A Study to Investigate Safety and Clinical Activity of Belantamab Mafodotin in Combination With Lenalidomide, Dexamethasone and Nirogacestat in Patients With Transplant Ineligible Newly Diagnosed Multiple Myeloma

NCT05573802 | Recruiting Phase 1

• 1 other identifier: EAE128
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 2

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.

Conditions

Multiple Myeloma; Neoplasms; Neoplasm, Plasma Cell; Gammopathy, Monoclonal; Paraproteinemias; Blood Protein Disorders; Haematologic Disease; Corneal Disease

Outcome Measures

Primary Outcomes (4)

• Part 1: Dose-Limiting Toxicity (DLT)

  The number (%) of participants with DLTs using the DLT evaluable population.

  Up to 28 days

• Part 1 and 2: Adverse Events (AEs) and Serious adverse events (SAEs)

  The number (%) of participants with AEs and SAEs using the DLT evaluable and Safety populations

  Up to 4 years

• Part 1 and 2: Ocular Toxicity

  The number (%) of participants with grade 2 or above KVA events

  Up to 4 years

• Part 2: Overall Response Rate (ORR)

  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.

  Up to 4 years

Secondary Outcomes (14)

• Part 1 and 2: Lenalidomide Relative Dose Intensity (RDI)

  Up to 4 years

• Part 1 and 2: Nirogacestat Relative Dose Intensity (RDI)

  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: Time To Response (TTR)

  Up to 4 years

Study Arms (1)

Part 1 : Dose finding

EXPERIMENTAL

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).

Drug: Belantamab Mafodotin-Blmf; Drug: Lenalidomide; Drug: Dexamethasone; Drug: Nirogacestat

Interventions

Belantamab Mafodotin-Blmf DRUG

Blmf will be available as 100 mg/vial in single-use vial for reconstitution, supplied as lyophilized powder. Blmf will be delivered as IV solution over at least 30 minutes.

Part 1 : Dose finding

Lenalidomide DRUG

Lenalidomide will be administered per os.

Part 1 : Dose finding

Dexamethasone DRUG

Dexamethasone will be administered intravenously or per os.

Part 1 : Dose finding

Nirogacestat DRUG

Nirogacestat will be administrated each day for all subsequent cycles were Blmf is also administrated.

Part 1 : Dose finding

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 ≥100.
• More than 1 focal lesion on magnetic resonance imaging (MRI) studies.
• Must have at least ONE aspect of measurable disease, defined as one of the following:
• Urine M-protein excretion ≥200 mg/24 hrs (≥0.2 g/24 hrs), or
• Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or
• Serum FLC assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (\<0.26 or \>1.65).

You may not qualify if:

• 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 5.
• 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.
• 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.
• Current active liver or biliary disease (except for Gilbert's syndrome or asymptomatic gallstones, or otherwise stable chronic liver disease as per the investigator's assessment).
• Participants with previous or concurrent malignancies other than MM are excluded. Exceptions are surgically treated cervical carcinoma in situ or any other malignancy that has been considered medically stable for at least 2 years. The participant must not be receiving active therapy other than hormonal therapy for this disease.
• NOTE: Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction.
• Evidence of cardiovascular risk including any of the following:
• Evidence of current clinically significant untreated arrhythmias, including clinically significant electrocardiogram (ECG) abnormalities, second degree (Mobitz Type II), or third degree atrioventricular (AV) block.
• History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of screening.

Sponsors & Collaborators

• Hellenic Society of Hematology: lead
• GlaxoSmithKline: collaborator

Study Sites (2)

General Hospital of Athens "Alexandra", NKUA, Therapeutic Clinic

Athens, 11528, Greece

RECRUITING

Anticancer Hospital of Thessaloniki "Theageneio"

Thessaloniki, 54639, Greece

NOT YET RECRUITING

MeSH Terms

Conditions

Multiple Myeloma; Neoplasms; Neoplasms, Plasma Cell; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Corneal Diseases

Interventions

Lenalidomide; Dexamethasone; nirogacestat

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Eye Diseases

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Evangelos Terpos, Prof

  Department of Clinical Therapeutics, School of Medicine, National Kapodistrian University of Athens (NKUA)

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Maria Pagoni, Dr

CONTACT

+302107211806; info@eae.gr

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2022
• First Posted: October 10, 2022
• Study Start: July 14, 2023
• Primary Completion (Estimated): October 31, 2026
• Study Completion (Estimated): October 31, 2026
• Last Updated: October 24, 2023

Record last verified: 2023-10

Data Sharing

• IPD Sharing: Will not share

Locations

GR (2)