A Phase 1/2 Multi-Center, Open Label, Dose Escalation Study to Determine the RP2D, Safety and Efficacy of GSK2857916 in Combination With Pomalidomide and Low-Dose Dexamethasone in Subjects With Relapsed and/or Refractory Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- GSK2857916 with Pomalidomide and Dexamethasone
- Conditions
- Relapsed and/or Refractory Multiple Myeloma
- Sponsor
- Canadian Myeloma Research Group
- Enrollment
- 120
- Locations
- 9
- Primary Endpoint
- Overall Response Rate (ORR)
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
This is a Phase 1/2, multi-centre, single-arm, open-label, dose-escalation study that will evaluate the safety and efficacy of IV GSK2857916 in combination with PO pomalidomide and low-dose PO dexamethasone in subjects with relapsed and/or refractory MM.
Detailed Description
This is a Phase 1/2, multi-centre, single-arm, open-label, dose-escalation study that will evaluate the safety and efficacy of IV GSK2857916 in combination with PO pomalidomide and low-dose PO dexamethasone in subjects with relapsed and/or refractory MM. This study will consist of a Part 1 dose-finding portion and a Part 2 expansion phase. Part 1 will determine the starting dose and schedule to be used in Part 2. All subjects will receive GSK2857916 given IV either on Day 1 (Single Dose) or on Days 1 and 8 (Split Dose) in combination with pomalidomide and dexamethasone administered orally in 28-day treatment cycles. Treatment will be administered as long as there is clinical benefit. The Part 1 portion of the study will determine the MTD and/or RP2D and dose limiting toxicities (DLTs) of GSK2857916 administered in combination with pomalidomide and dexamethasone. The following dose levels of GSK2857916 in combination with 4 mg of pomalidomide and low-dose dexamethasone are to be tested in this study: 2.5 mg/kg either Single Dose (dose level 1a) or Split Dose (dose level 1b), 1.92 mg/kg Single Dose (dose level -1), and 3.4 mg/kg Split Dose (dose level 2). The Part 1 segment of the study will follow a standard 3 + 3 dose escalation design and will include assessment of the safety of treatment between each dose cohort by the Safety Review Committee (SRC) consisting of the Study Investigators and the Sponsor. When the SRC has determined the RP2D of GSK2857916, the Part 2 portion of the study will be initiated. Pomalidomide will be administered based on the current approved dose and schedule: 4 mg PO QD on Days 1 to 21 of a 28-day cycle. The starting dose of dexamethasone will be 40 mg QD on Days 1, 8, 15 and 22 of each 28-day cycle for subjects who are ≤ 75 years of age. For Subjects who are \> 75 years of age, the starting dose of dexamethasone is 20 mg QD on Days 1, 8, 15, and 22. GSK2857916 will be administered at the RP2D and treatment will continue until progressive disease (PD) or toxicity requiring discontinuation of study drug. Efficacy assessments will be conducted every cycle for the duration of the treatment period. After discontinuation from treatment, follow up will continue by phone or in person until progression from the next line of treatment or death to a maximum of 36 months after enrolment for determination of PFS2 and OS.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Must be able to understand and voluntarily sign an informed consent form (ICF).
- •Must be ≥ 18 years of age at the time of signing the ICF.
- •Must be able to adhere to the study visit schedule and other protocol requirements.
- •Documented diagnosis of MM and relapsed and/or refractory disease with:
- •Have undergone stem cell transplant, or have been considered transplant ineligible
- •Previously treated with two or more prior lines of treatment that must have included lenalidomide and a proteasome inhibitor (in separate regimens or in combination). Induction therapy followed by ASCT and consolidation/maintenance will be considered as one line.
- •Documented evidence of progressive disease (PD) after achieving at least stable disease (SD) for ≥ 1 cycle during a previous MM treatment (i.e., relapsed MM) and/or
- •Disease progression during or within 60 days from the end of the most recent MM treatment (i.e., refractory MM).
- •Subjects with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met:
- •transplant was \> 100 days prior to study enrolment
Exclusion Criteria
- •Prior pomalidomide or BCMA therapy use.
- •History of allegeneic transplant
- •Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including lab abnormalities) that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures.
- •Pregnant or lactating females.
- •Subjects with previous or concurrent malignancies are allowed only if the second tumor is not contributing to the subject's illness. The subject must not be receiving active therapy, other than hormonal therapy for this disease and the disease must be considered medically stable for at least 2 years.
- •Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect subject's safety). Subjects with isolated proteinuria resulting from MM are eligible, provided they fulfil criteria given in inclusion criteria (i.e. albumin/creatinine \< 500 mg/ g (56 mg/mmol).
- •Evidence of cardiovascular risk including any of the following:
- •QTc interval ≥ 470 msecs. NOTE: The QT interval should be corrected for the heart rate by Fridericia's formula (QTcF)
- •Evidence of current clinically significant uncontrolled arrhythmias; including clinically significant ECG abnormalities; including 2nd degree (Type II) or 3rd degree atrioventricular (AV) block.
- •History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening.
Arms & Interventions
GSK2857916 with Pomalidomide and Dexamethasone
This will be a single arm study of GSK2857916 administered with pomalidomide and dexamethasone. GSK2857916 will be administered intravenously either on Day 1 of each 28 day cycle (Single Dose) or on Days 1 and 8 (Split Dose) and up to 4 dose levels will be evaluated during the phase I portion. Pomalidomide will be administered orally on Days 1-21 at 4 mg. Dexamethasone will be administered orally at 40 mg for patients ≤ 75 years old or 20 mg for patients older than 75 on days 1, 8, 15, 22.
Intervention: GSK2857916 with Pomalidomide and Dexamethasone
Outcomes
Primary Outcomes
Overall Response Rate (ORR)
Time Frame: 60 months
Overall response rate will be the percentage of patients achieving partial response or better according to IMWG response criteria
Recommended Phase 2 Dose (RP2D)
Time Frame: 9 months
RP2D and schedule of GSK2857916 for Part 2 will be determined by Part 1 of the study
Secondary Outcomes
- Maximum tolerated dose (MTD)(9 months)
- Treatment Emergent Adverse Events(60 months)
- Progression Free Survival(60 months)