E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Relapsed/Refractory Multiple Myeloma |
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E.1.1.1 | Medical condition in easily understood language |
Relapsed/Refractory Multiple Myeloma |
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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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Dose Exploration Reference to GSK'916 has been removed and replaced with belantamab mafodotin To determine the safety and tolerability of belantamab mafodotin in combination with other anti-cancer treatments (in each sub-study), and to establish the recommended Phase 2 dose for each combination treatment to explore in the CE Phase in participants with RRMM
Cohort Expansion To assess the clinical activity of belantamab mafodotin at the RP2D in combination with anti-cancer treatments compared to GSK’916 (belantamab mafodotin) monotherapy in participants with RRMM |
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E.2.2 | Secondary objectives of the trial |
DE Key Secondary Reference to GSK'916 has been removed and replaced with belantamab mafodotin To evaluate the clinical measures of efficacy of belantamab mafodotin and combination treatments in participants with RRMM
DE Secondary To further evaluate the clinical measures of efficacy of belantamab mafodotin and combination treatments in each sub-study in participants with RRMM
CE Secondary To further assess clinical activity of combination treatments with belantamab mafodotin at each potential RP2D compared with monotherapy within each sub study in participants with RRMM
Refer to the protocol for remaining Dose Exploration & Cohort Expansion secondary points. |
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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 |
SUB-STUDY 1 – GSK'916 (BELANTAMAB MAFODOTIN) AND GSK’998 (AOX40) (GSK3174998)
SUB-STUDY 2 – BELANTAMAB MAFODOTIN AND GSK’609 (AICOS) (GSK3359609)
SUB-STUDY 3 – BELANTAMAB MAFODOTIN AND NIROGACESTAT
SUB-STUDY 4 -GSK'916 (BELANTAMAB MAFODOTIN) AND DOSTARLIMAB
SUB-STUDY 5 - BELANTAMAB MAFODOTIN AND ISATUXIMAB
SUB-STUDY 6 - BELANTAMAB MAFODOTIN AND NIROGACESTAT AND LENALIDOMIDE AND DEXAMETHASONE
SUB-STUDY 7 - BELANTAMAB MAFODOTIN AND NIROGACESTAT AND POMALIDOMIDE AND DEXAMETHASONE |
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E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the criteria in Section 5.1 and Section 5.2 apply. In addition, participants must fulfil additional inclusion/exclusion criteria for at least 1 partner combination sub-study. Criteria for each individual sub-study can be found in the respective sub-study protocol section.
Age 1. Participant must be 18 years of age inclusive or older, at the time of signing the informed consent. Note: if country/site age requirements for consent differ, the more stringent (e.g., higher age) restriction will be required for that country/site.
Type of Participant and Disease Characteristics 2. Participants who have histologically or cytologically confirmed diagnosis of MM, as defined by the International Myeloma Working Group (IMWG, [Rajkumar, 2014]).
3. Participants who have been treated with at least 3 prior lines of anti-myeloma treatments including an immunomodulating agent (eg. lenalidomide), a proteasome inhibitor (eg. bortezomib) and an anti-CD38 monoclonal antibody. Lines of therapy are defined by consensus panel of the International Myeloma Workshop [Rajkumar, 2011a].
4. Participants with a history of autologous stem cell transplant are eligible for study participation provided the following eligibility criteria are met: a. transplant was >100 days prior to screening b. no active infection(s).
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, unless ECOG ≤2 is due solely to skeletal complications and/or skeletal pain due to MM.
6. Measurable disease defined as at least 1 of the following: • Serum M-protein ≥0.5 g/dL (≥5 g/L) • Urine M-protein ≥200 mg/24 hours • 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).
7. Have organ system functions as defined by the laboratory assessments in Table 15 in the protocol.
8. Participants who have tested positive for HBcAb can be enrolled if the following criteria are met: - Serology result: HBcAb+, HBsAg- - Screening: HBV DNA undetectable - During Study Treatment: Monitoring per protocol (Section 6.6.5), Initiating antiviral treatment if HBV DNA becomes detectable.
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 screening except for alopecia (any grade), neuropathy (Grade ≤2), or endocrinopathy managed with replacement therapy (any grade).
10. Participants who are currently receiving physiological doses oral steroids (<10mg/day), inhaled steroids or ophthalmalogical steroids are allowed on study.
Sex 11. Male or female (reference to section 12.7 removed) Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies (see Appendix 7 for further details).
a. Male Participants: Contraceptive use by men should be consistent with local regulations regarding the methods of contraception for those participating in the clinical studies. Male participants are eligible to participate if they agree to the following during the intervention period and for at least 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 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 when having sexual intercourse with a woman of childbearing potential who is not currently pregnant. Male participants should also use a condom when having sexual intercourse with pregnant females.
b. 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 one 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, as described in Appendix 7 during the intervention period and for 4 months after the last dose of study intervention 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 […]
For the remaining inclusion criteria please refer to the 208887 Protocol Amendment 05. |
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E.4 | Principal exclusion criteria |
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions 1. Symptomatic amyloidosis, active ‘polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes’ (POEMS) syndrome, current or past diagnosis of plasma cell leukemia.
2. 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.
3. Current corneal epithelial disease except mild punctate keratopathy.
4. Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal 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.
5. Malignancies other than disease under study are excluded, except for any other malignancy from which the participant has been disease-free for more than 2 years and, in the opinion of the principal investigators and GSK Medical Director, will not affect the evaluation of the effects of this clinical trial treatment on the currently targeted malignancy (MM). • Participants with curatively treated non-melanoma skin cancer are not excluded.
6. Evidence of cardiovascular risk including any of the following: Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Mobiz Type II) or 3rd degree atrioventricular (AV) block. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting or bypass grafting, all within three months of Screening. Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system Uncontrolled hypertension.
7. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab mafodotin or any of the components of the study treatment. History of severe hypersensitivity to other mAbs.
8. Active infection requiring antibiotic, antiviral, or antifungal treatment.
9. Known HIV infection, unless the participant can meet all the criteria as per protocol.
10. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
11. Presence of hepatitis B surface antigen (HBsAg) at screening or within prior history.
12. 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 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 undergo Hepatitis C RNA testing.
13. 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 15.
Prior/Concomitant Therapy 14. Patients who have received prior therapy with belantamab mafodotin are excluded. Patients previously treated with other BCMA-targeting agents, such as CAR-T cells or bispecific antibodies, are permitted only during the DE phase.
15. Other monoclonal antibodies within 30 days or systemic anti-myeloma therapy within <14 days of first dose of study drug.
16. Prior radiotherapy within 2 weeks of start of study therapy. Participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-central nervous system (CNS) disease.
17. Plasmapheresis within 7 days prior to the first dose of study drug.
18. Prior allogeneic transplant is prohibited.
19. Patients who have received prior CAR-T therapy with lymphodepletion with chemotherapy within 3 months of screening.
20. Any major surgery (other than bone-stabilizing surgery) within 30 days of first dose.
21. 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.
For 'Other Exclusions' please refer to the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
Dose Exploration - Percentage (number) of participants with dose limiting toxicities (DLTs) - Percent of subjects with AEs, changes in clinical signs and laboratory parameters
Cohort Expansion Overall Response Rate (ORR), according to the International Myeloma Working Group (IMWG) Response Criteria [Kumar, 2016].
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
From when the first participant initiated treatment until the last participant has received 3 cycles of study drug(s).
Cohort Expansion: 6 months after the last participant is dosed for each sub-study. |
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E.5.2 | Secondary end point(s) |
Dose Exploration • Clinical activity measured as Overall Response Rate (ORR), according to the International Myeloma Working Group (IMWG) Response Criteria [Kumar, 2016]
• Rates of: - Partial Response (PR); - Very Good Partial Response (VGPR); - Complete Response (CR); - stringent Complete Response (sCR)
The following text GSK'916 observed concentrations up to Cycle 6 has been replaced with Belantamab mafodotin observed concentrations
• Anti-cancer combination treatment’s observed concentration
• Incidence and titers of ADAs against belantamab mafodotin and combination treatments, when measured.
• Incidence of AEs of special interest for belantamab mafodotin • Incidence of AEs of special interest for combination treatments • Incidence of ocular findings on ophthalmic exam
Cohort Expansion • Assess the Clinical Benefit Rate (CBR) [Kumar, 2016] • PFS • DoR • TTR • Rates of: PR, VGPR, CR, sCR • OS
• Incidence of AEs, SAEs, AEs leading to discontinuation or dose reduction/delay, changes in clinical signs, and laboratory parameters • Incidence of AESIs for belantamab mafodotin • Incidence of AESIs for the individual partner for each sub-study • Incidence of ocular findings on ophthalmic exam for belantamab mafodotin
• Belantamab mafodotin and combination treatments’ plasma concentrations.
• Incidence and titers of ADAs against belantamab mafodotin and combination treatments, when measured. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From when the first participant initiated treatment until the last participant has received 3 cycles of study drug(s).
Cohort Expansion: 6 months after the last participant is dosed for each sub-study. |
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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 | No |
E.6.11 | Pharmacogenomic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
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 | No |
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) | No |
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.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Israel |
Korea, Republic of |
Mexico |
Russian Federation |
United States |
Czechia |
France |
Germany |
Greece |
Netherlands |
Norway |
Poland |
Spain |
Sweden |
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E.8.7 | Trial has a data monitoring committee | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |