Clinical trial NCT02400242: Study of ACY-241 Alone and in Combination With Pomalidomide and Dexamethasone in Multiple Myeloma
Official title: A Phase 1a/1b Multicenter, Single-Arm, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, and Preliminary Activity of Oral ACY-241 Alone and in Combination With Pomalidomide and Low-Dose Dexamethasone in Patients With Relapsed or Relapsed-and-Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Multiple Myeloma
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2015-03-27
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a phase 1a/1b, multicenter, single-arm, open-label, dose escalation study to determine the maximum tolerated dose (MTD) and evaluate the safety and preliminary antitumor activity of ACY-241 for oral administration as monotherapy and in combination therapy with orally administered pomalidomide and low-dose dexamethasone in eligible patients with relapsed or relapsed-and-refractory multiple myeloma (MM).

Detailed description: During phase 1a, patients will receive 1 cycle of ACY-241 monotherapy. Patients who complete the ACY-241 monotherapy cycle without a dose limiting toxicity (DLT) and are clinically stable may continue to phase 1b combination therapy, beginning with Cycle 2. During phase 1b, patients will receive ACY 241 in combination with pomalidomide and low dose dexamethasone at the currently approved pomalidomide dose and schedule. Each cohort of patients in phase 1a and phase 1b will consist of at least 3 patients. The first patient enrolled in each cohort of phase 1a will be observed for 1 week before enrollment of subsequent patients in the cohort. Patients who withdraw consent before entering phase 1b will be replaced. (Replacement patients must complete phase 1a prior to continuing to phase 1b.) Patients who experience a DLT or other unacceptable toxicity in Cycle 1 of phase 1a monotherapy or Cycle 2, the first cycle of phase 1b combination therapy, will be removed from study treatment. An assessment of the safety of treatment will be completed by the Safety Review Committee (SRC) prior to dose-escalation.

Eligibility criteria: Key Inclusion Criteria:

* Must have a documented diagnosis of MM and have relapsed or relapsed-and-refractory disease. All patients must have relapsed after having achieved at least stable disease (SD) for at least 1 cycle of treatment to at least 1 prior regimen and then developed progressive disease (PD). Relapsed-and-refractory patients also have documented evidence of PD during or within 60 days of completing last treatment
* Must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of proteasome inhibitor unless not a candidate.
* May have undergone prior treatment with pomalidomide if patient is not refractory to pomalidomide and has previously achieved a response of MR or better to pomalidomide.
* Must have measurable disease (serum M-protein or urine M-protein).
* Must have Eastern Cooperative Oncology Group (ECOG) Performance score of 0, 1, or 2.
* Must be able to take low-dose aspirin, low molecular weight heparin, or other equivalent antithrombotic or anticoagulant daily as prophylactic anticoagulation.

Key Exclusion Criteria:

* Prior therapy with pomalidomide with best response of PD or SD.
* Prior therapy with histone deacetylase (HDAC) inhibitor.
* Any of the following laboratory abnormalities: Absolute neutrophil count(ANC) \< 1,000/µL, Platelet count \< 75,000/µL or \< 50,000/µL for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells, Hemoglobin \< 8 g/dL, Creatinine clearance \< 45 mL/min according to Cockcroft-Gault formula. If creatinine clearance calculated from the 24 hour urine sample is ≥ 45 mL/min, patient will qualify for the trial, Aspartate transaminase (AST) or Alanine transaminase (ALT) \> 3.0 × Upper Limited Normal (ULN), Serum total bilirubin \> 2.0 mg/dL or \> 3.0 × ULN for patients with hereditary benign hyperbilirubinaemia.
* Hematologic growth factors are not allowed at screening or during the first cycle of phase 1a or 1b.
* Nonsecretory myeloma or free light chain detected in serum only (ogliosecretory).
* Hypersensitivity to thalidomide, lenalidomide, pomalidomide, or dexamethasone
* Patients who received an allogeneic bone marrow or allogeneic peripheral blood stem cell transplant less than 12 months prior to initiation of study

Primary outcomes:
measure: Maximum tolerated dose of ACY-241 as monotherapy as assessed by dose limiting toxicities
timeFrame: Cycle 1 (28 days)
measure: Maximum tolerated dose of ACY-241 in combination with pomalidomide and low dose dexamethasone as assessed by dose limiting toxicities
timeFrame: Cycle 2 (28 days)
Secondary outcomes:
measure: Frequency and severity of AEs as measured by safety and tolerability
timeFrame: Cycle 1 (28 days)
measure: Single- and multiple-dose peak-plasma concentration
timeFrame: Cycle 1 days 1, 2, 15 and 16
measure: Single- and multiple-dose area under the plasma concentration versus time curve
timeFrame: Cycle 1 days 1, 2, 15 and 16
measure: Change in acetylation of histone and tubulin as a measure of pharmacodynamics
timeFrame: Cycles 1 days 1, 2, 15, 16 and 22
measure: Change in fetal hemoglobin expression as a measure of pharmacodynamics
timeFrame: Cycles 1 days 1, 2, 15, 16 and 22
measure: ACY-241 metabolite concentration in blood samples
timeFrame: Cycles 1 days 1, 2, 15, 16 and 22
measure: Exposure response analyses of potential biomarkers of response.
timeFrame: Cycles 1 days 1, 2, 15, 16 and 22
measure: Frequency and severity of AEs as measured by safety and tolerability in combination
timeFrame: Beginning at Cycle 2 (28 day cycle each) until end of treatment
measure: Change in fetal hemoglobin expression as a measure of pharmacodynamics
timeFrame: Cycle 2 days 1, 2, 15, 16 and 22
measure: Change in acetylation of histone and tubulin as a measure of pharmacodynamics
timeFrame: Cycle 2 days 1, 2, 15, 16 and 22
measure: Single- and multiple-dose area under the plasma concentration versus time curve
timeFrame: Cycle 2 days 1, 2, 15, and 16
measure: Quantification of M-protein as a measure of anti-tumor activity
timeFrame: Day 1 of each cycle beginning at Cycle 2
Other outcomes:
Locations:
city: Tucson
country: United States
facility: Local Institution - 109
state: Arizona
city: Denver
country: United States
facility: Colorado Blood Cancer Institute
state: Colorado
city: Miami
country: United States
facility: University of Miami Medical Center
state: Florida
city: Tampa
country: United States
facility: Local Institution - 108
state: Florida
city: Atlanta
country: United States
facility: Local Institution - 103
state: Georgia
city: Boston
country: United States
facility: Local Institution - 104
state: Massachusetts
city: Boston
country: United States
facility: Local Institution - 105
state: Massachusetts
city: New York
country: United States
facility: Local Institution - 101
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center Research
state: Ohio
city: San Antonio
country: United States
facility: CTRC at The UT Health Science Center at San Antonio
state: Texas
city: Seattle
country: United States
facility: Local Institution - 111
state: Washington
city: Lille
country: France
facility: Local Institution - 340
city: Nantes Cedex 01
country: France
facility: Local Institution - 341
city: Heidelberg
country: Germany
facility: Local Institution - 330
city: Athens
country: Greece
facility: Local Institution - 320
city: Pamplona
country: Spain
facility: Local Institution - 301
city: Salamanca
country: Spain
facility: Local Institution - 300
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References: