Duvelisib and Romidepsin or Bortezomib in Treating Patients with Relapsed or Refractory T-cell Lymphoma

Status: Active

Description

This phase I trial studies the side effects and best dose of duvelisib when given together with romidepsin or bortezomib in treating patients with T-cell lymphoma that has come back or does not respond to treatment. Duvelisib, romidepsin, and bortezomib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Eligibility Criteria

Inclusion Criteria

  • Pathologically confirmed T-cell lymphomas at the enrolling institution, including stage >= Ib cutaneous T-cell lymphoma (CTCL), which has relapsed or progressed after at least one systemic therapy
  • Previous systemic anti-cancer therapy for T-cell lymphoma must have been discontinued at least 3 weeks prior to treatment; for the dose expansion phase, in progressing subjects, a 2 week washout may be allowed after discussion with Memorial Sloan-Kettering (MSK) principal investigator
  • Previous radiation and/or surgery must have been discontinued or completed at least 2 weeks prior to treatment in this study and adverse effects must have resolved to grade 1 or baseline; lymph node or other diagnostic biopsies within 2 weeks are not considered exclusionary * Patients who have received localized radiation therapy (RT) as part of their immediate prior therapy may be allowed to enroll with shorter washout period after discussion with the MSK principal investigator
  • Eastern Cooperative Oncology Group (ECOG) =< 2
  • Absolute neutrophil count >= 1.0 K/mcL, without use of growth factor support for 1 week
  • Platelet count >= 80 K/uL (in the expansion cohorts, if thrombocytopenia is due to bone marrow involvement platelet count must be >= 50 K/uL), without platelet transfusion for 1 week
  • Patients enrolled in the dose escalation phase who are not enrolled on the expansion cohorts must have calculated creatinine clearance >= 50 ml/min by Cockcroft-Gault formula; patients enrolled in the dose expansion phase must have calculated creatinine clearance >= 40 ml/min by Cockcroft-Gault formula, without use of growth factor support for 1 week
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) or =< 3 x ULN if documented hepatic involvement with lymphoma, or =< 5 x ULN if history of Gilbert's syndrome, without use of growth factor support for 1 week
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN; =< 5 x ULN if due to lymphoma involvement, without use of growth factor support for 1 week
  • Measurable disease for dose expansion and lead in phases only; measurable disease defined by: * Revised International Working Group (Cheson, 2007) classification for systemic lymphoma or * Atypical and or malignant lymphocytes quantifiable by flow cytometry or morphology in blood * Or bone marrow modified severity weighted assessment tool (mSWAT) > 0 or Sezary count >= 1000 cells/uL
  • Short course systemic corticosteroids for disease control, improvement of performance status or non-cancer indication (=< 7 days) must have been discontinued at least 6 days prior to study treatment; stable ongoing corticosteroid use (>= 30 days) up to an equivalent dose of 20 mg of prednisone is permissible * CTCL: Topical steroids that have been used for > 3 weeks may be continued * All other histologies (not CTCL): Topical steroids use is permissible without restriction
  • Women of reproductive potential (a female of reproductive potential is a sexually mature female who: has not undergone a hysterectomy or bilateral oophorectomy; or has not been naturally postmenopausal for at least 24 consecutive months [i.e. has had menses at any time in the preceding 24 consecutive months]) must have a negative serum or urine beta human chorionic gonadotropin (beta-hCG) pregnancy test; all women of reproductive potential, all sexually active male patients, and all partners of patients must agree to use adequate methods of birth control (e.g. latex condoms) throughout the study and for 30 days after the last dose of study drug

Exclusion Criteria

  • Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form
  • Pregnant females; (lactating females must agree not to breast feed while taking the study medications)
  • Prior use of duvelisib if discontinued due to toxicity
  • For the romidepsin arm of the study, prior therapy with romidepsin if discontinued due to toxicity
  • For the bortezomib arm of the study, prior therapy with a proteasome inhibitor if discontinued due to toxicity
  • For the bortezomib arm of the study, patients with grade >= 2 peripheral neuropathy
  • History of chronic liver disease, veno-occlusive disease, or current alcohol abuse
  • Administration of a live vaccine within 6 weeks of first dose of study drug
  • Prior surgery or gastrointestinal dysfunction that may affect drug absorption (e.g, gastric bypass surgery, gastrectomy)
  • Known seropositive and requiring anti-viral therapy for human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
  • Subjects with chronic hepatitis B or C as defined as test subjects with positive hepatitis (Hep) B serology: * Subjects with a negative hepatitis B virus surface antigen (HBsAg) and a positive hepatitis B core antibody (HBcAb) require an undetectable/negative hepatitis B deoxyribonucleic acid (DNA) (e.g., polymerase chain reaction [PCR] test) to be enrolled, and will require prophylactic antiviral treatment (e.g., F) initiated prior to the first dose of study drug, and continued until approximately 6 to 12 months after completion of study drug(s)
  • Patients with positive hepatitis C virus
  • Subjects with active Epstein-Barr virus (EBV) unrelated to underlying lymphoma (positive serology for anti-EBV virus capsid antigen [VCA] IgM antibody and negative for anti-EBV Epstein-Barr nuclear antigen [EBNA] IgG antibody, or clinical manifestations and positive EBV PCR consistent with active EBV infection)
  • Subjects with active cytomegalovirus (CMV) (positive serology for anti-CMV IgM antibody and negative for anti-CMV IgG antibody and positive CMV PCR with clinical manifestations consistent with active CMV infection) and requiring therapy will be excluded from participation in the study; carriers will be monitored per institutional guidelines
  • Receiving systemic therapy for another primary malignancy (other than T-cell lymphoma); * Patients with more than one type of lymphoma may be enrolled after discussion with the MSK principal investigator * Adjuvant or maintenance therapy to reduce the risk of recurrence of other malignancy (other than T-cell lymphoma) is permissible after discussion with the MSK principal investigator
  • Known central nervous system or meningeal involvement (in the absence of symptoms, investigation into central nervous system involvement is not required)
  • The following cardiac abnormalities: * Congenital long QT syndrome * Corrected QT (QTc)/ Fridericia's correction QT (QTf) interval >= 480 milliseconds; unless secondary to pacemaker or bundle branch block * Myocardial infarction within 6 months (subjects with a history of myocardial infarction within the last 6 to 12 months who are asymptomatic and have had a negative cardiac risk assessment [treadmill stress test, nuclear medicine stress test, or stress echocardiogram] since the event may participate) * Other significant electrocardiogram (ECG) abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block * Symptomatic coronary artery disease (CAD), e.g. angina Canadian class II-IV; in any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present * An ECG recorded at screening showing evidence of cardiac ischemia (ST depression of >= 2 mm, measured from isoelectric line to the ST segment); if in any doubt, the patient should have a stress imaging study and. if abnormal, angiography to define whether or not CAD is present * Congestive heart failure (CHF) that meets New York Heart Association (NYHA) class II to IV and/or ejection fraction < 45% by multigated acquisition (MUGA), echocardiogram, or cardiac magnetic resonance imaging (MRI) * A known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), torsade de pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD) * Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatment or other causes * Uncontrolled hypertension, i.e., blood pressure (BP) of >= 170/95; patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month prior to study registration) and meet all other inclusion criteria * Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers) * For patients enrolling on the romidepsin arm; taking drugs associated with significant QTc/QTf prolongation, unless able to be switched to non-QTc/QTf prolonging medication or on a stable dose without significant QT prolongation (> 470 msec) ** Caution should be used when administering study drugs to patients taking medications significantly metabolized by these enzymes; particular attention should be paid to patients receiving warfarin; patients should have coagulation parameters monitored regularly, and warfarin dose adjusted accordingly; if these drugs cannot be discontinued or replaced, enrollment may be allowed after discussion with MSK principal investigator (PI)

Locations & Contacts

California

Palo Alto
Stanford Cancer Institute Palo Alto
Status: Active
Contact: Youn H Kim
Phone: 650-498-6000

Missouri

Saint Louis
Siteman Cancer Center at Washington University
Status: Active
Contact: Neha Mehta-Shah
Phone: 212-639-3045

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: Active
Contact: Steven Michael Horwitz
Phone: 212-639-3045
Email: horwitzs@mskcc.org
Middletown
Memorial Sloan Kettering Monmouth
Status: Active
Contact: Steven Michael Horwitz
Phone: 212-639-3045
Email: horwitzs@mskcc.org

New York

Commack
Memorial Sloan Kettering Commack
Status: Active
Contact: Steven Michael Horwitz
Phone: 212-639-3045
Email: horwitzs@mskcc.org
New York
Memorial Sloan Kettering Cancer Center
Status: Active
Contact: Steven Michael Horwitz
Phone: 212-639-3045
Email: horwitzs@mskcc.org
Uniondale
Memorial Sloan Kettering Nassau
Status: Active
Contact: Steven Michael Horwitz
Phone: 212-639-3045
Email: horwitzs@mskcc.org
West Harrison
Memorial Sloan Kettering Westchester
Status: Active
Contact: Steven Michael Horwitz
Phone: 212-639-3045
Email: horwitzs@mskcc.org

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and characterize the safety and toxicity profile of extended use with the combination of duvelisib with bortezomib and duvelisib with romidepsin in patients with relapsed or refractory T-cell lymphomas.

SECONDARY OBJECTIVES:

I. Overall response rate (ORR) of duvelisib with bortezomib and duvelisib with romidepsin collectively as well as by disease subtype. (Dose Expansion Phase)

II. Complete response (CR) and partial response (PR) rate. (Dose Expansion Phase)

III. Time to response (TTR), duration of response (DOR) and event free survival (EFS). (Dose Expansion Phase)

TERTIARY OBJECTIVES:

I. Tissue collected from patients in the lead in phase and where available on patients on combination therapy will be utilized for exploratory translational biological studies aimed at determining mechanisms of response or resistance to phosphoinositide-3-kinase (PI3K)-delta and PI3K-gamma inhibition.

OUTLINE: This is a dose-escalation study of duvelisib followed by a dose expansion phase. Patients are assigned to 1 of 2 arms.

ARM A: Patients receive romidepsin intravenously (IV) over 4 hours on days 1, 8, and 15 and duvelisib orally (PO) twice daily (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive bortezomib subcutaneously (SC) on days 1, 4, 8, and 11 and duvelisib as in Arm A. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days and every 6 months.

Trial Phase & Type

Trial Phase

Phase I

Trial Type

Treatment

Lead Organization

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Steven Michael Horwitz

Trial IDs

Primary ID 16-042
Secondary IDs NCI-2016-00894
Clinicaltrials.gov ID NCT02783625