| 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 |
| Relapsed / Refectory Multiple Myeloma |
|
| 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 pomalidomide and dexamethasone (BPd) with that of pomalidomide, bortezomib and dexamethasone (PVd) in participants with relapsed/refractory multiple myeloma (RRMM) |
|
| E.2.2 | Secondary objectives of the trial |
To further compare the efficacy of belantamab mafodotin in combination with pomalidomide and dexamethasone (B-Pd) with that of pomalidomide, bortezomib and dexamethasone (PVd) in participants with RRMM
To further assess the efficacy of B-Pd in terms of other efficacy outcomes in participants with RRMM
To evaluate the safety and tolerability of belantamab mafodotin when administered in combination with pomalidomide and dexamethasone
To document exposure of belantamab mafodotin when administered in combination with pomalidomide and dexamethasone
To evaluate the PK of pomalidomide in combination with belantamab mafodotin and dexamethasone, in a subset of participants
To assess anti-drug antibodies against belantamab mafodotin
To evaluate the safety and tolerability of belantamab mafodotin based on selfreported symptomatic AEs when administered in combination with pomalidomide and dexamethasone
To evaluate and compare changes in symptoms and health-related quality of life |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the following criteria are met:
1. Capable of giving signed informed consent as described in Section 10.1.3, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
2. Male or female, 18 years or older (at the time consent is obtained).
3. Have a confirmed diagnosis of multiple myeloma as defined by the IMWG criteria [Rajkumar, 2016].
4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Section 10.6).
5. Have been previously treated with at least 1 prior line of MM therapy including a lenalidomide-containing regimen (lenalidomide must have been administered for at least 2 consecutive cycles) and must have documented disease progression during or after their most recent therapy.
Note: Participants intolerant or refractory to bortezomib at 1.3 mg/m2 dose twice weekly dosing schedule are not eligible.
6. Must have at least ONE aspect of measurable disease, defined as one the following:
a. Urine M-protein excretion ≥200 mg/24 h, 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) only if patient has no measurable urine or serum M spike.
7. Have undergone autologous stem cell transplant (SCT) or are considered transplant ineligible. Participants with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met:
a. Autologous SCT was >100 days prior to the first dose of study medication
b. No active bacterial, viral, or fungal infection(s) present
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 enrolment, except for alopecia.
9. Adequate organ system functions as defined by the laboratory assessments listed in 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
Due to pomalidomide being a thalidomide analogue with a risk for embryofetal toxicity and prescribed under a pregnancy prevention/controlled distribution programme, WOCBP participants will be eligible if they commit either to abstain continuously from heterosexual sexual intercourse or use two methods of reliable birth control (one method that is highly effective plus an additional barrier method), beginning 4 weeks prior to initiating treatment with pomalidomide, during therapy, during dose interruptions and continuing for at least 4 weeks following discontinuation of pomalidomide treatment. Thereafter, WOCBP participants must use one contraceptive method that is highly effective (with a failure rate of <1% per year) for a further 8 months for WOCBP in Arm A, and 5 months for WOCBP in Arm B.
All WOCBP must agree 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.
Two negative pregnancy tests must be obtained prior to initiating pomalidomide therapy in Arm A and Arm B. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing pomalidomide therapy.
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.
Additional requirements for pregnancy testing during and after study intervention are provided in Section 10.3 and the SoA.
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 specific criteria - full details in the protocol.
12. In France, a participant will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category
|
|
| E.4 | Principal exclusion criteria |
A participant will not be eligible for inclusion in this study if any of the following criteria are met:
1. Active plasma cell leukemia at the time of screening. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, and skin changes).
2. Participants after prior allogeneic SCT.
• NOTE: Participants who have undergone syngeneic transplant will be allowed only if no history of or no currently active graft versus host disease (GvHD).
3. Systemic anti-myeloma therapy (including chemotherapy and systemic steroids) or use of an investigational drug within 14 days or five half-lives (whichever is shorter) preceding the first dose of study drug; Prior treatment with a monoclonal antibody drug within 30 days of receiving the first dose of study drugs.
4. Plasmapheresis within 7 days prior to the first dose of study drug.
5. Received prior treatment with or intolerant to pomalidomide.
6. Received prior BCMA targeted therapy.
7. Intolerant to bortezomib or refractory to bortezomib (i.e., participant experienced progressive disease during treatment, or within 60 days of completing treatment, with a bortezomib-containing regimen of 1.3 mg/m2 twice weekly).
8. Evidence of cardiovascular risk including any of the following:
a. Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including 2nd degree (Mobitz Type II) or 3rd 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)
d. Uncontrolled hypertension.
9. Any major surgery within the last 4 weeks.
10. Previous or concurrent invasive malignancy other than multiple myeloma, except:
• The disease must be considered medically stable for at least 2 years; or
• The participant must not be receiving active therapy, other than hormonal therapy for this disease.
11. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to belantamab mafodotin or drugs chemically related to belantamab mafodotin, or any of the components of the study treatment.
12. Evidence of active mucosal or internal bleeding.
13. Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal 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).
14. Active infection requiring treatment.
15. Known human immunodeficiency virus (HIV) infection.
16. 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).
17. 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.
• 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. Hepatitis RNA testing is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing.
18. Intolerance or contraindications to anti-viral prophylaxis.
19. Presence of active renal conditions (e.g. infection, severe renal impairment requiring 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 4.
20. Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain.
21. Active or history of venous thromboembolism within the past 3 months.
22. Contraindications to or unwilling to undergo protocol-required anti-thrombotic prophylaxis
23. Current corneal disease except for mild punctuate keratopathy (Section 10.9).
24. 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.
26. Pregnant or lactating female.
|
|
| 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.5.2 | Secondary end point(s) |
•Minimal Residual Disease (MRD) negativity rate, defined as the percentage of participants who are MRD negative by next-generation sequencing (NGS)
•Overall Response Rate (ORR), defined as the percentage of participants with a confirmed partial response (PR) or better (i.e., PR, VGPR, CR, and sCR)
•Complete Response Rate (CRR), defined as the percentage of participants with a confirmed CR or better (i.e., CR, and sCR)
•VGPR or better rate, defined as the percentage of participants with a confirmed Very Good Partial Response (VGPR) or better (i.e., VGPR, CR, and
sCR)
•Duration of Response (DoR), defined as the time from first documented evidence of PR or better until progressive disease (PD) or death due to PD among participants who achieve confirmed PR or better
•Time to Best Response (TTBR), defined as the interval of time between the date of randomization and the earliest date of achieving best response
among participants with a confirmed PR or better
•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
•Overall Survival (OS), defined as the time from the date of randomization until the date of death due to any cause
•PFS2, defined as time from randomization to disease progression after initiation of new anti-cancer therapy or death from any cause, whichever is earlier. If disease progression after new anti-cancer therapy cannot be measured, a PFS event is defined as the date of discontinuation of new anti-cancer 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, total mAb and cys-mcMMAF
•Derived pomalidomide pharmacokinetic parameter values, as data permit
•Incidence and titers of ADAs against belantamab mafodotin
•Changes from baseline in symptoms and related impacts as measured by PRO-CTCAE
•Change from baseline in HRQOL as measured by EORTC QLQ-C30, EORTC IL52 (the disease symptoms domain of the EORTC QLQ-MY20) |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 |
| Australia |
| Canada |
| Czech Republic |
| France |
| Germany |
| Greece |
| India |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Poland |
| Spain |
| Turkey |
| United States |
|
| 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 Subject 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 21 |
| 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 | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 21 |
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