ACY-1215 (Ricolinostat) in Combination With Pomalidomide and Low-dose Dex in Relapsed-and-Refractory Multiple Myeloma

Phase 1

Terminated

Conditions: Multiple Myeloma

Interventions: Drug: ACY-1215 (Ricolinostat) in combination with pomalidomide and dexamethasone

Registration Number: NCT01997840

Lead Sponsor: Celgene

Brief Summary: Phase 1b: To evaluate the side effects and determine the best dose of ACY-1215 in combination with Pomalidomide and low-dose dexamethasone in patients with relapsed-and-refractory multiple myeloma.

Phase 2: To determine the overall response rate of ACY-1215 in combination with Pomolidomide and low-dose dexamethasone in patients with relapsed-and-refractory multiple myeloma

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 103

Inclusion Criteria

Must have a documented diagnosis of multiple myeloma and have relapsed-and-refractory disease. Patients must have received at least 2 lines of prior therapies. Patients must have relapsed after having achieved at least stable disease (SD) for at least one cycle of treatment to at least one prior regimen and then developed progressive disease (PD). Patients must also have documented evidence of PD during or within 60 days (measured from the end of the last cycle) of completing treatment with the last anti-myeloma drug regimen used just prior to study entry (refractory disease)
Must have undergone prior treatment with at least 2 cycles of lenalidomide and at least 2 cycles of a proteasome inhibitor (either in separate regimens or within the same regimen)
Must not be a candidate for autologous stem cell transplant (ASCT), has declined the option of ASCT, or has relapsed after prior ASCT
Must have measurable levels of myeloma paraprotein in serum (≥ 0.5 g/dL) or urine (≥ 0.2 g/24 hours)
Must have Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2
Females of child bearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 - 14 days prior to, and again within 24 hours of starting pomalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 28 days before she starts taking pomalidomide. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure. Risks of Fetal Exposure, Pregnancy Testing Guidelines and Acceptable Birth Control Methods,and Education and Counseling Guidance must be followed per protocol
Must be able to take acetylsalicylic acid (ASA) (81 or 325 mg) daily as prophylactic anticoagulation. Patients intolerant to ASA may use low molecular weight heparin. Lovenox is recommended. Coumadin will be allowed provided the patient is fully anticoagulated, with an international normalized ratio (INR) of 2 to 3

Exclusion Criteria

Pregnant or lactating females
Prior therapy with HDAC inhibitor
Any of the following laboratory abnormalities:
- ANC < 1,000/µL
- Platelet count < 75,000/ µL for patients in whom < 50% of bone marrow nucleated cells are plasma cells; and < 50,000/ µL for patients in whom ≥ 50% of bone marrow nucleated cells are plasma cells
- Hemoglobin < 8g/dL (<4.9 mmol/L; prior red blood cell [RBC] transfusion is permitted)
- Creatine clearance < 45mL/min according to Cockcroft-Gault formula. If creatine clearance calculated from the 24-hour urine sample is ≥ 45 mL/min, patient will qualify for the study
- Serum glutamic oxaloacetic transaminase (SGOT)/aspartate aminotransferase (AST), or serum glutamic pyruvic transaminase (SGPT)/ alanine aminotransferase (ALT) > 3.0 × ULN
- Serum total bilirubin > 2.0 mg/dL
Prior history of malignancies, other than MM, unless the patient has been free of the disease for ≥ 3 years. Exceptions include the following:
- Basal or squamous cell carcinoma of the skin
- Carcinoma in situ of the cervix or breast
- Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b)
Corrected QT interval using Fridericia's formula (QTcF) value > 480 msec at screening; family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy; previous history of drug-induced QTc prolongation or the need for treatment with medications known or suspected of producing prolonged QTc intervals on electrocardiogram (ECG)
Positive human immunodeficiency virus (HIV), hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infection
Hypersensitivity to thalidomide, lenalidomide, or dexamethasone (such as Steven Johnson Syndrome). Hypersensitivity, such as rash, that can be medically managed is allowable
Peripheral neuropathy ≥ Grade 2 despite supportive therapy
Radiotherapy or systemic therapy (standard or an investigational or biologic anticancer agent) within 14 days of initiation of study drug treatment
Current enrollment in another clinical trial involving treatment and/or is receiving an investigational agent for any reason
Inability or unwillingness to comply with birth control requirements or regional REMS/RevAid programs

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
ACY-1215 in combination with pomalidomide and dexamethasone	ACY-1215 (Ricolinostat) in combination with pomalidomide and dexamethasone	ACY-1215 (Ricolinostat) in combination with pomalidomide and dexamethasone

Primary Outcome Measures

Name	Time	Method
Maximum Tolerated Dose (MTD) of ACY-1215- Phase 1b	From first dose until the end of Phase 1b (up to a maximum of approximately 50 weeks).	The maximum tolerated dose (MTD) was defined as the highest dose level at which no more than 1 of 6 patients experienced a dose-limiting toxicity (DLT) within the first 28-day cycle. If no more than 1 of these 6 patients experienced a DLT within the first 28-day cycle, then the last dose level enrolled to meet these criteria was identified as the recommended dose for the Phase 2 segment of the study.
Overall Response Rate (ORR) Per Investigator - Phase 2	From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).	Overall response rate (ORR) is defined as the percentage of participants with a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: * No detectable myeloma cells in the bone marrow. * Normal free light chain ratio. * Absence of clonal cells in the bone marrow. CR: * Negative immunofixation on the serum and urine. * Disappearance of any soft tissue plasmacytomas. * Less than 5% plasma cells in the bone marrow. VGPR: * Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or * At least a 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 hours. PR: * At least a 50% reduction in serum M-protein. * Reduction in 24-hour urinary M-protein by at least 90% or to less than 200 mg per 24 hours. * For patients with non-secretory myeloma, a reduction of at least 50% in the size of soft tissue plasmacytomas is required.

Secondary Outcome Measures

Name	Time	Method
Time to Response (TTR)	From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).	Time to response (TTR) was defined as the time from first dose of study treatment to the first documentation of response (either partial response (PR) or complete response (CR)). CR: * Negative immunofixation on the serum and urine. * Disappearance of any soft tissue plasmacytomas. * Less than 5% plasma cells in the bone marrow. PR: * At least a 50% reduction in serum M-protein. * Reduction in 24-hour urinary M-protein by at least 90% or to less than 200 mg per 24 hours. * For patients with non-secretory myeloma, a reduction of at least 50% in the size of soft tissue plasmacytomas is required.
Duration of Response (DoR)	From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).	Duration of Response (DOR) was defined as the time from first partial response (PR) or complete response (CR) to the first documentation of progressive disease (PD) or death. PR: * \>= 50% reduction in serum M-protein. * Reduction in 24-hour urinary M-protein by \>= 90% or to less than 200 mg per 24 hours. * For non-secretory myeloma, a reduction of \>= 50% in size of soft tissue plasmacytomas. CR: * Negative immunofixation on the serum and urine. * Disappearance of any soft tissue plasmacytomas. * \< 5% plasma cells in the bone marrow. PD: * Increase of 25% or more from nadir in serum M-protein, absolute increase of \>= 0.5 g/dL. * Increase of 25% or more from nadir in 24-hour urinary M-protein, absolute increase of \>=200 mg/24 hours. * Increase of 25% or more in the percentage of bone marrow plasma cells, absolute increase of \>=10%. Calculated using Kaplan-Meier estimates.
Time to Progression (TTP)	From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).	Time to progression (TTP) was defined as the time from the date of first dose to the date of first documentation of progressive disease (PD). PD: * Increase of 25% or more from nadir in serum M-protein, absolute increase of \>= 0.5 g/dL. * Increase of 25% or more from nadir in 24-hour urinary M-protein, absolute increase of \>=200 mg/24 hours. * Increase of 25% or more in the percentage of bone marrow plasma cells, absolute increase of \>=10%. * New bone lesions or soft tissue plasmacytomas or increase size of existing bone lesions or soft tissue plasmacytomas. * Hypercalcemia attributed to myeloma.
Progression-free Survival (PFS)	From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).	Progression-free survival (PFS) was defined as the time from first dose of study treatment to the first documentation of progressive disease (PD) or death from any cause during study PD: * Increase of 25% or more from nadir in serum M-protein, absolute increase of \>= 0.5 g/dL. * Increase of 25% or more from nadir in 24-hour urinary M-protein, absolute increase of \>=200 mg/24 hours. * Increase of 25% or more in the percentage of bone marrow plasma cells, absolute increase of \>=10%. * New bone lesions or soft tissue plasmacytomas or increase size of existing bone lesions or soft tissue plasmacytomas. * Hypercalcemia attributed to myeloma. Calculated using Kaplan-Meier estimates.
Overall Response Rate (ORR) Per Central Adjudication Committee	From first dose until disease progression, study drug toxicity, end of study, or death due to any cause (up to approximately 120 months).	Overall response rate (ORR) per Central Adjudication Committee is the percentage of participants with a best response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR). sCR: * No detectable myeloma cells in the bone marrow. * Normal free light chain ratio. * Absence of clonal cells in the bone marrow. CR: * Negative immunofixation on the serum and urine. * Disappearance of any soft tissue plasmacytomas. * Less than 5% plasma cells in the bone marrow. VGPR: * Serum and urine M-protein detectable by immunofixation but not on electrophoresis, or * At least a 90% reduction in serum M-protein plus urine M-protein level less than 100 mg per 24 hours. PR: * At least a 50% reduction in serum M-protein. * Reduction in 24-hour urinary M-protein by at least 90% or to less than 200 mg per 24 hours. * For patients with non-secretory myeloma, a reduction of at least 50% in the size of soft tissue plasmacytomas is required
Number of Participants With Adverse Events (AEs)	From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks)	An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
Number of Participants With Serious Adverse Events (SAEs)	From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks)	A serious adverse event (SAE) is defined as any adverse event (AE) occurring at any dose that: * Results in death; * Is life-threatening (ie, in the opinion of the Investigator, the participant is at immediate risk of death from the AE); * Requires inpatient hospitalization or prolongation of existing hospitalization (hospitalization is defined as an inpatient admission, regardless of length of stay). * Results in persistent or significant disability/incapacity (a substantial disruption of the participant's ability to conduct normal life functions); * Is a congenital anomaly/birth defect; * Constitutes an important medical event. Graded according to NCI CTCAE (Version 4) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
Number of Participants With Adverse Events (AEs) Leading to Discontinuation	From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks)	An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
Number of Participants With Adverse Events (AEs) Related to Study Drug	From first dose until 30 days after last dose of study drug (assessed for an average of approximately 55 weeks to a maximum of approximately 456 weeks)	An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the participant's health, including laboratory test values, regardless of etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE. Graded according to NCI CTCAE (Version 4.03) guidelines where grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life threatening, grade 5 = death.
Plasma Levels of ACY-1215 and Pomalidomide - Phase 1b	Cycle 1 day 1, Cycle 1 Day 2, Cycle 1 Day 8
Number of Participants With Anti-Drug Antibodies (ADA) - Phase 1b	Cycle 1 day 1, Cycle 1 Day 2, Cycle 1 Day 8