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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
CD79 Mutant or ABC-subtype Diffuse Large B-Cell Lymphoma	Drug: AEB071; Drug: Everolimus	Phase 1

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 Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	31 participants
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Actual Study Start Date :	December 5, 2013
Actual Primary Completion Date :	June 1, 2016
Actual Study Completion Date :	June 1, 2016

Arms and Interventions

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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 Name: sotrastuarin Drug: Everolimus; mTOR inhibitor; Other Name: RAD001

Outcome Measures

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Primary Outcome Measures :

1. Phase Ib- Incidence of dose limiting toxicities (DLT) during the first cycle [ Time Frame: 12 months ]
   Estimate the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of the AEB071and EVEROLIMUS combination therapy in patients with DLBCL.
2. Phase II- Overall response rate (ORR) = complete response (CR) + partial response (PR) according to the non-Hodgkin's Lymphoma International Working Group criteria [ Time Frame: 12 months ]
   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 :

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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Locations

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

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Additional Information:

Results for COEB071X2103 from the Novartis Clinical Trials website 

Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT01854606 History of Changes
Other Study ID Numbers:	COEB071X2103
First Posted:	May 15, 2013
Last Update Posted:	May 30, 2017
Last Verified:	May 2017
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	No

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Diffuse Large B-Cell Lymphoma, DBCL, AEB071, Everolimus

Additional relevant MeSH terms:

Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Lymphoma, Non-Hodgkin	Everolimus; Sirolimus; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Anti-Bacterial Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antifungal Agents