Panobinostat Maintenance Therapy in Treating Patients with Multiple Myeloma after Stem Cell Transplant

Status: Closed to Accrual

Description

This phase II trial studies the side effects and best dose schedule of panobinostat maintenance therapy in treating patients with multiple myeloma after stem cell transplant. Panobinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving panobinostat maintenance therapy after stem cell transplant may help prevent or delay the return of multiple myeloma.

Eligibility Criteria

Inclusion Criteria

  • RESEARCH SAMPLE COLLECTION: Histologically confirmed diagnosis of multiple myeloma
  • RESEARCH SAMPLE COLLECTION: Considered for high-dose melphalan followed by autologous hematopoietic cell transplantation and undergoing pre-HCT workup
  • PANOBINOSTAT MAINTENANCE INCLUSION
  • Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
  • Histologically confirmed diagnosis of multiple myeloma
  • Meeting the criteria for symptomatic multiple myeloma (hypercalcemia renal [kidney] impairment, anemia, bone lesions "[CRAB]” criteria) before the initiation of systemic chemotherapy
  • Received high-dose melphalan (>= 140 mg/m^2) followed by autologous HCT based on the institutional guidelines and within +45 and +180 after autologous HCT at the time of panobinostat maintenance initiation
  • Patients must have achieved at least partial response (PR) prior to autologous HCT and must not have progressive disease (PD) prior to the initiation of maintenance therapy
  • Absolute neutrophil count (ANC) >= 1 x 10^9/L
  • Hemoglobin >= 8 g/dl
  • Platelets >= 50 x 10^9/L (without transfusion support)
  • Creatinine clearance >= 40 ml/min or serum creatinine =< 2.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN
  • Serum bilirubin =< 1.5 x ULN
  • Albumin > 3.0 g/dl
  • Clinically euthyroid; Note: patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism
  • Baseline (pre-HCT) multi-gated acquisition (MUGA) or echocardiography (ECHO) must demonstrate left ventricular ejection fraction (LVEF) >= the lower limit of normal (LLN) of the institutional normal
  • Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 or Karnofsky performance status >= 70%
  • Prior histone deacetylase (HDAC), deacetylase (DAC), heat shock protein (HSP)90 inhibitors or valproic acid for the treatment of cancer is allowed

Exclusion Criteria

  • RESEARCH SAMPLE COLLECTION: Myeloma patients who are not candidates for high-dose melphalan followed by autologous HCT based on institutional standards
  • PANOBINOSTAT MAINTENANCE EXCLUSION
  • Patients who have purely non-secretory multiple myeloma (i.e., the absence of a measurable protein in serum by electrophoresis and immunofixation and the absence of Bence-Jones protein in the urine defined by use of electrophoresis and immunofixation)
  • Prior allogeneic HCT
  • Prior solid organ transplant requiring immunosuppressive therapy
  • Patients who will need valproic acid for any medical condition during the study or within 5 days prior to first panobinostat treatment
  • Impaired cardiac function or clinically significant cardiac diseases, including any one of the following: * History or presence of sustained ventricular tachyarrhythmia; (patients with a history of atrial arrhythmia are eligible but should be discussed with Novartis prior to enrollment) * Any history of ventricular fibrillation or torsade de pointes * Bradycardia defined as heart rate (HR) < 50 beats per minute (bpm); patients with pacemakers are eligible if HR >= 50 bpm * Screening electrocardiogram (ECG) with a corrected QT (QTc) > 470 msec * Right bundle branch block + left anterior hemiblock (bifascicular block) * Patients with myocardial infarction or unstable angina =< 12 months prior to starting study drug * Other clinically significant heart disease (e.g., congestive heart failure [CHF] New York [NY] Heart Association class III or IV, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen)
  • Patients with diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade 2
  • Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled diabetes or active or uncontrolled infection) including abnormal laboratory values, that could cause unacceptable safety risks or compromise compliance with the protocol
  • Patients using medications that have a relative risk of prolonging the QT interval or inducing torsade de pointes if treatment cannot be discontinued or switched to a different medication prior to starting study drug
  • Patients who have received targeted agents within 2 weeks or within 5 half-lives of the agent and active metabolites (whichever is longer) and who have not recovered from side effects of those therapies
  • Patients who have received either immunotherapy within =< 8 weeks; chemotherapy within =< 4 weeks; or radiation therapy to > 30% of marrow-bearing bone within =< 2 weeks prior to starting study treatment; or who have not yet recovered from side effects of such therapies
  • Patients who have undergone major surgery =< 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy
  • Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not using an effective method of birth control; WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e., who has had menses any time in the preceding 12 consecutive months); women of childbearing potential must have a negative serum pregnancy test within 24hrs of receiving the first dose of study medication
  • Male patients whose sexual partners are WOCBP not using effective birth control
  • Patients with a prior malignancy with in the last 5 years (except for basal or squamous cell carcinoma, or in situ cancer of the cervix)
  • Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
  • Patients with any significant history of non-compliance to medical regimens or unwilling or unable to comply with the instructions given to him/her by the study staff

Locations & Contacts

See trial information on ClinicalTrials.gov for a list of participating sites.

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To determine tolerability and safety profile of 2 different dosing schedule of single agent panobinostat maintenance therapy for a maximum of 12 intended cycles after autologous hematopoietic cell transplantation (HCT) in patients with multiple myeloma.

SECONDARY OBJECTIVES:

I. To evaluate the complete response rate to panobinostat maintenance therapy after autologous HCT.

II. To determine the 2-year progression-free survival (PFS) and overall survival (OS) of autologous HCT followed by panobinostat maintenance therapy in patients with multiple myeloma.

TERTIARY OBJECTIVES:

I. To evaluate histone acetylation (H3 and/or H4) of peripheral blood mononuclear cells.

II. To isolate and identify clonotypic B cell progenitors in multiple myeloma patients from the bone marrow, peripheral blood and stem cell grafts.

III. To evaluate T-cell immune response against known myeloma tumor associated antigens while on panobinostat maintenance.

IV. To evaluate humoral immunity against pneumococcal serotypes included in the standard of care heptavalent pneumococcal conjugate vaccine, and to assess cellular immune responses against circumferential resection margin (CRM) adjuvant found in the heptavalent pneumococcal conjugate vaccine.

V. To evaluate minimal residual disease (MRD) after autologous HCT followed by panobinostat maintenance therapy using flow cytometry.

VI. To evaluate MRD after autologous HCT followed by panobinostat maintenance therapy using multiplex polymerase chain reaction (PCR) for complementary determining region (CDR)3 sequences.

OUTLINE: Patients are assigned to 1 of 2 cohorts.

COHORT A: Patients receive higher dose panobinostat orally (PO) once daily (QD) 3 times per week, every other week. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

COHORT B: Patients receive lower dose panobinostat PO QD for 7 days, every other week. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for at least 4 weeks.

Trial Phase & Type

Trial Phase

Phase II

Trial Type

Treatment

Lead Organization

Lead Organization
Moffitt Cancer Center

Principal Investigator
Taiga Nishihori

Trial IDs

Primary ID MCC-18430
Secondary IDs NCI-2016-00910
Clinicaltrials.gov ID NCT02722941