| 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/Refractory Multiple Myeloma |
|
| 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 with belantamab mafodotin vs pomalidomide plus low dose dexamethasone (pom/dex) in participants with relapsed/refractory multiple myeloma (RRMM) |
|
| E.2.2 | Secondary objectives of the trial |
- To compare the overall survival with belantamab mafodotin vs Pom/Dex in participants with RRMM
- To compare other markers of efficacy of belantamab mafodotin vs pom/dex in participants with RRMM
- To evaluate the safety and tolerability of belantamab mafodotin vs pom/dex in participants with RRMM
- To evaluate the pharmacokinetic profile of belantamab mafodotin
- To assess anti-drug antibodies (ADAs) against belantamab mafodotin
- To evaluate the tolerability of belantamab mafodotin vs pom/dex based on self-reported symptomatic adverse effects
- To evaluate and compare changes in symptoms and health-related quality of life (HRQOL) of belantamab mafodotin to pom/dex
- To assess Minimal Residual Disease (MRD) in participants who achieve ≥VGPR or better for belantamab mafodotin vs pom/dex |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Ocular sub-study added as part of Amendment 1 dated 23Oct2020
Objective: To explore BCLs as possible management of belantamab mafodotin related corneal events |
|
| E.3 | Principal inclusion criteria |
1. Capable of giving signed informed consent as described in Protocol Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol.
2. Participants must be 18 or older, at the time of signing the ICF.
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 (Protocol Appendix 9).
4. Histologically or cytologically confirmed diagnosis of multiple myeloma (MM) as defined according to International Myeloma Working Group (IMWG), and:
a. Has undergone autologous stem cell transplant (SCT), or is considered transplant ineligible, and
b. Has received at least 2 prior lines of anti-myeloma treatments, including at least 2 consecutive cycles of both lenalidomide and a proteasome inhibitor (given separately or in combination), and must have documented disease progression on, or within 60 days of, completion of the last treatment.
5. Has measurable disease with at least one of the following:
a. Serum M-protein ≥0.5 g/dL (≥5 g/L)
b. Urine M-protein ≥200 mg/24 hours
c. Serum free light chain (FLC) assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an abnormal serum FLC ratio (<0.26 or >1.65)
6. Participants with a history of autologous SCT are eligible for study participation provided the following eligibility criteria are met:
a. Transplant was >100 days prior to initiating study treatment
b. No active infection(s)
c. Participant meets the remainder of the protocol eligibility criteria
7. Adequate organ system functions as defined in Protocol Table 9
8. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
a. Male Participants:
Male participants are eligible to participate if they agree to the following during the intervention period and until 6 months* after the last dose of study intervention 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 a male condom throughout study treatment including the 6 month* follow-up period even if they have undergone a successful vasectomy and a female partner to use an additional highly effective contraceptive method with a failure rate of <1% per year as described in Protocol Appendix 4 when having sexual intercourse with a pregnant woman or a woman of childbearing potential (WOCBP) who is not currently pregnant.
*4 weeks for male participants on Treatment Arm 2 (pom/dex).
b. Female Participants:
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP [Protocol Appendix 4]
OR
• Is a WOCBP and agrees to abide by the following:
• Arm 1 (belantamab mafodotin): Use a contraceptive method that is highly effective (with a failure rate of <1% per year) which includes abstinence, preferably with low user dependency during the intervention period and for 4 months after the last dose of study treatment.
• Arm 2 (pom/dex): Due to pomalidomide being a thalidomide analogue with risk for embryofetal toxicity and prescribed under a pregnancy prevention/controlled distribution program, WOCBP participants will be eligible if they commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control (one method that is highly effective), 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.
• 2 negative pregnancy tests must be obtained prior to initiating therapy. The 1st test should be performed within 10-14 days and the 2nd test within 24 hours prior to prescribing pomalidomide therapy.
• And agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period.
• The investigator should confirm the effectiveness of the contraceptive method(s) ahead of the 1st dose of study intervention.
Additional requirements for pregnancy testing during and after study intervention are located in Protocol Appendix 4.
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.
9. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 5.0, 2017) must be ≤Grade 1 at the time of enrollment, except for alopecia and Grade 2 peripheral neuropathy.
10. 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 |
1. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes); active plasma cell leukemia at the time of screening.
2. Systemic anti-myeloma therapy or use of an investigational drug within <14 days or 5 half-lives, whichever is shorter, before the first dose of study intervention.
3. Prior treatment with an anti-MM monoclonal antibody within 30 days prior to receiving the first dose of study intervention.
4. Prior BCMA-targeted therapy or prior pomalidomide treatment.
5. Plasmapheresis within 7 days prior to the first dose of study intervention.
6. Prior allogeneic stem cell transplant.
NOTE – Participants who have undergone syngeneic transplant will be allowed only if no history of, or currently active GvHD.
7. Any major surgery within the last 4 weeks.
8. 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 included in Table 9 of the protocol.
9. 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 with study procedures.
10. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
11. Evidence of active mucosal or internal bleeding.
12. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis.
NOTE: Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if participant otherwise meets entry criteria.
13. Participants with previous or concurrent malignancies other than multiple myeloma are excluded, 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.
14. Evidence of cardiovascular risk including any of the following:
a. QT interval corrected for heart rate by Fridericia's formula (QTcF) ≥480 msec
b. Evidence of current clinically significant uncontrolled arrhythmias including clinically significant electrocardiogram (ECG) abnormalities including 2nd degree (Mobitz Type II) or 3rd degree atrioventricular block.
c. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening.
d. Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system (Appendix 10 of the protocol)
e. Uncontrolled hypertension.
15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab mafodotin, pomalidomide, dexamethasone or any of the components of the study intervention.
16. Pregnant or lactating female.
17. Active infection requiring treatment.
18. Known human immunodeficiency virus (HIV), unless the participant can meet all of the following criteria:
• Established anti-retroviral therapy (ART) for at least 4 weeks and HIV viral load <400 copies/mL
• CD4+ T-cell (CD4+) counts ≥350 cells/uL
• No history of AIDS-defining opportunistic infections within the last 12 months
19. Patients with Hepatitis B will be excluded unless the following criteria can be met (see protocol).
20. 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 following criteria (see protocol).
21. Participants unable to tolerate thromboembolic prophylaxis
22. Current corneal epithelial disease except for mild punctate keratopathy |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the time from the date of randomization until the earliest date of documented disease progression (according to IMWG Response Criteria) or death due to any cause |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 20 months from randomization (progression-free survival final analysis) |
|
| E.5.2 | Secondary end point(s) |
- OS, defined as the time from randomization until death due to any cause
- ORR, defined as the percentage of participants with a confirmed PR or better per IMWG
- Clinical benefit rate (CBR), defined as the percentage of participants with a confirmed minimal response (MR) or better per IMWG
- DoR, defined as the time from first documented evidence of PR or better until PD per IMWG or death due to PD among participants who achieve confirmed PR or better
- 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
- TTP, defined as the time from the date of randomization until the earliest date of documented PD (per IMWG Response Criteria) or death due to PD
- Incidence of adverse events (AEs) and changes in laboratory parameters
- Ocular findings on ophthalmic exam
- Plasma concentrations of belantamab mafodotin, total mAb, and cysmcMMAF
- Incidence and titers of ADAs against belantamab mafodotin
- Symptomatic adverse effects as measured by the PRO-CTCAE and OSDI
- Health-related QOL as measured by EORTC QLQ-C30 and EORTC IL52* and EORTC QLQMY20*.
- MRD negativity rate, defined as; the percentage of participants who are MRD negative by NGS method |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Up to approximately 55 months from randomization (overall survival final analysis) 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 | 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 | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 73 |
| 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 |
| Brazil |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| Russian Federation |
| United States |
| Belgium |
| Bulgaria |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Spain |
| United Kingdom |
| Greece |
|
| 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 when the planned 250 deaths for final OS analysis have
occurred, long-term survival follow-up has been completed, or when all
participants have died/are lost to follow up/have withdrawn consent,
whichever occurs first. If OS is significant at 70% information fraction,
OS data will continue to be collected until all participants have died, are
lost to follow-up, or withdrawn consent, or for 2 years after the OS
analysis at 70% IF, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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