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

Primary Purpose

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

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
AEB071
Everolimus
Sponsored by
Novartis Pharmaceuticals
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for CD79 Mutant or ABC-subtype Diffuse Large B-Cell Lymphoma focused on measuring Diffuse Large B-Cell Lymphoma, DBCL, AEB071, Everolimus

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Washington University School of Medicine Dept of Oncology.
  • Memorial Sloan Kettering Cancer Center Onc. Dept.
  • Sarah Cannon Research Institute Dept of Onc
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site
  • Novartis Investigative Site

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

AEB071 and EVEROLIMUS

Arm Description

AEB071 and EVEROLIMUS will be taken together in this open-label non-randomized study

Outcomes

Primary Outcome Measures

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.
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

Secondary Outcome Measures

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
Best Overall Response (BOR)
Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS
Duration of Response (DOR)
Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS
Progression Free survival (PFS)
Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS
Overall Survival (OS)
Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS
Concentration-time profiles of Pharmacokinetics (PK) parameters - Phase Ib
To characterize the PK profiles of AEB071 and EVEROLIMUS

Full Information

First Posted
May 13, 2013
Last Updated
December 16, 2020
Sponsor
Novartis Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT01854606
Brief Title
Safety and Efficacy of AEB071 and EVEROLIMUS in Patients With CD79-mutant or ABC Subtype Diffuse Large B-Cell Lymphoma
Acronym
COEB071X2103
Official Title
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 Type
Interventional

2. Study Status

Record Verification Date
May 2017
Overall Recruitment Status
Completed
Study Start Date
December 5, 2013 (Actual)
Primary Completion Date
June 1, 2016 (Actual)
Study Completion Date
June 1, 2016 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Novartis Pharmaceuticals

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
CD79 Mutant or ABC-subtype Diffuse Large B-Cell Lymphoma
Keywords
Diffuse Large B-Cell Lymphoma, DBCL, AEB071, Everolimus

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
31 (Actual)

8. Arms, Groups, and Interventions

Arm Title
AEB071 and EVEROLIMUS
Arm Type
Experimental
Arm Description
AEB071 and EVEROLIMUS will be taken together in this open-label non-randomized study
Intervention Type
Drug
Intervention Name(s)
AEB071
Other Intervention Name(s)
sotrastuarin
Intervention Description
a Protein Kinase C Inhibitor
Intervention Type
Drug
Intervention Name(s)
Everolimus
Other Intervention Name(s)
RAD001
Intervention Description
mTOR inhibitor
Primary Outcome Measure Information:
Title
Phase Ib- Incidence of dose limiting toxicities (DLT) during the first cycle
Description
Estimate the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the AEB071and EVEROLIMUS combination therapy in patients with DLBCL.
Time Frame
12 months
Title
Phase II- Overall response rate (ORR) = complete response (CR) + partial response (PR) according to the non-Hodgkin's Lymphoma International Working Group criteria
Description
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
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Occurrence of Adverse Events (AEs), Serious Adverse Events (SAEs) assessments of clinical laboratory values and vital sign measurements.
Description
Safety and tolerability of AEB071 and EVEROLIMUS, including acute and chronic toxicities
Time Frame
24 months
Title
Best Overall Response (BOR)
Description
Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS
Time Frame
24 months
Title
Duration of Response (DOR)
Description
Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS
Time Frame
24 months
Title
Progression Free survival (PFS)
Description
Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS
Time Frame
24 months
Title
Overall Survival (OS)
Description
Evaluate preliminary anti-tumor activity for AE071 and EVEROLIMUS
Time Frame
24 months
Title
Concentration-time profiles of Pharmacokinetics (PK) parameters - Phase Ib
Description
To characterize the PK profiles of AEB071 and EVEROLIMUS
Time Frame
24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Novartis Pharmaceuticals
Organizational Affiliation
Novartis Pharmaceuticals
Official's Role
Study Director
Facility Information:
Facility Name
Washington University School of Medicine Dept of Oncology.
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63110
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center Onc. Dept.
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Sarah Cannon Research Institute Dept of Onc
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Novartis Investigative Site
City
Rouen Cedex 1
ZIP/Postal Code
76038
Country
France
Facility Name
Novartis Investigative Site
City
Mainz
ZIP/Postal Code
55131
Country
Germany
Facility Name
Novartis Investigative Site
City
Muenchen
ZIP/Postal Code
81377
Country
Germany
Facility Name
Novartis Investigative Site
City
Hong Kong
Country
Hong Kong
Facility Name
Novartis Investigative Site
City
New Territories
Country
Hong Kong
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20133
Country
Italy
Facility Name
Novartis Investigative Site
City
Milano
State/Province
MI
ZIP/Postal Code
20141
Country
Italy
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
03080
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Seoul
State/Province
Korea
ZIP/Postal Code
06351
Country
Korea, Republic of
Facility Name
Novartis Investigative Site
City
Rotterdam
ZIP/Postal Code
3015 CE
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Rotterdam
ZIP/Postal Code
3075 EA
Country
Netherlands
Facility Name
Novartis Investigative Site
City
Taipei
ZIP/Postal Code
10002
Country
Taiwan

12. IPD Sharing Statement

Plan to Share IPD
No
Links:
URL
https://www.novctrd.com/ctrdweb/trialresult/trialresults/pdf?trialResultId=16288
Description
Results for COEB071X2103 from the Novartis Clinical Trials website

Learn more about this trial

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

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