Study of ACY-241 Alone and in Combination With Pomalidomide and Dexamethasone in Multiple Myeloma

Sponsor

Celgene (Industry)

Overall Status

Active, not recruiting

CT.gov ID

NCT02400242

Collaborator

(none)

Enrollment

Locations

Arm

85.8

Anticipated Duration (Months)

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: ACY-241 Drug: Pomalidomide Drug: Dexamethasone	Phase 1

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

85 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

May 7, 2015

Anticipated Primary Completion Date :

Jun 30, 2022

Anticipated Study Completion Date :

Jun 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ACY-241, Pomalidomide, and dexamethasone Open label dosing cohorts will evaluate oral ACY-241 (dosing ranging from 180 mg to 480 mg days 1-21) in combination with oral pomalidomide (4 mg days 1-21), and oral dexamethasone (40 mg qd on days 1, 8, 15, 22).	Drug: ACY-241 Dose escalation up to 480 mg administered orally on Days 1-21 of a 28 day cycle. Other Names: Histone deacetylase inhibitor Drug: Pomalidomide 4 mg qd dosed on days 1-21 of a 28 day cycle Other Names: immunomodulatory agent Drug: Dexamethasone 40 mg qd on days 1, 8, 15, 22 Other Names: corticosteriod

Arm

Intervention/Treatment

Experimental: ACY-241, Pomalidomide, and dexamethasone

Open label dosing cohorts will evaluate oral ACY-241 (dosing ranging from 180 mg to 480 mg days 1-21) in combination with oral pomalidomide (4 mg days 1-21), and oral dexamethasone (40 mg qd on days 1, 8, 15, 22).

Drug: ACY-241

Dose escalation up to 480 mg administered orally on Days 1-21 of a 28 day cycle.

Other Names:

Histone deacetylase inhibitor

Drug: Pomalidomide

4 mg qd dosed on days 1-21 of a 28 day cycle

Other Names:

immunomodulatory agent

Drug: Dexamethasone

40 mg qd on days 1, 8, 15, 22

Other Names:

corticosteriod

Outcome Measures

Primary Outcome Measures

Maximum tolerated dose of ACY-241 as monotherapy as assessed by dose limiting toxicities [Cycle 1 (28 days)]
Maximum tolerated dose of ACY-241 in combination with pomalidomide and low dose dexamethasone as assessed by dose limiting toxicities [Cycle 2 (28 days)]
First cycle of combination therapy

Secondary Outcome Measures

Frequency and severity of AEs as measured by safety and tolerability [Cycle 1 (28 days)]
Single- and multiple-dose peak-plasma concentration [Cycle 1 days 1, 2, 15 and 16]
Single- and multiple-dose area under the plasma concentration versus time curve [Cycle 1 days 1, 2, 15 and 16]
Change in acetylation of histone and tubulin as a measure of pharmacodynamics [Cycles 1 days 1, 2, 15, 16 and 22]
Change in fetal hemoglobin expression as a measure of pharmacodynamics [Cycles 1 days 1, 2, 15, 16 and 22]
ACY-241 metabolite concentration in blood samples [Cycles 1 days 1, 2, 15, 16 and 22]
Exposure response analyses of potential biomarkers of response. [Cycles 1 days 1, 2, 15, 16 and 22]
Frequency and severity of AEs as measured by safety and tolerability in combination [Beginning at Cycle 2 (28 day cycle each) until end of treatment]
Change in fetal hemoglobin expression as a measure of pharmacodynamics [Cycle 2 days 1, 2, 15, 16 and 22]
Change in acetylation of histone and tubulin as a measure of pharmacodynamics [Cycle 2 days 1, 2, 15, 16 and 22]
Single- and multiple-dose area under the plasma concentration versus time curve [Cycle 2 days 1, 2, 15, and 16]
Quantification of M-protein as a measure of anti-tumor activity [Day 1 of each cycle beginning at Cycle 2]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Arizona	Tucson	Arizona	United States	85719
2	Colorado Blood Cancer Institute	Denver	Colorado	United States	80218
3	University of Miami Medical Center	Miami	Florida	United States	33136-2107
4	Local Institution - 108	Tampa	Florida	United States	33612
5	Moffitt Cancer Center	Tampa	Florida	United States	33612
6	Local Institution - 103	Atlanta	Georgia	United States	30322
7	Winship Cancer Institute of Emory University	Atlanta	Georgia	United States	30322
8	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
9	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
10	Weill Cornell Medical College	New York	New York	United States	10065
11	Gabrail Cancer Center Research	Canton	Ohio	United States	44718
12	CTRC at The UT Health Science Center at San Antonio	San Antonio	Texas	United States	78229
13	Swedish Cancer Institute	Seattle	Washington	United States	98104
14	CHRU de Lille-Hopital Claude Huriez Service des Maladies du Sang	Lille		France	59037
15	Local Institution - 340	Lille		France	59037
16	Hotel Dieu CHU Nantes	Nantes Cedex 01		France	44093
17	Universitatsklinikum Heidelberg Medizinische Klinik Krehl-Klinik Haematologie, Onkologie, Rheumato	Heidelberg		Germany	69120
18	Alexandra Hospital, University of Athens	Athens		Greece	11528
19	Clinica Universitaria de Navarra	Pamplona		Spain	31008
20	Hospital Universitario de Salamanca	Salamanca		Spain	37007
21	Local Institution - 300	Salamanca		Spain	37007