
    • Milano, MI, Italy, 20141
      • Novartis Investigative Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 06351
      • Novartis Investigative Site
    • Seoul, Korea, Korea, Republic of, 03080
      • Novartis Investigative Site
• Netherlands
  • Rotterdam, Netherlands, 3075 EA
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3015 CE
    • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10002
    • Novartis Investigative Site
• United States
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Dept of Oncology.
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center Onc. Dept.
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute Dept of Onc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: AEB071 and EVEROLIMUS; AEB071 and EVEROLIMUS will be taken together in this open-label non-randomized study	Drug: AEB071; a Protein Kinase C Inhibitor; Other Names: sotrastuarin; Drug: Everolimus; mTOR inhibitor; Other Names: RAD001

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for COEB071X2103 from the Novartis Clinical Trials website

Study record dates

Study Major Dates

• Study Start (Actual): December 5, 2013
• Primary Completion (Actual): June 1, 2016
• Study Completion (Actual): June 1, 2016

Study Registration Dates

• First Submitted: May 13, 2013
• First Submitted That Met QC Criteria: May 13, 2013
• First Posted (Estimate): May 15, 2013

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: May 1, 2017

More Information

Terms related to this study

• Keywords: Diffuse Large B-Cell Lymphoma, DBCL, AEB071, Everolimus
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Everolimus
• Other Study ID Numbers: COEB071X2103

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No