| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Form of blood cancer that forms in the bone marrow. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10028229 |
| E.1.2 | Term | Multiple myelomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
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 |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Within protocol amendment 1, dated 6 November 2015
Open-Label Sub-Study Treatment Arm C (Phase 2b)
• To evaluate the efficacy and safety of ibrutinib in combination with pomalidomide and dexamethasone in subjects who either have:
- Less than a partial response (<PR) following at least 112 days (4 x 28 day cycles) of pomalidomide and dexamethasone (regimen must not have included other anti cancer agents) and are without evidence of disease progression
OR
- Disease progression following an initial confirmed response of MR or better to the combination of pomalidomide and dexamethasone (regimen must not have included other anti-cancer agents) |
|
| E.3 | Principal 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.
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 after the last dose of ibrutinib and pomalidomide, whichever is later. Male subjects must agree to not donate sperm during the study treatment period and up to 90 days after the last dose of ibrutinib and pomalidomide, whichever is later.
Inclusion Criteria for Open-label Sub-study Arm C (Phase 2b)
To be enrolled in the sub-study, each potential subject must meet all inclusion criteria defined in Section 4.1 of the protocol. IN ADDITION the following criteria must be met:
Subject must have received pomalidomide in combination with dexamethasone (regimen must not have included other anti-cancer agents) as their most recent line of therapy and have:
• Achieved less than a partial response (<PR) following at least 112 days (4 x 28 day cycles) and are without evidence of progression disease (PD)
OR
• Disease progression following an initial confirmed response of MR or better to the combination (according to IMWG response criteria; Rajkumar 2011) |
|
| E.4 | Principal 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 ≤21 days prior to first administration of study treatment.
b. High dose corticosteroids, IMiDs or proteasome inhibitors ≤14 days prior to first administration of study treatment.
c. Monoclonal antibody ≤6 weeks prior to first administration of study treatment.
4. Prior exposure to Bruton’s tyrosine kinase (BTK) inhibitors.
5. Prior exposure to pomalidomide (except Treatment Arm C).
6. History of serious hypersensitivity reactions to prior thalidomide, lenalidomide or pomalidomide.
7. History of other malignancies, except:
a. Malignancy treated with curative intent and with no known active disease present for ≥3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
c. Adequately treated carcinoma in situ without evidence of disease.
8. Peripheral neuropathy Grade ≥2 with pain at Screening.
9. Concurrent systemic immunosuppressant therapy (eg, cyclosporine A, tacrolimus, etc., or chronic administration of >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 affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
20. Requires treatment with a strong cytochrome P450 (CYP) 3A4 inhibitor.
21. Women who are pregnant or breast-feeding.
22. Unwilling or unable to participate in all required study evaluations and procedures.
23. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
Exclusion Criteria for Open-Label Sub-Study Arm C (Phase 2b)
To be enrolled in the sub-study, each potential subject must not meet any exclusion criteria defined above EXCEPT for exclusion criteria 5 which is related to prior pomalidomide and does not apply for the sub-study Arm C. |
|
| E.5 End points |
| E.5.1 | 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.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | 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). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Every 4 weeks after the start of study treatment. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Czech Republic |
| Germany |
| Greece |
| Spain |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of the study will occur approximately 2 years after the last subject is randomized, or the Sponsor terminates the study, whichever comes first. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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