| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1
-Determine safety and tolerability of belantamab mafodotin in combination with VRd to establish a recommended dose for participants with transplant ineligible (TI) newly diagnosed multiple myeloma (NDMM)
Part 2
-To compare the efficacy of belantamab mafodotin in combination with VRd with that of VRd alone in participants with TI NDMM |
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| E.2.2 | Secondary objectives of the trial |
Part 1
-Effect of combining belantamab mafodotin with VRd in relation to lenalidomide & bortezomib relative dose intensity (RDI)
-To evaluate the pharmacokinetics profile of belantamab mafodotin, when administered in combination with VRd
-To assess ADAs against belantamab mafodotin
Part 2
-To assess the efficacy of belantamab mafodotin in combination with VRd with that of VRd alone in participants with TI NDMM
- To evaluate the safety and tolerability of belantamab mafodotin when administered in combination with VRd
-To further characterize the exposure to belantamab mafodotin when administered in combination with VRd
-To assess ADAs against belantamab mafodotin
- To evaluate and compare changes in HRQOL
- To evaluate the safety and tolerability of belantamab mafodotin based on self-reported symptomatic adverse effects when administered in combination with VRd
- To evaluate self-reported ocular symptomatic adverse effects of belantamab mafodotin in combination with VRd |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Age
1. Participant must be over 18 years of age.
Type of Participant and Disease Characteristics
2. 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:
a. Urine M-protein excretion ≥200 mg/24 hrs (≥0.2g/24 hrs), or
b. Serum M-protein concentration ≥0.5 g/dL (≥5.0 g/L), or
c. Serum free light chain (FLC) assay: involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum free light chain ratio (<0.26 or >1.65).
3. Not a candidate for high-dose chemotherapy with 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.
4. ECOG status of 0-2
5. Adequate organ system functions as defined by the laboratory assessments listed in the protocol.
Sex
6. Male and/or female
a. Female Participants:
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.
b. Male Participants:
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 agree to use contraception/barrier as detailed in the protocol.
Informed Consent
7. Capable of giving signed informed consent.
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| E.4 | Principal exclusion criteria |
Type of Participant and Disease Characteristics
1. Smoldering multiple myeloma (SMM).
2. 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.
3. Patient is eligible for high dose chemotherapy with ASCT.
Medical Conditions
4. Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI-CTCAE Version 5.
5. Major surgery within 4 weeks prior to the first dose of study drug.
6. 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 MM are eligible, provided they fulfil criteria given in the protocol.
7. 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.
8. Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not explained by reversible coagulopathy.
9. 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).
10. 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.
Note: Participants with curatively treated non-melanoma skin cancer are allowed without a 2-year restriction.
11. Evidence of cardiovascular risk
12. Active infection requiring treatment.
13. Known HIV infection.
14. 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.
15. 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.
16. Current corneal epithelial disease except for mild punctate keratopathy (Appendix 12 of the protocol).
Note: Participants with mild punctate keratopathy are allowed.
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 has a known history of meningeal or central nervous system involvement by multiple myeloma.
Prior/Concomitant Therapy
21. Use of an investigational drug within 14 days or five half-lives (whichever is longer) preceding the first dose of study drug. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
- Number (%) of participants with dose limiting toxicities (DLTs)
- Number (%) of participants with adverse events (AEs)
Part 2
- Minimal Residual Disease (MRD) negativity rate, defined as the percentage of participants who are MRD negative by next-generation sequencing (NGS) with sensitivity of 10-5
- PFS, defined as the time from the date of randomization until the earliest date of documented disease progression or death due to any cause
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1
The review of DLTs and AEs will be continuous to inform dose escalation, and then after all patients recruited in Part 1 have completed four cycles of treatment.
Part 2
- MRD endpoint: (Part 2) final analysis (i.e. when all participants have
been followed for up to 12 months from first dose)
- PFS endpoint: (Part 2) 1st interim analysis for futility (approximately
25 months from First Subject First Visit [FSFV]), 2nd interim analysis for efficacy (approximately 42 months from FSFV) and final analysis (approximately 51 months from FSFV). |
|
| E.5.2 | Secondary end point(s) |
Part 1:
- Lenalidomide RDI after 4 cycles of treatment with belantamab mafodotin in combination with VRd
- Bortezomib RDI after 4 cycles of treatment with belantamab mafodotin in combination with VRd
- Cumulative administered dose of belantamab mafodotin after 4 cycles of treatment in combination with VRd
- Belantamab mafodotin, total mAb, and cys-mcMMAF PK parameters, as data permit
- Incidence and titers of ADAs against belantamab mafodotin
Part 2:
- ORR, defined as the percentage of participants with a confirmed PR or better (i.e., PR, VGPR, CR, sCR)
- CRR, defined as the percentage of participants with a confirmed CR or better (i.e., CR, sCR)
- Rate of VGPR or better, defined as the percentage of participants with a confirmed VGPR or better (i.e. VGPR, CR, sCR)
- DoR, 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
- TTP, defined as the time from the date of randomization until the earliest date of documented PD or death due to PD
- OS, defined as the time from the date of randomization until the date of death due to any cause
- Sustained MRD negativity defined as the percentage of patients with MRD negativity confirmed 1 year apart
- Incidence of adverse events (AEs)
- Ocular findings on ophthalmic exam
-Plasma concentrations of belantamab mafodotin, total mAb, and cys-mcMMAF
-ncidence and titers of ADAs against belantamab mafodotin
-Change from baseline in HRQOL as measured by EORTC QLQ-C30 and EORTC QLQ-MY20 symptoms (pain) domain
- Changes from baseline in symptoms and related impacts as measured by PRO-CTCAE
- Changes from baseline in symptoms and related impacts as measured by OSDI |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part 1:
- Lenalidomide and bortezomib RDI endpoints: after all patients
recruited in Part 1 have completed 4 cycles of treatment.
- PK and ADAs endpoints: final analysis
Part 2:
-Efficacy endpoints: Part 2 1st interim analysis (IA) for futility
(approximately 25 months from FSFV), 2nd IA for efficacy (approximately 42 months from FSFV) & final analysis (approximately 51 months from FSFV)
-Safety and tolerability endpoints (AEs and ocular findings): safety IAs
(every 6 months), Part 2 1st IA for futility, 2nd IA for efficacy and final
analysis
- Belantamaf mafodotin exposure endpoint, ADAs endpoint, HRQOL
endpoint, safety and tolerability endpoint (self-reported symptomatic
adverse effects), self-reported ocular symptomatic adverse effects
endpoint: final analysis |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Design in 2 parts: Part 1 (dose selection) and Part 2 (randomized Phase 3 part) |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 7 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 96 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Belgium |
| Brazil |
| Canada |
| China |
| Denmark |
| France |
| Germany |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Netherlands |
| Norway |
| Poland |
| Romania |
| Russian Federation |
| Spain |
| Sweden |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| When the last participant in Part 2 (Randomised Phase 3 part) of the study completes the last overall survival (OS) follow-up visit (expected to occur at completion of the 5-year OS follow-up period from disease progression) |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 12 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 12 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
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