Relapsed/Refractory Multiple Myeloma MedDRA version: 16.1 Level: HLT Classification code 10028229 Term: Multiple myelomas System Organ Class: 100000004851
Conditions
Sponsors
Pharmacyclics LLC
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Disease Related 1. Subjects with relapsed/refractory MM who have received at least two prior lines of therapy including LEN and either bortezomib or carfilzomib and have demonstrated disease progression on or within 60 days of the completion of the most recent treatment regimen. - Subjects must have received at least 2 cycles of treatment with LEN and either bortezomib or carfilzomib at the approved dose and schedule (maintenance will be excluded). 2. Measurable disease defined by at least ONE of the following: • Serum monoclonal protein (SPEP) =1 g/dL. • Urine monoclonal protein (UPEP) =200 mg by 24 hour urine. Laboratory 3. Adequate hematologic function independent of platelet transfusion and growth factor support for at least 7 days prior to Screening and dosing (Phase 1) or randomization/enrollment (Phase 2b), with the exception of pegylated G-CSF (granulocyte-colony stimulating factor pegfilgrastim) and darbopoeitin which require at least 14 days, defined as: • Absolute neutrophil count =1500 cells/mm^3(1.5 x 10^9/L). • Platelet count >75,000 cells/mm^3 (75 x 109/L). • Hemoglobin =8.0 g/dL. 4. Adequate hepatic and renal function defined as: • Serum aspartate transaminase (AST) or alanine transaminase (ALT) =3.0 x upper limit of normal (ULN). • Serum creatinine <3.0 mg/dL AND Creatinine Clearance =30 mL/min (by Cockcroft-Gault OR as measured by 24 hour urine collection). • Total Bilirubin =2.0 mg/dL (unless bilirubin rise is due to Gilbert´s syndrome or of non hepatic origin). 5. PT/INR =1.5 x ULN and PTT (aPTT) =1.5 x ULN (unless on warfarin, then INR =3.0). Demographic 6. Men and women = 18 years of age. 7. Eastern Cooperative Oncology Group (ECOG) performance status of =2. Ethical/Other 8. All study participants must be registered into the mandatory Pomalyst REMS™ or RevAid® program, and be willing and able to comply with the requirements of the Pomalyst REMS™ or RevAid® program as appropriate for the country in which the drug is being used. (for US/Canada Sites Only). 9. Female subjects of childbearing potential (FCBP)a must adhere to the scheduled pregnancy testing as required in the Pomalyst REMS™ or RevAid® program as appropriate for the country in which the drug is being used. (for US/Canada Sites Only). 10. Female subjects of childbearing potential (FCBP)a must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10 – 14 days and again within 24 hours prior to starting Cycle 1 of pomalidomide. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure (for ex US sites only). 11. Male subjects must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. (for US/Canada sites only). 12. Male subjects must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All subjects must be counseled at a minimum of every 28 days about pregnancy precautions and risks of fetal exposure, (for ex US sites only). 13. FCBP and male subjects who are sexually active must use TWO acceptable methods of birth control, one highly effective method of birth control plus one additional effective method of birth control for at least 28 days prior to study treatment and during the study treatment period. For female and male subjects, these birth control requirements must be adhered to for 90 days
Exclusion criteria
Exclusion criteria: Disease-Related 1. Primary refractory disease defined as nonresponsive in patients who have never achieved a minimal response or better with any therapy. 2. History of plasma cell leukemia, primary amyloidosis, POEMS syndrome within 12 months prior to first administration of study treatment. Concurrent Conditions 3. Recent prior chemotherapy a. Alkylators (eg, melphalan, cyclophosphamide) and/or anthracyclines 20 mg/day of prednisone or equivalent) within 28 days of the first dose of study treatment. 10. Recent infection requiring systemic treatment that was completed <7 days before the first dose of study treatment and/or uncontrolled active systemic infection. 11. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), Grade =1 or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia. 12. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia). 13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment/randomization. 14. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus (HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before enrollment/ randomization. Those who are PCR positive will be excluded. 15. Major surgery within 4 weeks of first dose of study treatment. 16. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator’s opinion, could compromise the subject’s safety or put the study outcomes at undue risk. 17. Currently active, clinically significant hepatic impairment (= mild hepatic impairment according to the Child Pugh classification. 18. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to enrollment/randomization. • QTc =470 msec calculated using Fridericia formula (QTcF) at Screening. 19. Unable to swallow capsules or malabsorption syndrome, disease significantly
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Phase 1: • To determine the maximum tolerate dose (MTD)/maximum administered dose (MAD) and the Phase 2b dose of the ibrutinib, pomalidomide and dexamethasone combination. • To determine the safety and tolerability of ibrutinib in combination with pomalidomide and dexamethasone in subjects with relapsed/refractory Multiple Myeloma (MM). Phase 2b: • To evaluate the effect of ibrutinib in combination with pomalidomide and dexamethasone compared to placebo in combination with pomalidomide and dexamethasone on progression-free survival (PFS), as assessed by independent review committee (IRC), in subjects with relapsed/refractory MM.;Secondary Objective: Phase 1: • Overall response rate (ORR) defined as =partial response (PR) according to the International Myeloma Working Group (IMWG) response criteria (Rajkumar 2011) • Duration of response (DOR) • The clinical benefit rate (CBR) and its duration, defined as =MR according to the IMWG response criteria (Rajkumar 2011) • To evaluate the PK of ibrutinib and pomalidomide when given in combination with dexamethasone Phase 2b: • To compare the treatment arms as assessed by both IRC and investigator in terms of the following: - ORR (=PR; according to IMWG [Rajkumar 2011]) - DOR - CBR (=MR; according to IMWG [Rajkumar 2011]) and its duration - Overall survival (OS) - Time-to-progression (TTP) In addition, • To evaluate the safety and tolerability of ibrutinib in combination with pomalidomide and dexamethasone • To evaluate the PK of ibrutinib and pomalidomide when given in combination with dexamethasone;Primary end point(s): The primary efficacy endpoint of the Phase 2b portion of this study is PFS, as assessed by the IRC. Progression-free survival will be assessed on all subjects in the ITT population. ;Timepoint(s) of evaluation of this end point: Every visit. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): • The ORR will be assessed by investigator (for Phase 1) and by IRC (for Phase 2b) according to the IMWG criteria and is defined as the proportion of subjects who achieve a PR or better over the course of the study. • The DOR is defined as the interval between the date of initial documentation of a response and the date of first documented evidence of progressive disease as assessed by investigator (for Phase 1) and by IRC (for Phase 2b), death, or date of censoring if applicable, for responders only. Subjects who start new anti-cancer treatment before documentation of disease progression will be censored on the date of the last adequate disease assessment that is on or before the start date of new anti-cancer therapy. Responders are subjects in the ITT population who achieve PR or better according to the IMWG response criteria. Non responders (=MR) will be excluded from the analysis for DOR. • Clinical benefit rate (CBR) and its duration as assessed by investigator (for Phase 1) and by IRC (for Phase 2b) including subjects with minimal response (MR) or better according to the IMWG. • OS is defined as the time from date of randomization until date of death due to any cause. Subjects who are known to be alive or whose survival status is unknown will be censored at the date last known to be alive. Subjects who are completely lost to follow-up for survival after randomization will be censored at randomization date (Phase 2b). • TTP is defined as the time from the start of treatment until date of disease progression as assessed by IRC. Subjects who die before disease progression due to causes other than progression will be censored at the date of death (Phase 2b).;Timepoint(s) of evaluation of this end point: Every 4 weeks after the start of study treatment. | — |
Countries
Australia, Czech Republic, Germany, Greece, Spain, United States
Contacts
Public ContactSenior Director, Reg Affairs
Pharmacyclics Limited Liability Company
Outcome results
None listed