Clinical trial NCT01402440: Study of AEB071 (a Protein Kinase C Inhibitor) in Patients With CD79-mutant Diffuse Large B-Cell Lymphoma
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Diffuse Large B-Cell Lymphoma
Keywords: Diffuse Large B-Cell Lymphoma,
Phase 1,
CD79 Mutation
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2011-07-26
Enrollment: 15
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: 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.


Eligibility criteria: 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

Primary outcomes:
measure: Frequency of Dose Limiting Toxicity (DLT) during cycle 1 (Dose Escalation phase)
timeFrame: Cycle 1 (28 days)
measure: Number of Pparticipants reporting Serious Adverse Events and Adverse Events (Dose Expansion phase)
timeFrame: Baseline, 28 days
Secondary outcomes:
measure: Overall Response Rate, using NHLIWG criteria
timeFrame: Baseline, 12 months
measure: Number of Participants reporting Serious Adverse Events and Adverse Events
timeFrame: Baseline, 12 months
measure: AEB071 PK parameters including Cmax, tmax, AUCt, Ctrough, CL/F and RA
timeFrame: First 7 months of treatment period
measure: Pre and post-dose gene and protein expression of cytokines and any correlations with exposure to AEB071
timeFrame: First 7 months of treatment period
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: Saint Louis
country: United States
facility: Washington University School of Medicine Div. of Medical Oncology
state: Missouri
city: Hackensack
country: United States
facility: Hackensack University Medical Center Hackensack (SC)
state: New Jersey
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center MSK 2
state: New York
city: Columbus
country: United States
facility: Ohio State Comprehensive Cancer Center/James Cancer Hospital Ohio State
state: Ohio
city: Houston
country: United States
facility: University of Texas/MD Anderson Cancer Center SC Location
state: Texas
city: Creteil
country: France
facility: Novartis Investigative Site
city: Lille Cedex
country: France
facility: Novartis Investigative Site
city: Pierre-Benite Cédex
country: France
facility: Novartis Investigative Site
city: Rouen Cedex 1
country: France
facility: Novartis Investigative Site
city: Berlin
country: Germany
facility: Novartis Investigative Site
city: Muenchen
country: Germany
facility: Novartis Investigative Site
city: Shatin, New Territories
country: Hong Kong
facility: Novartis Investigative Site
city: Milano
country: Italy
facility: Novartis Investigative Site
state: MI
city: Torino
country: Italy
facility: Novartis Investigative Site
state: TO
city: Seoul
country: Korea, Republic of
facility: Novartis Investigative Site
state: Korea
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Groningen
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Rotterdam
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
city: Barcelona
country: Spain
facility: Novartis Investigative Site
city: Taipei
country: Taiwan
facility: Novartis Investigative Site
city: Manchester
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
affiliation: Novarts Pharmaceuticals
name: Novarts Pharmaceuticals
role: STUDY_DIRECTOR
References: