| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Multiple Myeloma |
|
| 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 |
|
| 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 |
| To compare the efficacy of belantamab mafodotin in combination with bortezomib and dexamethasone (bor/dex) with that of daratumumab in combination with bor/dex in participants with RRMM |
|
| E.2.2 | Secondary objectives of the trial |
-To compare the efficacy of belantamab mafodotin in combination with bor/dex with that of daratumumab in combination with bor/dex in participants with RRMM- (Key secondary objective)
-To further assess the efficacy of belantamab mafodotin in combination with bor/dex with that of daratumumab in combination with bor/dex in terms of other efficacy outcomes in participants with RRMM
-To evaluate the safety and tolerability of belantamab mafodotin when administered in combination with bor/dex
-To further describe the exposure to belantamab mafodotin when administered in combination with bor/dex
-To assess anti-drug antibodies (ADAs) against belantamab mafodotin
-To evaluate the safety and tolerability of belantamab mafodotin based on self-reported symptomatic adverse effects when administered in combination with bor/dex
-To evaluate and compare changes in symptoms and health-related quality of life (HRQOL) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Capable of giving signed informed consent as described in Section 10.1.3 of the protocol, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
2. Male or female, 18 years or older (at the time consent is obtained).
3. Confirmed diagnosis of multiple myeloma as defined by the IMWG criteria.
4. Previously treated with at least 1 prior line of multiple myeloma (MM) therapy, and must have documented disease progression during or after their most recent therapy. Note: induction + autologous stem cell transplant (ASCT) + maintenance is 1 line of therapy
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Section 10.6 of the protocol).
6. Participants with a history of ASCT are eligible for study participation provided the following eligibility criteria are met:
a. ASCT was >100 days prior to initiating study treatment, and
b. No active bacterial, viral, or fungal infection(s) present.
7. Must have at least ONE aspect of measurable disease, defined as one the following:
a. Urine M-protein excretion ≥200 mg/24h, 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).
8. All prior treatment-related toxicities (defined by National Cancer Institute Common Toxicity Criteria for Adverse Events [NCI-CTCAE] v5.0) must be ≤ Grade 1 at the time of enrollment, except for alopecia.
9. Adequate organ system functions as defined by the laboratory assessments listed in Table 6 of the protocol.
10. Female Participants:
Contraceptive use by women 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 1 of the following conditions applies:
Is not a woman of childbearing potential (WOCBP)
OR
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency (Section 10.3 of the protocol) during the intervention period and for 4 months after the last dose of belantamab mafodotin, 3 months from the last dose of daratumumab, and 7 months from the last dose of bortezomib, whichever is longer, and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
WOCBP must have a negative highly sensitive serum pregnancy test within 72 hours of dosing on C1D1.
Additional requirements for pregnancy testing during and after study intervention are provided in Section 10.3 and the Schedule of Activities (SoA) of the protocol.
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.
11. Male Participants:
Contraceptive use by men 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 from the time of first dose of study until 6 months after the last dose of belantamab mafodotin, and 4 months from the last dose of bortezomib, 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 described in Section 10.3 of the protocol when having sexual intercourse with a WOCBP (including pregnant females). |
|
| E.4 | Principal exclusion criteria |
1. Intolerant to daratumumab.
2. Refractory to daratumumab or any other anti-CD38 therapy (defined as progressive disease during treatment with anti-CD38 therapy, or within 60 days of completing that treatment).
3. Intolerant to bortezomib, or refractory to bortezomib (defined as progressive disease during treatment with a bortezomib-containing regimen of 1.3 mg/m2 twice weekly, or within 60 days of completing that treatment). Note: participants with progressive disease during treatment with a weekly bortezomib regimen are allowed.
4. Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain.
5. Prior treatment with anti-BCMA therapy.
6. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drugs, or treatment with an investigational agent or approved systemic anti-myeloma therapy (including systemic steroids) within 14 days or 5 half-lives of receiving the first dose of study drugs, whichever is shorter.
7. Plasmapheresis within 7 days prior to the first dose of study drug.
8. Has received radiotherapy to a large pelvic area (check with sponsor). Bridging radiotherapy otherwise is allowed. NOTE: Disease assessment should be repeated if RT is done prior to first dose of study drug within screening window.
9. Prior allogenic stem cell transplant. NOTE – Participants who have undergone syngeneic transplant will be allowed, only if no history of GvHD.
10. Any major surgery within 4 weeks prior to the first dose of study drug. Exception allowed for bone stabilizing surgery after consultation with medical monitor.
11. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect participant’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil criteria given in Table 3 of the protocol.
12. 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.
13. Evidence of active mucosal or internal bleeding.
14. Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria.
15. Previous or concurrent malignancies other than multiple myeloma, unless the second malignancy 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.
16. Evidence of cardiovascular risk including any of the following:
a. Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including second degree (Mobitz Type II) or third degree atrioventricular (AV) block.
b. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening.
c. Class III or IV heart failure as defined by the New York Heart Association functional classification system (Section 10.8 of the protocol).
d. Uncontrolled hypertension.
17. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, daratumumab, bortezomib, boron or mannitol or any other components of the study treatment.
18. Active infection requiring treatment.
19. Known HIV infection, unless the participant can meet all required criteria (see protocol section 5.2 Exclusion Criteria)
20. Patients with Hepatitis B will be excluded unless certain criteria can be met. (see protocol section 5.2 Exclusion Criteria). Note: presence of Hep B surface antibody (HBsAb) indicating previous vaccination will not exclude a participant.
21. Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months prior to first dose of study treatment unless the
participant can meet the required criteria (see protocol section 5.2 Exclusion Criteria)
22. Current corneal epithelial disease except for mild punctate keratopathy (Section 10.9 of the protocol).
23. Intolerance or contraindications to anti-viral prophylaxis.
24. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukaemia at the time of screening. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free Survival (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 |
| Up to approximately 34 months from the time when the first participant is randomized (progression-free survival final analysis) |
|
| E.5.2 | Secondary end point(s) |
(KEY secondary endpoints)
-Duration of Response (DoR), defined as the time from first documented evidence of PR or better until progressive disease (PD) or death due to any cause
-Minimal Residual Disease (MRD) negativity rate, defined as the percentage of participants who are MRD negative by next-generation sequencing (NGS)
-Overall Survival (OS), defined as the time from the date of randomization until the date of death due to any cause
Secondary endpoints
-Complete Response Rate (CRR), defined as the percentage of participants with a confirmed complete response (CR) or better (i.e., CR, stringent complete response (sCR))
-Overall Response Rate (ORR), defined as the percentage of participants with a confirmed partial response (PR) or better (i.e., PR, VGPR, CR, sCR)
-Clinical Benefit Rate (CBR), defined as the percentage of participants with a confirmed minimal response (MR) or better per IMWG
-Time to Response (TTR), defined as the time between the date of randomization and the first documented evidence of response (PR or better) among participants who achieve confirmed PR or better
-Time to Progression (TTP), defined as the time from the date of randomization until the earliest date of documented PD or death due to PD
-PFS2, defined as time from randomization to disease progression after initiation of new anti-myeloma therapy or death from any cause, whichever is earlier. If disease progression after new anti-myeloma therapy cannot be measured, a PFS event is defined as the date of discontinuation of new anti-myeloma therapy, or death from any cause, whichever is earlier
- Incidence of adverse events (AEs) and changes in laboratory parameters
- Ocular findings on ophthalmic exam
- Plasma concentrations of belantamab mafodotin, and cys-mcMMAF
- Incidence and titers of anti-drug antibodies (ADAs) against belantamab mafodotin
- Maximum post-baseline PRO-CTCA score for each item attribute
- Change from baseline in HRQOL as measured by EORTC QLQ-C30 and EORTC IL52 (disease symptoms domain from the EORTC QLQ-MY20) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 74 months (at completion of the study) from the time when the first participant is randomized for all secondary endpoints |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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 | No |
| 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 | 2 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 59 |
| 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 | No |
| 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 |
| New Zealand |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United Kingdom |
| United States |
| Belgium |
| Czechia |
| France |
| Germany |
| Greece |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| 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
|
End of study is defined as 5 years from Last Participant First Visit (LSFV), or when all participants have died, withdrawn consent, or have been lost to follow-up, whichever occurs first.
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 1 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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