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

Overview

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.

Eligibility

Inclusion Criteria:

1. Participant must be >18 years of age
2. 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:

3. 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:

   1. Clonal BM plasma cell percentage ≥60%.
   2. Involved: uninvolved serum free light chain (sFLC) ratio ≥100.
   3. More than 1 focal lesion on magnetic resonance imaging (MRI) studies.
4. 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).
5. 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).

6. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2.
7. 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.
• Spot urine (albumin/creatinine ratio) <500 mg/g (56 mg/mmol) OR
• Urine Dipstick: Negative trace; if ≥1+ only eligible if confirmed <500 mg/g [56 mg/mmol] by albumin/creatinine ratio (spot urine from first void). 7. Female participants: contraceptive use should be consistent with local regulations

  regarding the methods of contraception for those participating in clinical studies:

             A female participant is eligible to participate if she is not pregnant or
             breastfeeding, and at least one of the following conditions applies:
               -  Is not a woman of childbearing potential (WOCBP) defined as follows:
               -  ≥ 45 years of age and has not had menses for > 1 year
               -  Patients who have been amenorrhoeic for < 2 years without history of a
                  hysterectomy and oophorectomy must have a follicle stimulating hormone value in
                  the postmenopausal range upon screening evaluation
               -  Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.
                  Documented hysterectomy or oophorectomy must be confirmed with medical records of
                  the actual procedure or confirmed by an ultrasound. Tubal ligation must be
                  confirmed with medical records of the actual procedure.
             OR
               -  Is a WOCBP and using two methods of reliable birth control (one method that is
                  highly effective and one additional effective [barrier] method), beginning 4
                  weeks before initiating treatment with lenalidomide, during therapy, during dose
                  interruptions and continuing for 4 weeks following discontinuation of
                  lenalidomide treatment. WOCBP participants must use one method of reliable birth
                  control that is highly effective for 4 months following discontinuation of
                  belantamab mafodotin. WOCBP must also agree not to donate eggs (ova, oocytes) for
                  the purpose of reproduction during treatment, during dose interruptions and for
                  28-days following the last dose of lenalidomide or 4 months following
                  discontinuation of belantamab mafodotin treatment, whichever is longer.
             A WOCBP must have two negative pregnancy tests before therapy initiation. The first
             test should be performed within 10-14 days, and the second test within 24 hours before
             the start of lenalidomide therapy.
             The participant should not receive lenalidomide until the investigator has verified
             that the results of these pregnancy tests are negative. The investigator should
             evaluate the effectiveness of the contraceptive method in relation to the first dose
             of the study treatment. The investigator is responsible for a review of medical
             history, menstrual history, and recent sexual activity to decrease the risk for
             inclusion of a woman with a nearly undetected pregnancy.
             WOCBP is a female who:
               -  has achieved menarche at some time point
               -  has not undergone a hysterectomy or bilateral oophorectomy or
               -  has not been naturally postmenopausal (amenorrhea following cancer therapy does
                  not rule out childbearing potential) for at least 24 consecutive months (i.e.,
                  has had menses at any time in the preceding 24 consecutive months).
          8. Male participants: contraceptive use should be consistent with local regulations
             regarding the methods of contraception for those participating in clinical studies:
             Male participants are eligible to participate if they agree to the following during
             the intervention period and until 28 days after the last dose of lenalidomide or 6
             months after the last dose of belantamab mafodotin, whichever is longer, to allow for
             clearance of any altered sperm.
               -  Refrain from donating sperm
             PLUS either:
               -  Be abstinent from heterosexual intercourse as their preferred and usual lifestyle
                  (abstinent on a long term and persistent basis) and agree to remain abstinent, OR
               -  Must agree to use contraception/barrier as detailed below:
             Agree to use a male condom, even if they have undergone a successful vasectomy, and
             female partner to use an additional highly effective contraceptive method with a
             failure rate of <1% per year as when having sexual intercourse with a woman of
             childbearing potential (including pregnant females).
          9. Participants must be able to understand the study procedures and agree to participate
             in the study by providing written informed consent.
        Exclusion Criteria:
          1. 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.
          2. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the
             National Cancer Institute Common Toxicity Criteria for AEs version 5.
          3. 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.
          4. 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.
          5. 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.
          6. Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not
             explained by reversible coagulopathy.
          7. 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).
          8. 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.
          9. 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.
         10. Class III or IV heart failure as defined by the New York Heart Association functional
             classification system.
         11. Uncontrolled hypertension.
         12. Active infection requiring treatment.
         13. 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
         14. Seropositivity for hepatitis B (defined by a positive test for hepatitis B surface
             antigen [HBsAg]).
               -  NOTE 1: Participants with resolved infection (i.e., participants who are positive
                  for antibodies to hepatitis B core antigen [antiHBc] or antibodies to hepatitis B
                  surface antigen [antiHBs]) must be screened using real-time polymerase chain
                  reaction (PCR). Those who are PCR positive will be excluded.
               -  NOTE 2: presence of antiHBs indicating previous vaccination will not constitute
                  an exclusion criterion.
         15. Positive hepatitis C antibody test result or positive hepatitis C RNA test result at
             screening or within 3 months before the first dose of the study treatment unless the
             participant can meet the following criteria:
               -  RNA test negative
               -  Successful anti-viral treatment (usually 8 weeks duration) is required, followed
                  by a negative hepatitis C virus RNA test after a washout period of at least 4
                  weeks.
         16. Current corneal epithelial disease except for mild punctate keratopathy.
               -  NOTE: Participants with mild punctate keratopathy are allowed. Mild (Grade 1)
                  punctuate keratopathy is characterized by the appearance of only a few, if any,
                  microcyst-like epithelial changes (MECs), as identified in the slit-lamp
                  examination, with a low density (non-confluent), and predominantly (≥80%) located
                  in the periphery of the cornea
         17. Intolerance or contraindications to anti-viral prophylaxis.
         18. Unable to tolerate antithrombotic prophylaxis.
         19. AL amyloidosis (light chain amyloidosis), active POEMS syndrome (polyneuropathy,
             organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes)
             or active plasma cell leukemia at the time of screening.
         20. Exhibiting clinical signs of or with known history of meningeal or central nervous
             system involvement by MM.
         21. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to
             drugs chemically related to belantamab mafodotin or any of the components of the study
             treatment.
         22. Use of an investigational drug within 14 days or 5 half-lives (whichever is shorter)
             preceding the first dose of study drug.
         23. Plasmapheresis within 7 days before the first dose of the study drug.
         24. Participants with active small and/or large intestinal disease which is not adequately
             controlled with the appropriate treatment (e.g., uncontrolled diarrheal disease).
         25. Participants with uncontrolled skin disease.
         26. Participants with any condition causing hypophosphatemia, hypokalemia or
             hypomagnesemia which is refractory to electrolyte replacement.
         27. Participants with previous administration of a gamma secretase inhibitor.
         28. Participants with concomitant administration of a strong or moderate CYP3A4 inhibitor
             or inducer.
         29. Any serious and/or unstable pre-existing medical, psychiatric disorder or other
             conditions (including lab abnormalities) that could interfere with participant's
             safety, obtaining informed consent or compliance to the study procedures.
         30. Participant must not have received a live or live-attenuated vaccine within 30 days
             prior to first dose of belantamab mafodotin.
         31. Participant should not use contact lenses while receiving belantamab mafodotin.
         32. Because of the embryo-fetal risk of lenalidomide, all participants must adhere to the
             lenalidomide pregnancy prevention program applied in their region.