Study of AEB071 (a Protein Kinase C Inhibitor) in Patients With CD79-mutant Diffuse Large B-Cell Lymphoma

An Open-Label, Single-arm, Phase I Study of AEB071 (a Protein Kinase C Inhibitor) in Patients With CD79-mutant Diffuse Large B-Cell Lymphoma

This study has two phases, a dose escalation phase and a dose expansion phase. For dose escalation, the primary objective is to estimate the maximum tolerated dose of AEB071 in patients with diffuse large b-cell lymphoma. The endpoint for this objective will be occurrence of Dose Limiting Toxicity. For dose expansion, the primary objective is to characterize the safety and tolerability of the maximum tolerated dose or recommended phase 2 dose of AEB071 in patients with diffuse large b-cell lymphoma. The endpoints for this objective will be occurrence of Adverse Events (AEs), Serious Adverse Events (SAEs), assessment of clinical laboratory values, and vital sign measurements.

Study Overview

• Status: Terminated
• Conditions: Diffuse Large B-Cell Lymphoma
• Intervention / Treatment: Drug: AEB071

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 1

Contacts and Locations

Study Locations

• France
  • Creteil, France, 94010
    • Novartis Investigative Site
  • Lille Cedex, France, 59 037
    • Novartis Investigative Site
  • Pierre-Benite Cédex, France, F-69495
    • Novartis Investigative Site
  • Rouen Cedex 1, France, 76038
    • Novartis Investigative Site
• Germany
  • Berlin, Germany, 13353
    • Novartis Investigative Site
  • Muenchen, Germany, 81377
    • Novartis Investigative Site
• Hong Kong
  • Shatin, New Territories, Hong Kong
    • Novartis Investigative Site
• Italy
  • MI
    • Milano, MI, Italy, 20133
      • Novartis Investigative Site
  • TO
    • Torino, TO, Italy, 10126
      • Novartis Investigative Site
• Korea, Republic of
  • Korea
    • Seoul, Korea, Korea, Republic of, 135-710
      • Novartis Investigative Site
• Netherlands
  • Amsterdam, Netherlands, 1066 CX
    • Novartis Investigative Site
  • Groningen, Netherlands, 9713 GZ
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3075 EA
    • Novartis Investigative Site
  • Rotterdam, Netherlands, 3015 CE
    • Novartis Investigative Site
• Spain
  • Barcelona, Spain, 08025
    • Novartis Investigative Site
  • Catalunya
    • Barcelona, Catalunya, Spain, 08003
      • Novartis Investigative Site
• Taiwan
  • Taipei, Taiwan, 10048
    • Novartis Investigative Site
• United Kingdom
  • Manchester, United Kingdom, M20 2BX
    • Novartis Investigative Site
• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope National Medical Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine Div. of Medical Oncology
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Hackensack University Medical Center Hackensack (SC)
  • New York
    • New York, New York, United States, 10021
      • Memorial Sloan Kettering Cancer Center MSK 2
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State Comprehensive Cancer Center/James Cancer Hospital Ohio State
  • Texas
    • Houston, Texas, United States, 77030-4009
      • University of Texas/MD Anderson Cancer Center SC Location

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:

• Diffuse large B-cell lymphoma (DLBCL) with activating mutations in CD79 (A or B subunits). DLBCL that arose from transformed indolent lymphoma is allowed.

• Prior treatment and relapse following anthracycline-based chemotherapy and autologous bone marrow or stem cell transplant. Patients who are not transplant eligible may be considered for the study following a single regimen of chemotherapy such as R-CHOP or R-EPOCH alone. There is no limit to prior therapy allowed.

  • Patients may be treated with localized radiation to as many as two sites of disease, so long as measurable or evaluable disease remains at untreated sites.
  • Patients may be treated with corticosteriods immediately prior to enrollment and during the course of the study treatment as long as steriod treatment is tapered to a toal daily dosage of 10mg or less of prednisone (or it's equivalent) prior to AEB071 administration
• WHO performance status of ≤2

Exclusion Criteria:

• Patients at screening who are treated with strong inducers or inhibitors of cytochrome P450 3A4 (CYP3A4) that can not be discontinued.
• Impaired cardiac function or clinically significant cardiac diseases, including any of the following:
• History or presence of ventricular tachyarrhythmia
• Presence of unstable atrial fibrillation (ventricular response > 100 bpm); Patients with stable atrial fibrillation are eligible, provided they do not meet any of the other cardiac exclusion criteria.
• Angina pectoris or acute myocardial infarction ≤ 3 months prior to starting study drug
• Other clinically significant heart disease (e.g., symptomatic congestive heart failure; uncontrolled arrhythmia or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen)
• Patients with another malignancy that was treated within the last three years with the exceptions of localized basal cell carcinoma and cervical carcinoma.
• Patients with impairment of GI function or GI disease that could interfere with the absorption of AEB071.

• Patients with a known history of Human Immunodeficiency Virus (HIV)

  • HIV testing is not required as part of this study

• Patients with a known history of active hepatitis B or C infection unless they are on antiviral therapy

  • The determination of active hepatitis status should be as per standard of care at each site
  • Hepatitis B and C testing is not required as part of this study

Time since the last prior therapy for treatment of underlying malignancy**:

• Cytotoxic chemotherapy: ≤ than the duration of the most recent cycle of the previous regimen (with a minimum of 2 weeks for all)
• Biologic therapy (e.g., antibodies): ≤ 4 weeks

• ≤ 5 x t1/2 of a small molecule therapeutic, not otherwise defined above

  **Patients must have recovered or stabilized from all toxicities related to their previous treatment except for alopecia

• Patients with any history of significant coagulopathy or a medical condition requiring long term systemic anticoagulation that would interfere with biopsies.
• Patients having undergone major surgery less than 4 weeks prior to enrollment or that have not fully recovered from prior surgery.
• Pregnant or nursing (lactating) women

Other protocol-defined inclusion/exclusion criteria may apply

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	Drug: AEB071

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Frequency of Dose Limiting Toxicity (DLT) during cycle 1 (Dose Escalation phase)	Cycle 1 (28 days)
Number of Pparticipants reporting Serious Adverse Events and Adverse Events (Dose Expansion phase)	Baseline, 28 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate, using NHLIWG criteria	Assess the overall response rate to AEB071	Baseline, 12 months
Number of Participants reporting Serious Adverse Events and Adverse Events		Baseline, 12 months
AEB071 PK parameters including Cmax, tmax, AUCt, Ctrough, CL/F and RA	Evaluate the single and multiple dose PK of AEB071 in patients with Diffuse Large B-Cell Lymphoma (DLBCL)	First 7 months of treatment period
Pre and post-dose gene and protein expression of cytokines and any correlations with exposure to AEB071	Assess the pharmacodynamic response to AEB071 in Lymphoma and blood specimens	First 7 months of treatment period

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Study Director: Novarts Pharmaceuticals, Novarts Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for OEB071X2101 can be found on the Novartis Clinical Trial Results Website

Study record dates

Study Major Dates

• Study Start: November 1, 2011
• Primary Completion (Actual): April 1, 2014
• Study Completion (Actual): April 1, 2014

Study Registration Dates

• First Submitted: July 5, 2011
• First Submitted That Met QC Criteria: July 24, 2011
• First Posted (Estimate): July 26, 2011

Study Record Updates

• Last Update Posted (Actual): December 19, 2020
• Last Update Submitted That Met QC Criteria: December 16, 2020
• Last Verified: January 1, 2015

More Information

Terms related to this study

• Keywords: Phase 1,; Diffuse Large B-Cell Lymphoma,; CD79 Mutation
• 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
• Other Study ID Numbers: COEB071X2101; 2010-024367-41 (EudraCT Number)