A Phase 1/2, Dose and Schedule Evaluation Study to Investigate the Safety and Clinical Activity of Belantamab Mafodotin Administrated in Combination With Lenalidomide, Dexamethasone and Nirogacestat in Patients With Transplant Ineligible Newly Diagnosed Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- Nirogacestat
- Conditions
- Multiple Myeloma
- Sponsor
- Hellenic Society of Hematology
- Enrollment
- 36
- Locations
- 2
- Primary Endpoint
- Part 1 and 2: Ocular Toxicity
- Status
- Recruiting
- Last Updated
- 2 years ago
Overview
Brief Summary
This is a phase 1/2, open-label study designed to assess the safety and clinical activity of different belantamab mafodotin doses in combination with lenalidomide, dexamethasone and nirogacestat in patients with transplant ineligible newly diagnosed multiple myeloma.
This will be a 2-part study. In part 1 participants will be enrolled in one cohort to receive belantamab mafodotin in combination with lenalidomide, dexamethasone and nirogacestat and will determine the recommended phase 2 dose (RP2D) to be further evaluated for safety and clinical activity in the dose expansion cohort. The RP2D dose will be used in future studies in the transplant-ineligible newly diagnosed multiple myeloma (NDMM) setting. In the dose expansion phase (Part 2) an expansion cohort will be treated with the RP2D. The expansion cohort will randomize participants (1:1) in two groups to evaluate two alternate dose modification guidelines for corneal AEs. Part 2 of the study will also evaluate an alternative dose modification guideline for corneal adverse events (AEs).
Overall, approximately 36 participants will be enrolled in the study. Participant follow-up will continue up to 3 years after the last participant is enrolled (follow-up period range: 3-4 years). The estimated accrual period will be 12 months, corresponding to an approximate total study duration of 4 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Participant must be \>18 years of age
- •Monoclonal plasma cells in the bone marrow (BM) ≥10% or presence of a biopsy proven plasmacytoma and documented Multiple Myeloma (MM) satisfying at least one of the calcium, renal, anemia, bone (CRAB) criteria or biomarkers of malignancy criteria:
- •CRAB criteria:
- •i. Hypercalcemia: serum calcium \>0.25 mmol/L (\>1 mg/dL) higher than upper limit of normal (ULN) or \>2.75 mmol/L (\>11 mg/dL).
- •ii. Renal insufficiency: creatinine clearance (CrCI) \<40mL/min or serum creatinine \>177 μmol/L (\>2 mg/dL).
- •iii. Anemia: hemoglobin \>2 g/dL below the lower limit of normal or hemoglobin \<10 g/dL.
- •iv. Bone lesions: one or more osteolytic lesions on skeletal radiography, Computed tomography (CT), or Positron emission tomography (PET-CT).
- •Biomarkers of Malignancy:
- •Clonal BM plasma cell percentage ≥60%.
- •Involved: uninvolved serum free light chain (sFLC) ratio ≥
Exclusion Criteria
- •Prior systemic therapy for MM or Smoldering MM.
- •NOTE 1: An emergency course of steroids (defined as not greater than 40 mg of dexamethasone \[or equivalent\] per day for a maximum of 4 days \[i.e., a total of 160 mg\]) is permitted.
- •NOTE 2: Focal palliative radiation is permitted before enrollment, provided that: it occurred at least 2 weeks before the first dose of the study drug; the participant has recovered from radiation-related toxicities; and the participant did not require corticosteroid administration (for a longer period than that specified in NOTE 1 above) for radiation-induced AEs.
- •Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the National Cancer Institute Common Toxicity Criteria for AEs version
- •Major surgery within 2 weeks before the first dose of the study drug.
- •NOTE 1: patients who underwent major surgery must be clinically stable to be enrolled in the study.
- •NOTE 2: major surgery shall be defined based on the Investigator's judgment according to the extent and complexity of the procedure, its pathophysiological consequences and consecutive clinical outcomes.
- •Presence of active renal condition (infection, requirement for dialysis or any other significant condition that could affect the participant's safety). Participants with isolated proteinuria resulting from MM are eligible, provided that they fulfil the other inclusion criteria.
- •Any serious and/or unstable pre-existing medical, psychiatric disorder, or other conditions (including laboratory abnormalities) that could interfere with the participant's safety, obtaining informed consent, or compliance with the study procedures.
- •Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not explained by reversible coagulopathy.
Arms & Interventions
Part 1 : Dose finding
Belantamab mafodotin will be administered as a combination therapy as a calculated dose on Day 1 of every other 28-day cycle. Belantamab mafodotin starting dose: • 1.4 mg/kg Q8W (i.e., on Day 1 of every other 28-day cycle) * Dose Level +1: 1.9 mg/kg Q8W * Dose Level -1: 1.0 mg/kg Q8W * Dose Level -2: 1.0 mg/kg Q12W Lenalidomide: 25 mg/d on day 1-21 of every 28-day cycle. Dexamethasone: 40 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants \< 75 years; 20 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants ≥ 75 years Nirogacestat: 100 mg twice a day (BID) starting on day -3 and then each day of every other 28-day cycle (i.e., to be given only on cycles where belantamab mafodotin is administered).
Intervention: Nirogacestat
Part 1 : Dose finding
Belantamab mafodotin will be administered as a combination therapy as a calculated dose on Day 1 of every other 28-day cycle. Belantamab mafodotin starting dose: • 1.4 mg/kg Q8W (i.e., on Day 1 of every other 28-day cycle) * Dose Level +1: 1.9 mg/kg Q8W * Dose Level -1: 1.0 mg/kg Q8W * Dose Level -2: 1.0 mg/kg Q12W Lenalidomide: 25 mg/d on day 1-21 of every 28-day cycle. Dexamethasone: 40 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants \< 75 years; 20 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants ≥ 75 years Nirogacestat: 100 mg twice a day (BID) starting on day -3 and then each day of every other 28-day cycle (i.e., to be given only on cycles where belantamab mafodotin is administered).
Intervention: Belantamab Mafodotin-Blmf
Part 1 : Dose finding
Belantamab mafodotin will be administered as a combination therapy as a calculated dose on Day 1 of every other 28-day cycle. Belantamab mafodotin starting dose: • 1.4 mg/kg Q8W (i.e., on Day 1 of every other 28-day cycle) * Dose Level +1: 1.9 mg/kg Q8W * Dose Level -1: 1.0 mg/kg Q8W * Dose Level -2: 1.0 mg/kg Q12W Lenalidomide: 25 mg/d on day 1-21 of every 28-day cycle. Dexamethasone: 40 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants \< 75 years; 20 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants ≥ 75 years Nirogacestat: 100 mg twice a day (BID) starting on day -3 and then each day of every other 28-day cycle (i.e., to be given only on cycles where belantamab mafodotin is administered).
Intervention: Lenalidomide
Part 1 : Dose finding
Belantamab mafodotin will be administered as a combination therapy as a calculated dose on Day 1 of every other 28-day cycle. Belantamab mafodotin starting dose: • 1.4 mg/kg Q8W (i.e., on Day 1 of every other 28-day cycle) * Dose Level +1: 1.9 mg/kg Q8W * Dose Level -1: 1.0 mg/kg Q8W * Dose Level -2: 1.0 mg/kg Q12W Lenalidomide: 25 mg/d on day 1-21 of every 28-day cycle. Dexamethasone: 40 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants \< 75 years; 20 mg/d on days 1, 8, 15, 22 of every 28-day cycle in participants ≥ 75 years Nirogacestat: 100 mg twice a day (BID) starting on day -3 and then each day of every other 28-day cycle (i.e., to be given only on cycles where belantamab mafodotin is administered).
Intervention: Dexamethasone
Outcomes
Primary Outcomes
Part 1 and 2: Ocular Toxicity
Time Frame: Up to 4 years
The number (%) of participants with grade 2 or above KVA events
Part 2: Overall Response Rate (ORR)
Time Frame: Up to 4 years
ORR as per International Myeloma Working Group (IMWG) by Investigator Assessment; defined as the percentage of participants with a confirmed Partial Response (PR), Very Good Partial Response (VGPR), Complete Response (CR) or stringent Complete Response sCR in the intent-to-treat (ITT) set.
Part 1 and 2: Adverse Events (AEs) and Serious adverse events (SAEs)
Time Frame: Up to 4 years
The number (%) of participants with AEs and SAEs using the DLT evaluable and Safety populations
Part 1: Dose-Limiting Toxicity (DLT)
Time Frame: Up to 28 days
The number (%) of participants with DLTs using the DLT evaluable population.
Secondary Outcomes
- Part 1 and 2: Nirogacestat Relative Dose Intensity (RDI)(Up to 4 years)
- Part 1 and 2: Very Good Partial Response (VGPR) or better(Up to 4 years)
- Part 1 and 2: Overall Survival (OS)(Up to 4 years)
- Part 1 and 2: Abnormal ocular findings(Up to 4 years)
- Part 1 and 2: Time To Response (TTR)(Up to 4 years)
- Part 1 and 2: Complete Response Rate (CRR)(Up to 4 years)
- Part 1 and 2: Lenalidomide Relative Dose Intensity (RDI)(Up to 4 years)
- Part 1 and 2: Minimal Residual Disease (MRD) negative rate(Up to 4 years)
- Part 1 and 2:Pharmacokinetics (PK) Analysis(Up to 4 years)
- Part 1 and 2: Cumulative dose of bentalamab mafodotin(Up to 4 years)
- Part 1: Overall Response Rate (ORR)(Up to 4 years)
- Part 1 and 2: Duration of Response (DoR)(Up to 4 years)
- Part 1 and 2: Progression Free Survival (PFS)(Up to 4 years)
- Part 1 and 2:Ocular symptoms and related impacts(Up to 4 years)