Clinical trial NCT01854606: Safety and Efficacy of AEB071 and EVEROLIMUS in Patients With CD79-mutant or ABC Subtype Diffuse Large B-Cell Lymphoma
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
Overall status: COMPLETED
Phase: PHASE1
Conditions: CD79 Mutant or ABC-subtype Diffuse Large B-Cell Lymphoma
Keywords: Diffuse Large B-Cell Lymphoma, DBCL, AEB071, Everolimus
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2013-05-15
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Phase Ib- Incidence of dose limiting toxicities (DLT) during the first cycle
timeFrame: 12 months
measure: Phase II- Overall response rate (ORR) = complete response (CR) + partial response (PR) according to the non-Hodgkin's Lymphoma International Working Group criteria
timeFrame: 12 months
Secondary outcomes:
measure: Occurrence of Adverse Events (AEs), Serious Adverse Events (SAEs) assessments of clinical laboratory values and vital sign measurements.
timeFrame: 24 months
measure: Best Overall Response (BOR)
timeFrame: 24 months
measure: Duration of Response (DOR)
timeFrame: 24 months
measure: Progression Free survival (PFS)
timeFrame: 24 months
measure: Overall Survival (OS)
timeFrame: 24 months
measure: Concentration-time profiles of Pharmacokinetics (PK) parameters - Phase Ib
timeFrame: 24 months
Other outcomes:
Locations:
city: Saint Louis
country: United States
facility: Washington University School of Medicine Dept of Oncology.
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center Onc. Dept.
state: New York
city: Nashville
country: United States
facility: Sarah Cannon Research Institute Dept of Onc
state: Tennessee
city: Rouen Cedex 1
country: France
facility: Novartis Investigative Site
city: Mainz
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Hong Kong
country: Hong Kong
facility: Novartis Investigative Site
city: New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: