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

Recruiting now · Phase 1/Phase 2

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

In brief

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.

Key facts

Study ID

NCT05573802

Run by

Hellenic Society of Hematology

People needed

36

Starts

2023-07-14

Expected to finish

2026-10-31

Last updated by the study team

2023-10-24

Who can join

Age: 18 and older. Sex: any. Healthy volunteers: not accepted.

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).
• Not a candidate for high-dose chemotherapy with autologous stem cell transplantation due to presence of significant comorbid condition(s), such as cardiac, pulmonary or other major organ dysfunction that are likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. The patients will be assessed with the IMWG frailty index, a scoring system based on age, comorbidities, and cognitive and physical conditions, which is recommended by the European Society for Medical Oncology (ESMO) guidelines. Patients with International Myeloma Working Group (IMWG) frailty index score 1 or 2 will be considered transplant ineligible. The reason(s) for transplant ineligibility will be collected in the case report forms (CRFs).
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2.
• Adequate organ system function as defined by the below laboratory assessments. Hematologic
• Absolute neutrophil count (ANC) ≥1.25 X 10\^9/L; granulocyte colony-stimulating factor (G-CSF) use for the past 14 days is NOT allowed.
• Hemoglobin ≥8.0 g/dL; transfusions are not permitted in the past 14 days prior to the assessment. Erythropoietin use is allowed.
• Platelet count ≥50 x 10\^9/L if the BM is >50% involved in myeloma. Otherwise, ≥75 x 10\^9/L; transfusions or platelet stimulating agents are NOT allowed in the past 14 days prior to the assessment.
• Hepatic
• Total bilirubin ≤1.5xULN (isolated bilirubin ≥1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%).
• ALT ≤ 2.5xULN. Renal
• Estimate glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2; calculated using the Modified Diet in Renal Disease (MDRD) formula.

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.
• 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.
• 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.
• Class III or IV heart failure as defined by the New York Heart Association functional classification system.
• Uncontrolled hypertension.
• Active infection requiring treatment.
• Known HIV infection, unless the participant can meet all of the following criteria:
• Established anti-retroviral therapy (ART) for at least 4 weeks and HIV viral load <400 copies/mL.
• CD4+ T-cell (CD4+) count ≥350 cells/uL.
• No history of AIDS-defining opportunistic infections within the last 12 months.
• NOTE: consideration must be given to ART and prophylactic antimicrobials that may have a drug:drug interaction and/or overlapping toxicities with belantamab mafodotin or other combination products as relevant
• Seropositivity for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]).

Where it is running

• General Hospital of Athens "Alexandra", NKUA, Therapeutic Clinic — Athens, Greece (enrolling)
• Anticancer Hospital of Thessaloniki "Theageneio" — Thessaloniki, Greece

Full record on ClinicalTrials.gov

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