A Phase I Study of Alisertib + R-EPOCH for Treatment of Myc-Positive Aggressive B-cell Lymphomas

Stopped early · Phase 1

Conditions studied: Diffuse Large B-cell Lymphoma, Follicular Lymphoma, Burkitt Lymphoma

In brief

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.

Key facts

Study ID: NCT02700022
Run by: UNC Lineberger Comprehensive Cancer Center
People needed: 1
Starts: 2016-10-01
Expected to finish: 2017-08-18
Last updated by the study team: 2017-11-20

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

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:
Aspartate aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN); ALT and AST up to 5 x ULN if liver metastases present
Total serum bilirubin ≤1.5 x ULN
Serum creatinine ≤1.5 x ULN or CrCl of ≥ 30
Adequate renal function as defined by: Calculated creatinine clearance must be ≥ 30 mL/minute based on Cockcroft-Gault formula
Documented negative serologic testing for human immunodeficiency virus (HIV), hepatitis B (unless serologically positive due to prior vaccination), and hepatitis C within the year prior to enrollment (note: for guidance in defining active infection for hepatitis B, please refer to the WHO guidelines. (World Health Organization, Global Alert and Response (GAR), Hepatitis B (who.int/csr/disease/hepatitis/ whocdscsrlyo20022/en/index4.html)
Patient agrees to consume no more than 1 standard unit of alcohol per day during the study and for 30 days from the last dose of alisertib. A standard unit of alcohol is defined as a 12 oz beer (350 mL), 1.5 oz (45 mL) of 80-proof alcohol, or one 6-oz (175 mL) glass of wine.
Women of childbearing potential (WOCBP) must have negative pregnancy test within 7 days prior to D1 of treatment
Female subjects must be:
Post-menopausal for at least one year before the screening visit, or
Surgically sterilized, or

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.
Female subject who is pregnant or breast-feeding; confirmation that the subject is not pregnant must be established by a negative serum beta-human chorionic gonadotropin (beta-hCG) pregnancy test result obtained during screening (within 7 days prior to D1 of treatment). Pregnancy testing is not required for post-menopausal or surgically sterilized women.
Serious medical or psychiatric illness likely to interfere with participation in this clinical study
Other severe acute or chronic medical or psychiatric condition, including uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for enrollment in this study.
Inability to swallow oral medication or inability or unwillingness to comply with the administration requirements related to alisertib.
Administration of myeloid growth factors or platelet transfusion within 14 days prior to the first dose of study treatment

Where it is running

City of Hope Comprehensive Cancer Center — Duarte, California, United States
University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center — Chapel Hills, North Carolina, United States

Full record on ClinicalTrials.gov

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