Clinical Trials /

Belantamab Mafodotin, Lenalidomide, and Daratumumab for the Treatment of Relapsed, Refractory, or Previously Untreated Multiple Myeloma

NCT04892264

Description:

This phase I/II trial studies the best dose and effect of belantamab mafodotin given together with lenalidomide and daratumumab in treating patients with multiple myeloma that has come back (relapsed), does not respond to treatment (refractory) or for which the patient has not received treatment in the past (previously untreated). Belantamab mafodotin is a monoclonal antibody, called belantamab, linked to a chemotherapy drug, called mafodotin. Belantamab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as BCMA receptors, and delivers mafodotin to kill them. Lenalidomide is an immunomodulatory drug (altering the immune effects on the tumor cell). Daratumumab is a drug that is a monoclonal antibody that is directed towards a protein on the myeloma cell. Giving belantamab mafodotin together with lenalidomide and daratumumab may kill more cancer cells.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Belantamab Mafodotin, Lenalidomide, and Daratumumab for the Treatment of Relapsed, Refractory, or Previously Untreated Multiple Myeloma
  • Official Title: Randomized Phase 1 / 2 Trial of Belantamab Mafodotin, Lenalidomide, and Daratumumab in Relapsed or Newly Diagnosed Multiple Myeloma Patients

Clinical Trial IDs

  • ORG STUDY ID: MC1989
  • SECONDARY ID: NCI-2021-03479
  • SECONDARY ID: MC1989
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04892264

Conditions

  • Plasma Cell Myeloma
  • Recurrent Plasma Cell Myeloma
  • Refractory Plasma Cell Myeloma

Interventions

DrugSynonymsArms
Belantamab MafodotinBelantamab Mafodotin-blmf, Blenrep, GSK2857916, J6M0-mcMMAFArm A (belantamab mafodotin, lenalidomide, daratumumab)
DaratumumabAnti-CD38 Monoclonal Antibody, Darzalex, HuMax-CD38, JNJ-54767414Arm A (belantamab mafodotin, lenalidomide, daratumumab)
DexamethasoneAacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hemady, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDexArm B (belantamab mafodotin, lenalidomide, daratumumab, Dxevo)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidArm A (belantamab mafodotin, lenalidomide, daratumumab)

Purpose

This phase I/II trial studies the best dose and effect of belantamab mafodotin given together with lenalidomide and daratumumab in treating patients with multiple myeloma that has come back (relapsed), does not respond to treatment (refractory) or for which the patient has not received treatment in the past (previously untreated). Belantamab mafodotin is a monoclonal antibody, called belantamab, linked to a chemotherapy drug, called mafodotin. Belantamab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as BCMA receptors, and delivers mafodotin to kill them. Lenalidomide is an immunomodulatory drug (altering the immune effects on the tumor cell). Daratumumab is a drug that is a monoclonal antibody that is directed towards a protein on the myeloma cell. Giving belantamab mafodotin together with lenalidomide and daratumumab may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine the maximum tolerated dose (MTD) of Belantamab in combination with
      daratumumab and lenalidomide in patients with relapsed or refractory multiple myeloma. (Phase
      I) II. To assess the confirmed complete response rate following induction therapy with
      belantamab, daratumumab, and lenalidomide (bortezomib-dexamethasone-rituximab [BDR]), OR
      alternating cycles of daratumumab, lenalidomide, dexamethasone and belantamab, lenalidomide
      and dexamethasone, when used as initial therapy in patients with previously untreated
      symptomatic multiple myeloma patients. (Phase II)

      SECONDARY OBJECTIVES:

      I. To describe the toxicities associated with the combination of belantamab, daratumumab, and
      lenalidomide when used as initial therapy in patients with relapsed multiple myeloma. (Phase
      I) II. To assess the overall response rate (ORR) and >= very good partial response (VGPR)
      rate of belantamab, daratumumab, and lenalidomide (BDR) (Phase II), OR alternating cycles of
      daratumumab, lenalidomide, dexamethasone and belantamab, lenalidomide and dexamethasone.
      (Phase II) III. To assess the progression free survival and overall survival among patients
      with previously untreated symptomatic multiple myeloma following treatment with belantamab,
      daratumumab, and lenalidomide (BDR) (Phase II), OR alternating cycles of daratumumab,
      lenalidomide, dexamethasone and belantamab, lenalidomide and dexamethasone. (Phase II) IV. To
      assess the time to response (defined as the time between the date of first dose and the first
      documented evidence of a partial response or better) following treatment with belantamab,
      daratumumab, and lenalidomide (BDR) (Phase II), OR alternating cycles of daratumumab,
      lenalidomide, dexamethasone and belantamab, lenalidomide and dexamethasone. (Phase II) V. To
      describe the toxicities associated with belantamab, daratumumab, and lenalidomide (BDR)
      (Phase II), OR alternating cycles of daratumumab, lenalidomide, dexamethasone and belantamab,
      lenalidomide and dexamethasone. (Phase II)

      CORRELATIVE RESEARCH OBJECTIVE:

      I. Examine the rate of MRD negativity following induction therapy with the combination of
      belantamab, daratumumab, and lenalidomide (BDR) (Phase II), OR alternating cycles of
      daratumumab, lenalidomide, dexamethasone and belantamab, lenalidomide and dexamethasone.
      (Phase II)

      OUTLINE: This is a phase I dose-escalation study of belantamab mafodotin, followed by a phase
      II study.

      PHASE I:

      INDUCTION: Patients receive belantamab mafodotin intravenously (IV) over 30 minutes on day 1,
      lenalidomide orally (PO) once daily (QD) on days 1-21, and daratumumab IV over 90 minutes on
      days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent
      cycles. Treatment with belantamab mafodotin repeats every 56 days for up to 12 cycles in the
      absence of disease progression or unacceptable toxicity. Treatment with lenalidomide and
      daratumumab repeats every 28 days for up to 12 cycles in the absence of disease progression
      or unacceptable toxicity.

      MAINTENANCE: Beginning cycle 13, patients receive belantamab mafodotin IV over 30 minutes on
      day 1 of odd number cycles, lenalidomide PO QD on days 1-21, and daratumumab IV over 90
      minutes on day 1. Treatment with belantamab mafodotin repeats every 56 days, and every 28
      days for lenalidomide and daratumumab in the absence of disease progression or unacceptable
      toxicity. Treatment with belantamab mafodotin repeats every 56 days (every other cycle) for
      up to 24 cycles in the absence of disease progression or unacceptable toxicity. Treatment
      with lenalidomide and daratumumab repeats every 28 days for up to 24 cycles in the absence of
      disease progression or unacceptable toxicity.

      PHASE II: Patients are randomized to 1 of 2 arms.

      ARM A:

      INDUCTION: Patients receive belantamab mafodotin IV over 30 minutes on day 1 of odd number
      cycles, lenalidomide PO QD on days 1-21, and daratumumab IV over 90 minutes on days 1, 8, 15,
      and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles.
      Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or
      unacceptable toxicity.

      MAINTENANCE: Beginning cycle 13, patients receive belantamab mafodotin IV over 30 minutes on
      day 1 of odd number cycles (starting cycle 13), lenalidomide PO QD on days 1-21, and
      daratumumab IV over 90 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles
      in the absence of disease progression or unacceptable toxicity.

      ARM B:

      INDUCTION: Patients receive belantamab mafodotin IV over 30 minutes on day 1 of cycles 2, 4,
      6, 8, 10, and 12, lenalidomide PO QD on days 1-21, daratumumab IV over 90 minutes on days 1,
      8, 15, and 22 of cycles 1 and 3, and days 1 and 15 on cycles 5, 7, 9, and 11. Patients also
      receive dexamethasone PO on days 1, 8, 15 and 22. Treatment repeats every 28 days for up to
      12 cycles in the absence of disease progression or unacceptable toxicity.

      MAINTENANCE: Beginning cycle 13, patients receive belantamab mafodotin IV over 30 minutes on
      day 1 of even numbered cycles, lenalidomide PO QD on days 1-21, and daratumumab IV over 90
      minutes on day 1 of odd numbered cycles. Treatment repeats every 28 days for up to 24 cycles
      in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days, then every 3-6
      months for up to 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (belantamab mafodotin, lenalidomide, daratumumab)ExperimentalINDUCTION: Patients receive belantamab mafodotin IV over 30 minutes on day 1 of odd number cycles, lenalidomide PO QD on days 1-21, and daratumumab IV over 90 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, days 1 and 15 of cycles 3-6, and day 1 of subsequent cycles. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Beginning cycle 13, patients receive belantamab mafodotin IV over 30 minutes on day 1 of odd number cycles (starting cycle 13), lenalidomide PO QD on days 1-21, and daratumumab IV over 90 minutes on day 1. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
  • Belantamab Mafodotin
  • Daratumumab
  • Lenalidomide
Arm B (belantamab mafodotin, lenalidomide, daratumumab, Dxevo)ExperimentalINDUCTION: Patients receive belantamab mafodotin IV over 30 minutes on day 1 of cycles 2, 4, 6, 8, 10, and 12, lenalidomide PO QD on days 1-21, daratumumab IV over 90 minutes on days 1, 8, 15, and 22 of cycles 1 and 3, and days 1 and 15 on cycles 5, 7, 9, and 11. Patients also receive dexamethasone PO on days 1, 8, 15 and 22. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Beginning cycle 13, patients receive belantamab mafodotin IV over 30 minutes on day 1 of even numbered cycles, lenalidomide PO QD on days 1-21, and daratumumab IV over 90 minutes on day 1 of odd numbered cycles. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
  • Belantamab Mafodotin
  • Daratumumab
  • Dexamethasone
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

          -  Age >= 18 years

          -  Phase I: Relapsed or refractory multiple myeloma with at least one prior line of
             therapy that includes a proteasome inhibitor and an immunomodulatory drug. Patient
             should be refractory or intolerant to lenalidomide

          -  Phase II: Previously untreated multiple myeloma (diagnosed by International Myeloma
             Working Group [IMWG] criteria) or have received no more than one cycle of Standard of
             Care treatment regimen

          -  Note: Prior radiation therapy for the treatment of solitary plasmacytoma is permitted.
             Prior therapy with clarithromycin, dehydroepiandrosterone (DHEA), anakinra,
             pamidronate or zoledronic acid is permitted. Any additional agents not listed must be
             approved by the principal investigator

          -  Measurable disease

               -  Note: Phase I patients can enter trial with M spike >= 0.5 g/dl

          -  Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2

          -  Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)

          -  Absolute neutrophil count (ANC) >= 1200/mm^3 (obtained =< 14 days prior to
             registration)

          -  Platelet count >= 100,000/mm^3 (obtained =< 14 days prior to registration)

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) (obtained =< 14 days prior to
             registration)

          -  Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 2.5 x ULN (=< 5 x
             ULN for patients with liver involvement) (obtained =< 14 days prior to registration)

          -  Prothrombin time (PT)/International Normalized Ratio (INR)/activated partial
             thromboplastin time (aPTT) =< 1.5 x ULN OR if patient is receiving anticoagulant
             therapy and INR or aPTT is within target range of therapy (obtained =< 14 days prior
             to registration)

          -  Calculated creatinine clearance >= 30 ml/min using the Cockcroft-Gault formula
             (obtained =< 14 days prior to registration)

          -  Female participants: Female participant is eligible to participate if she is not
             pregnant or breast feeding, and at least one of the following conditions applies:

               -  Is not a woman of childbearing potential (WOCBP) OR

               -  Due to lenalidomide being a thalidomide analogue with risk for embryofetal
                  toxicity and prescribed under a pregnancy prevention/controlled distribution
                  program, and bortezomib having the potential to cause fetal harm, WOCBP
                  participants will be eligible if they commit to either:

                    -  Abstain continuously from heterosexual sexual intercourse as their preferred
                       and usual lifestyle (abstinent on a long term and persistent basis) and
                       agree to remain abstinent OR

                    -  To use birth control as follows:

                         -  Two methods of reliable birth control (one method that is highly
                            effective and one additional effective (barrier) method), beginning 4
                            weeks prior to initiating treatment with lenalidomide, during therapy,
                            during dose interruptions and continuing for 4 weeks following
                            discontinuation of lenalidomide treatment. Thereafter, WOCBP
                            participants must use one method of reliable birth control that is
                            highly effective for a further 4 months following discontinuation of
                            belantamab mafodotin or a further 2 months after discontinuation of
                            daratumumab. 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.

                              -  Note: The Investigator is responsible for review of medical
                                 history, menstrual history, and recent sexual activity to decrease
                                 the risk for inclusion of a woman with an early undetected
                                 pregnancy

          -  Male participants: Male participants are eligible to participate if they agree to the
             following from the time of first dose of study treatment 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)

          -  Ability to understand the study procedures and provide written informed consent

          -  Negative hepatitis B test (defined by a negative test for hepatitis B surface antigen
             [HBsAg], or antibodies to hepatitis B surface and/or core antigens [antiHBs or
             antiHBc])

               -  Note: Participants with serologic findings suggestive of HBV vaccination (antiHBs
                  positivity as the only serologic marker) AND a known history of prior hepatitis B
                  virus (HBV) vaccination do not need to be tested for HBV deoxyribonucleic acid
                  (DNA) by polymerase chain reaction (PCR). Those who are PCR positive will be
                  excluded from the study

          -  Participant agrees not to use contact lenses while participating in the study

          -  Willingness to provide mandatory bone marrow and blood specimens for research

          -  Willing to return to enrolling institution for follow-up (during the Active Monitoring
             Phase of the study)

          -  All prior treatment-related toxicities (defined by National Cancer Institute Common
             Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0) must be =< grade 1 at
             the time of enrolment except for alopecia

        Exclusion Criteria:

          -  Monoclonal gammopathy of undetermined significance or smoldering multiple myeloma

          -  Major surgery =< 28 days prior to registration

          -  Plasmapheresis =< 14 days prior to registration

          -  Diagnosed or treated for another malignancy =< 2 years prior to registration or
             previously diagnosed with another malignancy and have any evidence of residual disease

               -  Note: Patients with nonmelanoma skin cancer or carcinoma in situ of any type are
                  not excluded if they have undergone complete resection

               -  Note: If there is a history of prior malignancy, they must not be receiving other
                  specific treatment (hormone therapy, chemotherapy, or immunotherapy) for their
                  cancer

          -  Receiving any other concurrent chemotherapy, systemic steroids, any ancillary therapy
             considered investigational for treatment of multiple myeloma, or receiving
             radiotherapy =< 14 days or five half-lives, whichever is shorter, prior to first dose
             of study treatment. Note: Bisphosphonates are considered to be supportive care rather
             than therapy and are thus allowed while on protocol treatment

          -  Known to be human immunodeficiency virus (HIV) positive

          -  Presence of positive hepatitis C antibody test result or positive hepatitis C
             ribonucleic acid (RNA) test result at screening or within 3 months prior to first dose
             of study treatment

               -  Note: Participants with positive hepatitis C antibody due to prior resolved
                  disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is
                  obtained

               -  Note: Hepatitis RNA testing is optional and participants with negative hepatitis
                  C antibody test are not required to also undergo hepatitis C RNA testing

          -  Uncontrolled intercurrent illness including, but not limited to:

               -  Ongoing or active infection (defined as infection undergoing treatment)

               -  Active mucosal or internal bleeding

               -  Social situations that would limit compliance with study requirements.

               -  Corneal epithelial disease (except for mild changes in the corneal epithelium)

               -  Known gastrointestinal disease (including difficulty swallowing) or
                  gastrointestinal procedure that could interfere with the oral absorption or
                  tolerance of lenalidomide or dexamethasone

               -  Unstable liver or biliary disease defined by the presence of ascites,
                  encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices,
                  persistent jaundice, or cirrhosis. Note: Stable non-cirrhotic chronic liver
                  disease (including Gilbert's syndrome or asymptomatic gallstones) or
                  hepatobiliary involvement of malignancy is acceptable if otherwise meets entry
                  criteria

               -  Active renal condition (infection, requirement for dialysis or any other
                  condition that could affect participant's safety). Note: Participants with
                  isolated proteinuria resulting from MM are eligible, provided they fulfill
                  inclusion criteria

          -  Evidence of cardiovascular disease risk, as defined by any of the following:

               -  Evidence of current clinically significant uncontrolled arrhythmias, including
                  clinically significant electrocardiogram (ECG) abnormalities such as 2nd degree
                  (Mobitz 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 =< 90 days prior to
                  registration

               -  Class III or IV heart failure as defined by the New York Heart Association
                  functional classification system

               -  Uncontrolled hypertension

          -  History of myocardial infarction, or congestive heart failure requiring use of ongoing
             maintenance therapy for life-threatening ventricular arrhythmias

          -  Known allergies, hypersensitivity, or intolerance to corticosteroids, monoclonal
             antibodies or human proteins, or their excipients (refer to respective package inserts
             or Investigator's Brochure) or known sensitivity to belantamab mafodotin or drugs
             chemically related to belantamab mafodotin, or any of the components of the study
             treatment
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD) of belantamab in combination with daratumumab and lenalidomide in patients with relapsed and/or refractory multiple myeloma (Phase I)
Time Frame:Up to 28 days
Safety Issue:
Description:The MTD will be determined by the dose limiting toxicities (DLTs) seen in cycle 1 of the therapy in the phase I portion. The phase II portion will be based on the determined MTD. MTD is defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients).

Secondary Outcome Measures

Measure:Incidence of toxicity (Phase I)
Time Frame:Up to 3 years
Safety Issue:
Description:Defined as adverse events that are classified as either possibly, probably, or definitely related to study treatment. Non-hematologic toxicities will be evaluated via the ordinal Common Terminology Criteria (CTC) standard toxicity grading. Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization via CTC standard toxicity grading. Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.
Measure:Overall response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Will be estimated by the number of patients with each response category (e.g: sCR, CR, VGPR, partial response [PR], etc) divided by the total number of evaluable patients.
Measure:Greater than or equal to very good partial response (VGPR) rate
Time Frame:Up to 3 years
Safety Issue:
Description:Will be estimated by the number of patients with each response category (e.g: sCR, CR, VGPR, PR, etc) divided by the total number of evaluable patients.
Measure:Overall survival
Time Frame:From registration to death due to any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier.
Measure:Progression-free survival
Time Frame:From registration to the earliest date of documentation of disease progression or relapse or death due to any cause, assessed up to 3 years
Safety Issue:
Description:Will be estimated using the method of Kaplan-Meier.
Measure:Time to response
Time Frame:Time between the date of first dose and the first documented evidence of a partial response or better, assessed up to 3 years
Safety Issue:
Description:Descriptive statistics will be estimated.
Measure:Incidence of adverse events
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Mayo Clinic

Last Updated

May 19, 2021