Clinical Trials /

Bortezomib, Lenalidomide and Dexamethasone (VRd) With Belantamab Mafodotin Versus VRd Alone in Transplant Ineligible Multiple Myeloma

NCT04091126

Description:

This study will evaluate the efficacy and safety of belantamab mafodotin in combination with VRd compared with VRd alone in adult participants with transplant ineligible (TI) newly diagnosed multiple myeloma (NDMM). The study will consist of 2 parts: part 1 will evaluate the safety and tolerability of different doses/dosing regimens of belantamab mafodotin in combination with VRd in an escalating manner and will determine the recommended phase 3 dose (RP3D). Part 2 will evaluate the efficacy and safety of the selected RP3D of belantamab mafodotin in combination with VRd compared with VRd alone.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Bortezomib, Lenalidomide and Dexamethasone (VRd) With Belantamab Mafodotin Versus VRd Alone in Transplant Ineligible Multiple Myeloma
  • Official Title: A Phase 3, Randomized, Open-Label Study of Belantamab Mafodotin Administered in Combination With Bortezomib, Lenalidomide and Dexamethasone Versus Bortezomib, Lenalidomide and Dexamethasone Alone in Participants With Newly Diagnosed Multiple Myeloma Who Are Ineligible for Autologous Stem Cell Transplantation

Clinical Trial IDs

  • ORG STUDY ID: 209664
  • NCT ID: NCT04091126

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
Belantamab mafodotinPart 1: Belantamab Mafodotin + VRd/Rd (Cohort 1)
BortezomibPart 1: Belantamab Mafodotin + VRd/Rd (Cohort 1)
LenalidomidePart 1: Belantamab Mafodotin + VRd/Rd (Cohort 1)
DexamethasonePart 1: Belantamab Mafodotin + VRd/Rd (Cohort 1)

Purpose

This study will evaluate the efficacy and safety of belantamab mafodotin in combination with VRd compared with VRd alone in adult participants with transplant ineligible (TI) newly diagnosed multiple myeloma (NDMM). The study will consist of 2 parts: part 1 will evaluate the safety and tolerability of different doses/dosing regimens of belantamab mafodotin in combination with VRd in an escalating manner and will determine the recommended phase 3 dose (RP3D). Part 2 will evaluate the efficacy and safety of the selected RP3D of belantamab mafodotin in combination with VRd compared with VRd alone.

Trial Arms

NameTypeDescriptionInterventions
Part 1: Belantamab Mafodotin + VRd/Rd (Cohort 1)ExperimentalParticipants will receive 1.9 milligram (mg)/kilogram (kg) single dose of belantamab mafodotin intravenously (IV) on Day 1 every 21-day cycle for the first 8 (induction) cycle in combination with VRd, and cycle 9 (28-day maintenance cycle) onward in combination with Rd (Revlimid [lenalidomide], dexamethasone).
  • Belantamab mafodotin
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
Part 1: Belantamab Mafodotin + VRd/Rd (Cohort 2a)ExperimentalParticipants will receive belantamab mafodotin 1.25 mg/kg on Day 1 and Day 8 through IV of every 21-day cycle for the first 8 (induction) cycles in combination with VRd, and cycle 9 (28-day maintenance cycle) onward in combination with Rd.
  • Belantamab mafodotin
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
Part 1: Belantamab Mafodotin + VRd/Rd (Cohort 2b)ExperimentalParticipants will receive 2.5 mg/kg on single dose of belantamab mafodotin through IV on Day 1, every 21-day cycle for the first 8 (induction) cycles in combination with VRd, and cycle 9 (28-day maintenance cycle) onward in combination with Rd.
  • Belantamab mafodotin
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
Part 1: Belantamab Mafodotin + VRd/Rd (Cohort 3)ExperimentalParticipants will receive belantamab mafodotin 1.7 mg/kg on Day 1 and Day 8 through IV, every 21-day cycle for the first 8 (induction) cycles in combination with VRd, and cycle 9 (28-day maintenance cycle) onward in combination with Rd.
  • Belantamab mafodotin
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
Part 1: Belantamab Mafodotin + VRd/Rd (Cohort 4)ExperimentalParticipants will receive 3.4 mg/kg single dose of belantamab mafodotin through IV on Day 1, every 21-day cycle for the first 8 (induction) cycles in combination with VRd, and cycle 9 (28-day maintenance cycle) onward in combination with Rd.
  • Belantamab mafodotin
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
Part 2: Belantamab Mafodotin + VRdExperimentalParticipants will receive selected dose of belantamab mafodotin RP3D plus VRd (1.3 milligrams per square meter [mg/m^2] of bortezomib subcutaneously [SC] on Days 1, 4, 8, and 11, lenalidomide 25 mg on Days 1-14, and dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 orally) of every 21-day cycle for the 8 induction cycles, and with Rd (lenalidomide 25 mg on Days 1-21 and dexamethasone 40 mg on Days 1, 8, 15, 22) of each 28-day cycle until PD (progressive disease) or unacceptable toxicity.
  • Belantamab mafodotin
  • Bortezomib
  • Lenalidomide
  • Dexamethasone
Part 2: VRd aloneExperimentalParticipants will receive VRd (1.3 mg/m^2 of bortezomib SC on Days 1, 4, 8, and 11, lenalidomide 25 mg on Days 1-14, and dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12 orally) of every 21-day cycle for the 8 induction cycles, and with Rd (lenalidomide 25 mg on Days 1-21 and dexamethasone on 40 mg on Days 1, 8, 15, 22) of each 28-day cycle until PD or unacceptable toxicity
  • Bortezomib
  • Lenalidomide
  • Dexamethasone

Eligibility Criteria

        Inclusion Criteria:

          -  Participant must be over 18 years of age.

          -  Diagnosis of multiple myeloma with a requirement for treatment as documented per
             international myeloma working group (IMWG) criteria.

          -  Must have at least one aspect of measurable disease, defined as one of the following:

          -  Urine M-protein excretion >=200 mg/24 hours (hrs) (>=0.2 gram [g]/24 hrs), or

          -  Serum M-protein concentration >=0.5 grams per deciliter (g/dL) (>=5.0 gram per liter
             [g/L]), or

          -  Serum free light chain (FLC) assay: involved FLC level >=10 milligrams per deciliter
             (mg/dL) (>=100 milligram per liter [mg/L]) and an abnormal serum free light chain
             ratio (<0.26 or >1.65).

          -  Not a candidate for high-dose chemotherapy with autologous stem cell transplant (ASCT)
             due to presence of frailty and/or 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, as judged by
             the investigator.

          -  Eastern cooperative oncology group (ECOG) status of 0-2

          -  Male and/or female

          -  A female participant is eligible to participate if she is not pregnant or
             breastfeeding, and at least 1 of the following conditions applies:

          -  Is not a woman of childbearing potential (WOCBP) or WOCBP participants must use a
             contraceptive method that is highly effective as detailed in the protocol.

          -  Male participants are eligible to participate if they agree to the following:

          -  Refrain from donating sperm

          -  Plus either:

          -  Be abstinent from heterosexual intercourse or must use a contraceptive method that is
             highly effective as detailed in the protocol.

          -  Capable of giving signed informed consent.

        Exclusion Criteria:

          -  Smoldering multiple myeloma (SMM).

          -  Prior systemic therapy for multiple myeloma, or SMM. An emergency course of steroids
             (defined as no greater than 40 mg of dexamethasone, or equivalent per day for a
             maximum of 4 days (that is, a total of 160 mg) is permitted.

          -  Patient is eligible for high dose chemotherapy with ASCT.

          -  Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the
             national cancer institute (NCI)-common terminology criteria for adverse events (CTCAE)
             Version 5.

          -  Major surgery within 4 weeks prior to the first dose of study drug.

          -  Presence of active renal condition (infection, requirement for dialysis or any other
             significant condition that could affect participant's safety). Participants with
             isolated proteinuria resulting from multiple myeloma (MM) are eligible, provided they
             fulfil criteria.

          -  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.

          -  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 multiple myeloma 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.

          -  Evidence of cardiovascular risk.

          -  Active infection requiring treatment.

          -  Known human immunodeficiency virus (HIV) infection.

          -  Presence of hepatitis B surface antigen (HbsAg), or hepatitis B core antibody (HbcAb),
             at Screening or within 3 months prior to first dose of study treatment.

          -  Positive hepatitis C antibody test result. 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.

          -  Current corneal epithelial disease except for mild punctate keratopathy. Note:
             Participants with mild punctate keratopathy are allowed.

          -  Intolerance or contraindications to anti-viral prophylaxis.

          -  Unable to tolerate antithrombotic prophylaxis.

          -  AL amyloidosis (light chain amyloidosis), active polyneuropathy, organomegaly,
             endocrinopathy, monoclonal plasma proliferative disorder, skin changes (POEMS)
             syndrome or active plasma cell leukemia at the time of screening.

          -  Exhibiting clinical signs of or has a known history of meningeal or central nervous
             system involvement by multiple myeloma.

          -  Use of an investigational drug within 14 days or five half-lives (whichever is longer)
             preceding the first dose of study drug.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Part 1: Number of participants with dose-limiting toxicities (DLTs)
Time Frame:1 cycle of treatment (21 days)
Safety Issue:
Description:An event is considered to be a DLT if the event occurs within the first 21 days of treatment and meets the DLT criteria. Number of participants with DLTs will be reported.

Secondary Outcome Measures

Measure:Part 1: Lenalidomide relative dose intensity (RDI ) of treatment with belantamab mafodotin in combination with VRd
Time Frame:Approximately 12 Weeks
Safety Issue:
Description:RDI of treatment with belantamab mafodotin in combination with VRd will be analyzed.
Measure:Part 1: Bortezomib RDI of treatment with belantamab mafodotin in combination with VRd
Time Frame:Approximately 12 Weeks
Safety Issue:
Description:RDI of treatment with belantamab mafodotin in combination with VRd will be analyzed.
Measure:Part 1: Cumulative administered dose of belantamab mafodotin treatment in combination with VRd
Time Frame:Approximately 12 Weeks
Safety Issue:
Description:Cumulative administered dose of belantamab mafodot in treatment in combination with VRd will be analyzed.
Measure:Part 1: Maximum plasma concentration (Cmax) of belantamab mafodotin
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points for pharmacokinetic analysis.
Measure:Part 1:Cmax of total monoclonal antibody (mAb)
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points for pharmacokinetic analysis.
Measure:Part1: Cmax of microtubule inhibitor monomethyl auristatin-F with a cysteine linker (cys-mcMMAF)
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points for pharmacokinetic analysis.
Measure:Part 1: Area under the concentration time curve (AUC) of belantamab mafodotin
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points for pharmacokinetic analysis.
Measure:Part 1: AUC of monoclonal antibody (mAb)
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points for pharmacokinetic analysis.
Measure:Part1: AUC of cys-mcMMAF
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points for pharmacokinetic analysis.
Measure:Part1: Number of participants with anti-drug antibodies (ADAs) against belantamab mafodotin
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Serum samples for the analysis of anti-belantamab mafodotin antibodies will be collected. The samples will be tested for anti-belantamab mafodotin antibodies using a tiered-testing scheme consisting of validated screening, confirmation, and titration assays.
Measure:Part1: Titers of ADAs against belantamab mafodotin
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Serum samples for the analysis of anti-belantamab mafodotin antibodies will be collected. The samples will be tested for anti-belantamab mafodotin antibodies using a tiered-testing scheme consisting of validated screening, confirmation, and titration assays.
Measure:Part 2: Overall Response Rate (ORR)
Time Frame:From study start for the duration of disease follow-up, for an average of 24 months
Safety Issue:
Description:ORR is defined as the percentage of participants with a confirmed partial response (PR) or better (i.e., PR, very good partial response [VGPR], complete response [CR], stringent complete response [sCR]).
Measure:Part 2: Complete Response Rate (CRR)
Time Frame:From study start for the duration of disease follow-up, for an average of 24 months
Safety Issue:
Description:CRR is defined as the percentage of participants with a confirmed CR or better (i.e, CR, sCR).
Measure:Part 2: Rate of VGPR or better
Time Frame:From study start for the duration of disease follow-up, for an average of 24 months
Safety Issue:
Description:Rate of VGPR or better is defined as the percentage of participants with a confirmed VGPR or better (i.e. VGPR, CR, sCR).
Measure:Part 2: Duration of Response (DoR)
Time Frame:From study start for the duration of disease follow-up, for an average of 24 months
Safety Issue:
Description:DoR is defined as the time from first documented evidence of PR or better until PD or death due to PD among participants who achieve confirmed PR or better.
Measure:Part 2: Time to progression (TTP)
Time Frame:From study start for the duration of disease follow-up, for an average of 24 months
Safety Issue:
Description:TTP is defined as the time from the date of randomization until the earliest date of documented PD or death due to PD
Measure:Part 2: Overall Survival (OS)
Time Frame:Up to 60 months
Safety Issue:
Description:OS is defined as the time from the date of randomization until the date of death due to any cause
Measure:Part 2: Percentage of participants with Sustained MRD negativity
Time Frame:1 year
Safety Issue:
Description:Sustained MRD negativity defined as the percentage of participants with MRD negativity confirmed 1 year apart.
Measure:Part 2: Number of participants with AEs and SAEs
Time Frame:Up to an average of 44 months
Safety Issue:
Description:An AE is any untoward medical occurrence in a clinical study subject, temporally associated with the use of a study intervention, whether or not considered related to the study intervention. SAE is defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent disability/incapacity, is congenital anomaly/birth defect, and, other situations which involve medical or scientific judgment.
Measure:Part 2: Number of participants with abnormal ocular findings
Time Frame:Up to an average of 44 months
Safety Issue:
Description:A full ophthalmic examination for all participants will be conducted for any abnormal ocular findings.
Measure:Part 2: Plasma concentrations of belantamab mafodotin
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze the plasma concentration.
Measure:Part 2: Plasma concentrations of total mAb
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze the plasma concentration.
Measure:Part 2: Plasma concentrations of cys-mcMMAF
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Blood samples will be collected at indicated time points to analyze the plasma concentration.
Measure:Part 2: Number of participants with ADAs against belantamab mafodotin
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Serum samples for the analysis of anti-belantamab mafodotin antibodies will be collected. The samples will be tested for anti-belantamab mafodotin antibodies using a tiered-testing scheme consisting of validated screening, confirmation, and titration assays.
Measure:Part 2: Titers of ADAs against belantamab mafodotin
Time Frame:Up to an average of 44 months
Safety Issue:
Description:Serum samples for the analysis of anti-belantamab mafodotin antibodies will be collected. The samples will be tested for anti-belantamab mafodotin antibodies using a tiered-testing scheme consisting of validated screening, confirmation, and titration assays
Measure:Part 2: Change from Baseline in Health-related quality of life (HRQOL) as measured by European Organization for Research and Treatment of Cancer Quality of life questionnaire (EORTC QLQ)-C30
Time Frame:Baseline and up to an average of 44 months
Safety Issue:
Description:EORTC QLQ-C30 is a 30-item questionnaire containing both single- and multi-item measures. These include 5 functional scales (physical, role, cognitive, emotional, and social functioning), three symptom scales (fatigue, pain, and nausea/vomiting), a global health status/QoL scale, and 6 single items (constipation, diarrhea, insomnia, dyspnea, appetite loss, and financial difficulties). Scores for each scale and single-item measure are averaged and transformed linearly to a score ranging from 0-100. A high score for functional scales and for Global Health Status/QoL represent better functioning ability or HRQoL, whereas a high score for symptom scales and single items represents significant symptomatology.
Measure:Part 2: Change from Baseline in HRQOL as measured by EORTC QLQ-MY20
Time Frame:Baseline and up to an average of 44 months
Safety Issue:
Description:EORTC QLQ-MY20 symptoms (pain) domain is a supplement to the QLQ-C30 instrument used in participants with multiple myeloma. Only the Disease Symptoms domain of the QLQ-MY20 will be administered, which includes bone aches or pain, back pain, hip pain, arm or shoulder pain, chest pain, and pain increasing with activity. As with the QLQ-C30, QLQ-MY20 domain scores are averaged and transformed linearly to a score ranging from 0-100. Higher score represents a high level of symptomatology or problems.
Measure:Part 2: Changes from Baseline in participants-reported outcome common terminology criteria for adverse events (PRO-CTCAE) score
Time Frame:Baseline and up to an average of 44 months
Safety Issue:
Description:The PRO-CTCAE includes an item library of 124 items representing 80 symptomatic toxicities drawn from the CTCAE. PRO-CTCAE provides a systematic yet flexible tool for descriptive reporting of symptomatic treatment side effects in cancer clinical trials. In the present study, a subset of items selected from the PRO-CTCAE Version 1.0 Item Library will be administered. The symptoms and related impacts will be assessed using PRO-CTCAE score.
Measure:Part 2: Changes from Baseline in ocular surface disease index (OSDI)
Time Frame:Baseline and up to an average of 44 months
Safety Issue:
Description:The impact of potential ocular toxicity on function and health-related quality of life will be assessed with the use of the visual function questionnaire the OSDI. OSDI is a 12-item questionnaire designed to assess both the frequency of dry eye symptoms and their impact on vision-related functioning. The OSDI has demonstrated good reliability, validity, sensitivity, and specificity, and can be used as a complement to other clinical and participative measures of dry eye disease by providing a quantifiable assessment of dry eye symptom frequency and the impact of these symptoms on vision-related functioning. The symptoms and related impacts will be assessed using OSDI score.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:GlaxoSmithKline

Trial Keywords

  • Bortezomib, lenalidomide and dexamethasone
  • Belantamab mafodotin
  • Dose escalation
  • Newly diagnosed multiple myeloma

Last Updated

March 6, 2020