Study Stopped
Lack of funding
A Phase I Study of Alisertib + R-EPOCH for Treatment of Myc-Positive Aggressive B-cell Lymphomas
A Phase I/Ib Study of Alisertib Plus R-EPOCH for Treatment of Myc-Positive Aggressive B-Cell Lymphomas
1 other identifier
interventional
1
1 country
2
Brief Summary
This phase I/Ib study is designed to establish the safety and maximum tolerated dose (MTD, which will also be the recommended phase II dose (RP2D)) of the aurora kinase A inhibitor alisertib when combined with dose-adjusted (DA)-R-EPOCH (rituximab, etoposide, doxorubicin, vincristine, cyclophosphamide and prednisone) in patients with CD20-positive diffuse large B-cell lymphoma (DLBCL), transformed follicular lymphoma or Burkitt lymphoma positive for Myc gene rearrangement (Myc+). Filgrastim or peg-filgrastim is also included with each cycle of R-EPOCH. Once we identify the MTD, an expansion cohort limited to the Myc+ DLBCL population will be opened to further characterize clinical activity and safety. Secondary objectives include estimates of complete response rate (CR) and progression free survival (PFS). We will also explore for associations between baseline kinome signatures and/or RNA sequencing and CR, and identify differential kinome and transcriptome prior to and during treatment.
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at below P25 for phase_1
Started Oct 2016
2 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
February 17, 2016
CompletedFirst Posted
Study publicly available on registry
March 7, 2016
CompletedStudy Start
First participant enrolled
October 1, 2016
CompletedPrimary Completion
Last participant's last visit for primary outcome
November 15, 2016
CompletedStudy Completion
Last participant's last visit for all outcomes
August 18, 2017
CompletedNovember 20, 2017
November 1, 2017
2 months
February 17, 2016
November 16, 2017
Conditions
Keywords
Outcome Measures
Primary Outcomes (1)
Maximum tolerated dose (MTD)
2 years
Secondary Outcomes (3)
Toxicity
from day 1 of treatment until up to 2 years after treatment
Rate of Response
from day 1 of treatment until up to 2 years after treatment
Progression free survival
from day 1 of treatment until up to 2 years after treatment or death, whichever occurs first
Study Arms (1)
Alisertib combined with R-EPOCH
EXPERIMENTALDose escalation will take place within cohorts. Subjects will receive alisertib tablets twice daily in combination with R-EPOCH chemotherapy on days 1 through 5 of each 21-day cycle. The treatment will be given in 6 cycles. The first 3 patients to be enrolled will receive a 20 milligram (mg) dose of alisertib. The dose of alisertib will be increased or decreased as more subjects enter the study. Each dose level will be evaluated for safety and tolerability before the next higher dose is given. The dose levels will be modified until the maximum tolerated dose (MTD) is reached. Once the MTD has been established, enrollment into that cohort will continue with up to a maximum of 24 patients total enrolled into the study.
Interventions
Dose escalation of alisertib: level 1 - 20 mg, level 2 - 30 mg, level 3 - 40 mg PO BID on Days 1-5 of six 21-day cycles, combined with R-EPOCH Rituximab, IV infusion on day 1 of each cycle; Etoposide, IV infusion for 96 hours on days 1, 2, 3, and 4 Doxorubicin, IV infusion for 96 hours on days 1, 2, 3, and 4 Vincristine, IV infusion for 96 hours on days 1, 2, 3, and 4 Cyclophosphamide, IV infusion for 15 minutes on day 5 Prednisone, PO daily on days 1, 2, 3, 4, and 5
Eligibility Criteria
You may qualify if:
- ≥18 y/o (no upper age limit)
- ECOG PS ≤2
- Disease - Histologically or cytologically documented newly diagnosed (stages II, III or IV) Myc-positive DLBCL, transformed follicular lymphoma, or high-grade unclassifiable with features intermediate between DLBCL and Burkitt lymphoma
- Myc Positive lymphoma is defined by:
- Positive for Myc gene rearrangement by fluorescence in-situ hybridization (FISH) involving various breakpoints (e.g. 8-14, 8-22 and 2-8) AND concurrent gene rearrangements in bcl-2 and/or bcl-6 by FISH OR
- Myc and Bcl-2 overexpression defined by \> 40% Myc and \> 70% Bcl-2 expression by IHC. Patients may enroll in the study based on the local laboratory evaluation, but these should be confirmed by the UNC Hematopathology Laboratory retrospectively
- Positive for CD20 via immunophenotyping
- Prior Treatment: Previously untreated or who received a maximum of one cycle of combination chemotherapy (i.e. R-CHOP, R-EPOCH, or R-hyperCVAD) within 4 weeks of study entry except patients who require dose reduction after the first cycle of off-study R-EPOCH.
- Measurable disease as assessed by 2 dimensional measurements by CT (≥ 1.5 cm).
- Adequate organ function as demonstrated by:
- Bone marrow function (without platelet transfusion or myeloid growth factor support within two weeks of screening) as demonstrated by:
- Hemoglobin ≥ 8 g/dL
- Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3
- Platelet count ≥75,000/mm3
- And hepatic and renal function as demonstrated by:
- +24 more criteria
You may not qualify if:
- CNS involvement of DLBCL
- Major surgery within 4 weeks prior to entry
- Receiving any other concurrent cytotoxic, biologic agent(s) or investigational agent ; NOTE: Concurrent intrathecal chemotherapy for CNS prophylaxis allowed per institutional standards
- Receipt of investigational drugs within 14 days before D1 of alisertib
- Prior administration of an Aurora A kinase-targeted agent, including alisertib
- Patients with a "currently active" second malignancy other than non-melanoma skin cancers, non-invasive bladder cancer, "low risk" adenocarcinoma of the prostate and carcinoma in situ of the cervix. Patients are not considered to have a "currently active" malignancy if they have completed therapy and are free of disease for ≥ 3 years.
- Treatment with clinically significant enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of alisertib and during the study.
- Radiation therapy to more than 25% of the bone marrow (note: whole pelvic radiation is considered to be over 25%)
- Prior allogeneic bone marrow or organ transplantation
- Known GI disease or GI procedures that could interfere with the oral absorption or tolerance of alisertib; examples include, but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease
- Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen
- Requirement for constant administration of proton pump inhibitor from 5 days prior to D1 of alisertib, and/or requirement for constant administration of H2 antagonist, or pancreatic enzymes; intermittent uses of antacids or H2 antagonists are allowed
- Requirement for drugs, juices and/or herbs strongly inhibit CYP3A4 from within 7 days prior to D1 of alisertib and throughout treatment NOTE: Glucocorticoids are considered inducers of CYP3A4. However, their use is allowed if patient has been taking a continuous dose of no more than 15 mg/day of prednisone (or its equivalent) for at least 1 month prior to D1 of alisertib. In addition, low dose steroid use for the control of nausea and vomiting will be allowed. Topical steroid use and inhaled steroids are also permitted.
- Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection
- Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
- +5 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
Study Sites (2)
City of Hope Comprehensive Cancer Center
Duarte, California, 91010, United States
University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center
Chapel Hills, North Carolina, 27599, United States
Related Links
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Christopher Dittus, DO
UNC Lineberger Comprehensive Cancer Center
Study Design
- Study Type
- interventional
- Phase
- phase 1
- Allocation
- NA
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- SINGLE GROUP
- Sponsor Type
- OTHER
- Responsible Party
- SPONSOR
Study Record Dates
First Submitted
February 17, 2016
First Posted
March 7, 2016
Study Start
October 1, 2016
Primary Completion
November 15, 2016
Study Completion
August 18, 2017
Last Updated
November 20, 2017
Record last verified: 2017-11
Data Sharing
- IPD Sharing
- Will not share