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Abexinostat and Ibrutinib in Treating Patients with Recurrent or Refractory Diffuse Large B-cell Lymphoma or Mantle Cell Lymphoma

Trial Status: Active

This phase I trial studies the side effects and best dose of abexinostat and to see how well it works when given together with ibrutinib in treating patients with diffuse large B-cell lymphoma or mantle cell lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Abexinostat blocks a protein called histone deacetylase (HDAC), and slows the growth of cancer cells. Ibrutinib blocks a protein called Bruton tyrosine kinase (BTK), which has been shown to be highly active in lymphoma, and may cause cancer cells to die. Giving abexinostat and ibrutinib together may boost their effectiveness and limit or stop the growth of cancer cells in patients with diffuse large B-cell lymphoma or mantle cell lymphoma.

Inclusion Criteria

  • Patient is able and willing to adhere to the study visit schedule and other protocol requirements
  • Patient has histologically confirmed diagnosis of R/R mantle cell lymphoma or diffuse large B cell lymphoma * Diffuse large B cell lymphoma patients must have received at least 1 prior systemic chemotherapy regimen and received, or is ineligible for autologous or allogeneic stem cell transplant * Diffuse large B cell lymphoma patients must have non-germinal center subtype disease applying the Hans classification algorithm using immunohistochemistry markers CD10, BCL6, and MUM1 * Mantle cell lymphoma patients must have received at least 1 line of therapy * Allogeneic stem cell transplant recipients be greater than 6 months post transplant, not on immunosuppression for prevention of graft versus host disease for > 3 months and without active graft versus host disease * Autologous stem cell transplant recipients must have adequate bone marrow recovery and are transfusion independent * Patients with transformed DLBCL from an antecedent or simultaneous indolent B-cell non-Hodgkin lymphoma are permitted * Patients who have received prior radiotherapy will be included
  • Patient has at least one measurable lesion (>= 1.5 cm) according to Response Evaluation Criteria in Lymphoma (RECIL)
  • Patient has an Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count (ANC) >= 1.0 x 10^9/L independent of growth factor support
  • Platelets >= 100 x 10^9/L independent of transfusion * For patients with documented bone marrow involvement of underlying MCL or DLBCL at time of study enrollment, platelets must be >= 75 x 10^9/L independent of transfusion
  • Hemoglobin (Hgb) >= 9.0 g/dL * For patients with documented bone marrow involvement of underlying MCL or DLBCL at time of study enrollment, Hgb must be >= 8.0 g/dL
  • International normalized ratio (INR) =< 1.5
  • Creatinine clearance > 25 mL/min as determined by the Cockcroft-Gault equation or a 24-hour urine collection
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< upper limit of normal (ULN) (or =< 3 x ULN if liver involved with disease)
  • Total serum bilirubin =< 1.5 ULN unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic origin
  • Normal serum potassium level with or without supplementation
  • Left ventricular ejection fraction (LVEF) >= 50%
  • Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trial. For females, these restrictions apply for 30 days month after the last dose of study drug. For males, these restrictions apply for 120 days after the last dose of study drug
  • Women of childbearing potential must have a negative urine pregnancy test at screening and at day 1 (with window of -7 days)
  • Men must agree to not donate sperm during and 12 months after the study. Women should not donate ova/ooctyes for the purposes of assisted reproduction until 12 months after the study
  • Patient is able to swallow and retain oral medications

Exclusion Criteria

  • Patients previously treated with any BTK inhibitor or HDAC inhibitor
  • Patient has a history of non-compliance to medical regimen or inability to grant consent
  • Patient is concurrently using other approved or investigational antineoplastic agent
  • Patient has not recovered to grade 1 or better (except alopecia) from related side effects of any prior antineoplastic therapy
  • Patient has had major surgery or a wound that has not fully healed within 4 weeks of starting study drugs
  • Patients who have had chemotherapy or radiotherapy within 2 weeks prior to entering the study
  • Patient has evidence of active graft versus host disease (GVHD)
  • Patient has active central nervous system (CNS) disease or meningeal involvement
  • Patient has history of stroke or intracranial hemorrhage =< 6 months from starting study drugs
  • Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  • Patient has clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional classification, left ventricular ejection fraction (LVEF) < 50% as determined by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO), unstable angina pectoris, symptomatic pericarditis, Fridericia's correction formula (QTcF) > 480 msec on the screening electrocardiography (ECG) (using the QTcF formula), or history of congenital long QT syndrome
  • Patient has a concurrent active malignancy
  • Malignancies treated with a curative intent with an expected life expectancy >= 5 years or a non-competing life expectancy risk are eligible (i.e. adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer, early stage breast cancer, treated prostate cancer or any other cancer from which the patient has been disease free for >= 3 years)
  • Patient with known history of human immunodeficiency virus (HIV), or any uncontrolled active systemic infection
  • Patient has acute viral hepatitis (typically defined by elevated AST/ALT), or a history of chronic or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. HBV infection is defined as having hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HBcAb) positive test with concurrent detectable HBV deoxyribonucleic acid (DNA) levels. HCV infection is defined as detectable HCV ribonucleic acid (RNA) levels
  • Patient has hepatic failure (Child-Pugh class C)
  • Patient is currently receiving increasing or chronic treatment (> 10 days) with corticosteroids or another immunosuppressive agent. Patients requiring chronic therapy with steroids may take no more than 10 mg daily of prednisone or equivalent
  • Patient requires chronic treatment with a strong cytochrome P450 (CYP) 3A4 inhibitors, and inducers, or drugs known to induce Torsades de Pointes and the treatment cannot be discontinued or switched to a different medication prior to starting study drug
  • Patients with known bleeding diathesis (e.g. von Willebrand ‘s disease) or hemophilia
  • Patient is currently receiving warfarin or other vitamin K antagonist. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed
  • Vaccinated with live, attenuated vaccines within 4 weeks of randomization
  • Patients with any life-threatening illness, medical condition or organ system dysfunction that in the opinion of the investigator could compromise the subject’s safety, interfere with absorption of metabolism of study drugs or put the study outcomes at undue risk
  • Women who are pregnant or breastfeeding
  • Patients in need of immediate cytoreductive chemotherapy

New Jersey

Basking Ridge
Memorial Sloan Kettering Basking Ridge
Status: ACTIVE
Contact: Gottfried von Keudell
Phone: 646-608-3704
Middletown
Memorial Sloan Kettering Monmouth
Status: ACTIVE
Contact: Gottfried von Keudell
Phone: 646-608-3704
Montvale
Memorial Sloan Kettering Bergen
Status: ACTIVE
Contact: Gottfried von Keudell
Phone: 646-608-3704

New York

Commack
Memorial Sloan Kettering Commack
Status: ACTIVE
Contact: Gottfried von Keudell
Phone: 646-608-3704
New York
Memorial Sloan Kettering Cancer Center
Status: ACTIVE
Contact: Gottfried von Keudell
Phone: 646-608-3704
Uniondale
Memorial Sloan Kettering Nassau
Status: ACTIVE
Contact: Gottfried von Keudell
Phone: 646-608-3704
West Harrison
Memorial Sloan Kettering Westchester
Status: ACTIVE
Contact: Gottfried von Keudell
Phone: 646-608-3704

Pennsylvania

Allentown
Lehigh Valley Hospital-Cedar Crest
Status: APPROVED
Contact: Don Jae Park
Phone: 610-402-7880

PRIMARY OBJECTIVES:

I. Assess the safety and establish the maximum tolerated dose (MTD) of the combination of abexinostat tosylate (abexinostat) and ibrutinib in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) or R/R non-germinal center subtype diffuse large B-cell lymphoma (DLBCL). (Dose escalation stage)

II. Assess preliminary efficacy using complete response (CR) rate. (Dose expansion stage)

SECONDARY OBJECTIVES:

I. Efficacy will also be assessed by overall response rate (CR + partial response [PR]), percent tumor reduction, duration of response, progression free survival, event free survival, and overall survival. (Dose expansion stage)

II. Describe the safety and tolerability of the combination of abexinostat and ibrutinib at the MTD or recommended phase II dose. (Dose expansion stage)

EXPLORATORY OBJECTIVE:

I. Preliminarily explore the biologic predictors of response and resistance to dual B-cell receptor pathway inhibitors (BCRi) and HDAC inhibition.

OUTLINE: This is a dose-escalation study of abexinostat tosylate.

Patients receive ibrutinib orally (PO) once daily (QD) on days 1-28 and abexinostat tosylate PO twice daily (BID) on days 1-7 and 15-21. Treatment repeats every 28 days for up to 24 cycles (not exceeding 2 years) in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 1 month.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
Memorial Sloan Kettering Cancer Center

Principal Investigator
Gottfried von Keudell

  • Primary ID 19-080
  • Secondary IDs NCI-2019-03632
  • Clinicaltrials.gov ID NCT03939182