Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) (DREAMM 5)

Sponsor

GlaxoSmithKline (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04126200

Collaborator

(none)

464

Enrollment

Locations

Arms

100.6

Anticipated Duration (Months)

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

B-cell maturation antigen (BCMA) is a target present on tumor cells in participants with multiple myeloma. Belantamab mafodotin (GSK2857916); is an antibody-drug conjugate (ADC) containing humanized anti-BCMA monoclonal antibody (mAb). This is a phase I/II, randomized, open-label, platform study designed to evaluate the effects of belantamab mafodotin in combination with other anti-cancer drugs in participants with relapsed/refractory multiple myeloma. The Platform design incorporates a single master protocol, where multiple treatment combinations, as sub-studies, will be evaluated simultaneously.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Belantamab mafodotin Drug: GSK3174998 Drug: Feladilimab Drug: Nirogacestat Drug: Dostarlimab Drug: Isatuximab Drug: Lenalidomide Drug: Dexamethasone Drug: Pomalidomide	Phase 1/Phase 2

Study Design

Study Type:

Interventional

Anticipated Enrollment :

464 participants

Allocation:

Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

There will be a dose exploration (DE) phase which will evaluate the safety and tolerability profile of belantamab mafodotin when administered in combination with other anti-cancer treatments. A recommended Phase 2 dose (RP2D) for each combination treatment will be identified based on the safety and preliminary efficacy in DE. This will be followed by a cohort expansion (CE) phase which will evaluate the clinical activity of the combination treatment in comparison to belantamab mafodotin monotherapy in additional participants.There will be a dose exploration (DE) phase which will evaluate the safety and tolerability profile of belantamab mafodotin when administered in combination with other anti-cancer treatments. A recommended Phase 2 dose (RP2D) for each combination treatment will be identified based on the safety and preliminary efficacy in DE. This will be followed by a cohort expansion (CE) phase which will evaluate the clinical activity of the combination treatment in comparison to belantamab mafodotin monotherapy in additional participants.

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I/II, Randomized, Open-label Platform Study Utilizing a Master Protocol to Study Belantamab Mafodotin (GSK2857916) as Monotherapy and in Combination With Anti-Cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM) - DREAMM 5

Actual Study Start Date :

Oct 7, 2019

Anticipated Primary Completion Date :

Feb 21, 2025

Anticipated Study Completion Date :

Feb 23, 2028

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Belantamab mafodotin+GSK3174998 dose exploration (Sub-study 1)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: GSK3174998 GSK3174998 will be administered
Experimental: Belantamab mafodotin+feladilimab dose exploration (Sub-study 2)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Feladilimab feladilimab will be administered.
Experimental: Belantamab mafodotin+nirogacestat dose exploration(Sub-study 3)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Nirogacestat Nirogacestat will be administered
Experimental: Belantamab mafodotin+dostarlimab dose exploration(Sub-study 4)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Dostarlimab Dostarlimab will be administered.
Experimental: Belantamab mafodotin+isatuximab dose exploration (Sub-study 5)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Isatuximab Isatuximab will be administered
Experimental: Belantamab mafodotin+ nirogacestat+ lenalidomide+ dexamethasone dose exploration (Sub-study 6)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Lenalidomide Lenalidomide will be administered Drug: Dexamethasone Dexamethasone will be administered
Experimental: Belantamab mafodotin+ nirogacestat+ pomalidomide + dexamethasone dose exploration (Sub-study 7)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Dexamethasone Dexamethasone will be administered Drug: Pomalidomide Pomalidomide will be administered
Active Comparator: Belantamab mafodotin monotherapy cohort expansion	Drug: Belantamab mafodotin Belantamab mafodotin will be administered
Experimental: Belantamab mafodotin+GSK3174998 cohort expansion (Sub-study 1)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: GSK3174998 GSK3174998 will be administered
Experimental: Belantamab mafodotin+ feladilimab cohort expansion (Sub-study 2)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Feladilimab feladilimab will be administered.
Experimental: Belantamab mafodotin+ nirogacestat cohort expansion (Sub-study 3)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Nirogacestat Nirogacestat will be administered
Experimental: Belantamab mafodotin+ dostarlimab cohort expansion (Sub-study 4)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Dostarlimab Dostarlimab will be administered.
Experimental: Belantamab mafodotin+ isatuximab cohort expansion (Sub-study 5)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Isatuximab Isatuximab will be administered
Experimental: Belantamab mafodotin+ nirogacestat+ lenalidomide+ dexamethasone cohort expansion (Sub-study 6)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Lenalidomide Lenalidomide will be administered Drug: Dexamethasone Dexamethasone will be administered
Experimental: Belantamab mafodotin+ nirogacestat+ pomalidomide + dexamethasone cohort expansion (Sub-study 7)	Drug: Belantamab mafodotin Belantamab mafodotin will be administered Drug: Dexamethasone Dexamethasone will be administered Drug: Pomalidomide Pomalidomide will be administered

Outcome Measures

Primary Outcome Measures

DE Phase: Number of participants achieving dose limiting toxicities (DLT) [Up to 12 months]
An event is considered to be a dose DLT if the event occurs within the first 21 days of treatment and meets the dose limiting toxicity criteria.
DE Phase: Number of participants with adverse events (AEs) and serious adverse events (SAEs) [Up to 12 months]
AEs and SAEs will be collected.
DE Phase: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis lab parameters [Up to 12 months]
Blood and urine samples will be collected to evaluate hematology, clinical chemistry and urinalysis lab parameters.
CE Phase: Number of participants achieving Overall Response Rate (ORR) [Up to 36 months]
ORR is defined as the percentage of participants with a Partial response (PR) or better, according to the International Myeloma Working Group (IMWG) Response Criteria.

Secondary Outcome Measures

DE Phase: Number of participants achieving ORR [Up to 12 months]
ORR is defined as the percentage of participants with PR or better, according to the IMWG Response Criteria.
CE Phase: Number of participants achieving Clinical Benefit Rate (CBR) [Up to 36 months]
CBR is defined as the percentage of participants with advanced or metastatic cancer who have achieved complete response, partial response and stable disease to a therapeutic intervention in clinical trials of anticancer agents.
DE Phase: Number of participants achieving Partial Response (PR) [Up to 12 months]
Number of participants with PR according to IMWG criteria will be analyzed.
CE Phase: Number of participants achieving PR [Up to 36 months]
Number of participants with PR according to IMWG criteria will be analyzed.
DE Phase: Number of participants achieving Very Good Partial Response (VGPR) [Up to 12 months]
Number of participants with VGPR according to IMWG criteria will be analyzed.
CE Phase: Number of participants achieving VGPR [Up to 36 months]
Number of participants with VGPR according to IMWG criteria will be analyzed.
DE Phase: Number of participants achieving Complete Response (CR) [Up to 12 months]
Participants with CR according to IMWG criteria will be analyzed.
CE Phase: Number of participants achieving CR [Up to 36 months]
Participants with CR according to IMWG criteria will be analyzed.
DE Phase: Number of participants achieving stringent Complete Response (sCR) [Up to 12 months]
Participants with sCR according to IMWG criteria will be analyzed.
CE Phase: Number of participants achieving sCR [Up to 36 months]
Participants with sCR according to IMWG criteria will be analyzed.
DE Phase: Belantamab mafodotin concentrations when administered in combination with anti-cancer treatments [Up to 12 months]
Blood samples will be collected for concentrations of belantamab mafodotin.
CE Phase: Belantamab mafodotin concentrations when administered in combination with anti-cancer treatments [Up to 36 months]
Blood samples will be collected for concentrations of belantamab mafodotin.
DE Phase: GSK3174998 concentration when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples will be collected for concentrations of GSK3174998.
CE Phase: GSK3174998 concentration when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples will be collected for concentrations of GSK3174998.
DE Phase: Feladilimab concentration when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples will be collected for concentrations of feladilimab.
CE Phase: Feladilimab concentration when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples will be collected for concentrations of feladilimab.
DE Phase: Nirogacestat concentration when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples will be collected for concentrations of nirogacestat.
CE Phase: Nirogacestat concentration when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples will be collected for concentrations of nirogacestat.
DE Phase: Dostarlimab concentration when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples will be collected for concentrations of dostarlimab.
CE Phase: Dostarlimab concentration when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples will be collected for concentrations of dostarlimab.
DE Phase: Isatuximab concentration when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples will be collected for concentrations of isatuximab.
CE Phase: Isatuximab concentration when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples will be collected for concentrations of isatuximab.
DE Phase: Concentration of anti-drug antibodies (ADAs) against belantamab mafodotin when administered in combination with anti-cancer treatments [Up to 12 months]
Blood samples for concentrations for ADAs will be collected.
CE Phase: Concentration of ADAs against belantamab mafodotin when administered in combination with anti-cancer treatments [Up to 36 months]
Blood samples for concentrations for ADAs will be collected.
DE Phase: Concentration of ADAs against GSK3174998 when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples for concentrations for ADAs will be collected.
CE Phase: Concentration of ADAs against GSK3174998 when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples for concentrations for ADAs will be collected.
DE Phase: Concentration of ADAs against feladilimab when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples for concentrations for ADAs will be collected.
CE Phase: Concentration of ADAs against feladilimab when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples for concentrations for ADAs will be collected.
DE Phase: Concentration of ADAs against dostarlimab when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples for concentrations for ADAs will be collected.
CE Phase: Concentration of ADAs against dostarlimab when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples for concentrations for ADAs will be collected.
DE Phase: Concentration of ADAs against isatuximab when administered in combination with belantamab mafodotin [Up to 12 months]
Blood samples for concentrations for ADAs will be collected.
CE Phase: Concentration of ADAs against isatuximab when administered in combination with belantamab mafodotin [Up to 36 months]
Blood samples for concentrations for ADAs will be collected.
DE Phase: Number of participants with adverse events of special interest (AESI) for belantamab mafodotin [Up to 12 months]
AESIs will be collected.
CE Phase: Number of participants with AESI for belantamab mafodotin [Up to 36 months]
AESIs will be collected.
DE Phase: Number of participants with AESI for GSK3174998 [Up to 12 months]
AESIs will be collected.
CE Phase: Number of participants with AESI for GSK3174998 [Up to 36 months]
AESIs will be collected.
DE Phase: Number of participants with AESI for Feladilimab [Up to 12 months]
AESIs will be collected.
CE Phase: Number of participants with AESI for Feladilimab [Up to 36 months]
AESIs will be collected.
DE Phase: Number of participants with AESI for Nirogacestat [Up to 12 months]
AESIs will be collected.
CE Phase: Number of participants with AESI for Nirogacestat [Up to 36 months]
AESIs will be collected.
DE Phase: Number of participants with AESI for Dostarlimab [Up to 12 months]
AESIs will be collected.
CE Phase: Number of participants with AESI for Dostarlimab [Up to 36 months]
AESIs will be collected.
DE Phase: Number of participants with AESI for Isatuximab [Up to 12 months]
AESIs will be collected.
CE Phase: Number of participants with AESI for Isatuximab [Up to 36 months]
AESIs will be collected.
DE Phase: Number of participants with abnormal ocular findings on ophthalmic examination [Up to 12 months]
Ophthalmic examination will assess abnormal findings.
CE Phase: Number of participants with abnormal ocular findings on ophthalmic examination [Up to 36 months]
Ophthalmic examination will assess abnormal findings.
CE Phase: Number of participants achieving Progression-free survival (PFS) [Up to 36 months]
PFS is defined as the time from randomization until the earliest date of confirmed progressive disease (PD) per IMWG, or death due to any cause.
CE Phase: Duration of response (DoR) [Up to 36 months]
DoR is defined as the time from first documented evidence or PR or better until progressive disease per IMWG or death due to progressive disease among participants who achieve confirmed partial response or better.
CE Phase: Time to response (TTR) [Up to 36 months]
TTR is defined as the time between the date of randomization and the first documented evidence of response (PR or better), among participants who achieve a response (confirmed PR or better).
CE Phase: Number of participants achieving Overall survival (OS) [Up to 36 months]
OS is defined as the time from randomization until death due to any cause.
CE Phase: Number of participants with AEs and SAEs [Up to 36 months]
AEs and SAEs will be collected.
CE Phase: Number of participants with AEs leading to discontinuation [Up to 36 months]
Number of participants with AEs leading to discontinuation will be evaluated.
CE Phase: Number of participants with dose reduction or delay [Up to 36 months]
Number of participants with dose reduction or delay will be evaluated.
CE Phase: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis lab parameters [Up to 36 months]
Blood and urine samples will be collected to evaluate hematology, clinical chemistry and urinalysis lab parameters.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Participant must be 18 years of age inclusive or older, at the time of signing the informed consent.
Participants must have histologically or cytologically confirmed diagnosis of Multiple Myeloma (MM), as defined by the IMWG.
Participants having at least 3 prior lines of prior anti-myeloma treatments including an immunodilating agent (IMID) a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody.
Participants with a history of autologous stem cell transplant are eligible for study participation when, transplant was >100 days prior to study enrolment and with no active infection(s).
Participants with Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, unless ECOG less than equal to (<=)2 is due solely to skeletal complications and/or skeletal pain due to MM.
Participants with measurable disease defined as at least one of the following: Serum M-protein greater than equal to (>=)0.5 gram per deciliter (>=5 gram per liter) or Urine M-protein >=200 mg per 24 hours or Serum free light chain (FLC) assay: Involved FLC level >=10 mg per deciliter (>=100 mg per Liter) and an abnormal serum FLC ratio (<0.26 or >1.65).
Participants who have tested positive for Hepatitis B core antibody (HBcAb) can be enrolled if the following criteria are met: Serology result HBcAb+, Hepatitis B surface antigen (HBsAg)-; HBV DNA undetectable during screening.
Participants who are currently receiving physiological doses oral steroids (<10 mg/day), inhaled steroids or ophthalmalogical steroids.

Inclusion Criteria Specific to Sub-study 6 and 7:

Participants with contraception requirements specific to Sub-study 6 and 7 respectively.
Participants with platelets value for Adequate Organ System Function is ≥75 × 10^9/L.

Exclusion Criteria:

Participants with current corneal epithelial disease except mild punctate keratopathy.
Participants with evidence of cardiovascular risk
Participants with 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 mAb.
Participants with active infection requiring antibiotic, antiviral, or antifungal treatment.
Participants with other monoclonal antibodies within 30 days or systemic anti-myeloma therapy within <14 days.
Participants with prior radiotherapy within 2 weeks of start of study therapy.
Participants with prior allogeneic transplant are prohibited.
Participants who have received prior Chimeric Antigen T cell therapy (CAR-T) therapy with lymphodepletion with chemotherapy within 3 months of screening.
Participants with any major surgery (other than bone-stabilizing surgery) within the last 30 days.
Participants with prior treatment with an investigational agent within 14 days or 5 half-lives of receiving the first dose of study drugs, whichever is shorter.
Participants with >=grade 3 toxicity considered related to prior check-point inhibitors and that led to treatment discontinuation.
Participants who have received transfusion of blood products within 2 weeks before the first dose of study drug.
Participants must not receive live attenuated vaccines within 30 days prior to first dose of study treatment or whilst receiving belantamab mafodotin +- partner agent in any sub-study arm of the platform trial and for at least 70 days following last study treatment.
Participants with 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.

Additional Exclusion Criteria for Sub-study 1 and Sub-study 2:

Participants with autoimmune disease (current or history) or syndrome that required systemic treatment within the past 2 years.
Exclusion for a recent (within the past 6 months) history of symptomatic pericarditis.

Additional Exclusion Criteria for Sub-study 3, 6 & 7:

Participants with uncontrolled small and/or large intestinal disease.
Participants with uncontrolled skin disease.
Participants with any condition causing hypophosphatemia, hypokalemia or hypomagnesemia which is refractory to electrolyte replacement.
Participants with previous administration of a gamma secretase inhibitor.
Participants with concomitant administration of a strong CYP3A4 inhibitor or inducer.

Additional Exclusion Criteria for Sub-study 4:

Participant has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).
Participants who have received prior therapy with an anti-programmed death-1 (anti-PD-1), anti-PD-1-ligand-1 (anti-PD-L1), or anti-PD-1 ligand-2 (anti-PD-L2) agent.
Participant has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. Use of inhaled steroids, local injection of steroids, and steroid eye drops are allowed.

Additional Exclusion Criteria for Sub-study 5:

Participants with Severe hypersensitivity to Isatuximab-irfc or to any of its excipients.
Participants with prior treatment with other anti-CD38 monoclonal antibody within 6 months of the first dose of study drug treatment.
Participants with known intolerance or hypersensitivity to infused proteins products, sucrose, histidine, and polysorbate 80.

Additional Exclusion Criteria for Sub-study 6 and 7:

Participants with active or history of venous thromboembolism within the past 3 months.
Participants with evidence of active mucosal or internal bleeding
Participants with contraindications to or are unwilling to undergo protocol-required anti-thrombotic prophylaxis or unable to tolerate antithrombolitic prophalaxis,

Additional Exclusion Criteria for Sub-study 6:

Participants who discontinued prior treatment with lenalidomide due to intolerable adverse events

Additional Exclusion Criteria for Sub-study 7:

Participants who discontinued prior treatment with pomalidomide due to intolerable adverse events

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Atlanta	Georgia	United States	30322
2	GSK Investigational Site	Indianapolis	Indiana	United States	46202
3	GSK Investigational Site	Boston	Massachusetts	United States	02215
4	GSK Investigational Site	Grand Rapids	Michigan	United States	49546
5	GSK Investigational Site	San Antonio	Texas	United States	78229
6	GSK Investigational Site	Madison	Wisconsin	United States	53792
7	GSK Investigational Site	Fitzroy	Victoria	Australia	3065
8	GSK Investigational Site	Melbourne	Victoria	Australia	3000
9	GSK Investigational Site	Vancouver	British Columbia	Canada	V5Z1M9
10	GSK Investigational Site	Halifax	Nova Scotia	Canada	B3K 1V7
11	GSK Investigational Site	Toronto	Ontario	Canada	M5G 2M9
12	GSK Investigational Site	Lille Cedex		France	59037
13	GSK Investigational Site	Mont-de-Marsan		France	40000
14	GSK Investigational Site	Villejuif Cedex		France	94805
15	GSK Investigational Site	Frankfurt am Main	Hessen	Germany	60590
16	GSK Investigational Site	Leipzig	Sachsen	Germany	04103
17	GSK Investigational Site	Kiel	Schleswig-Holstein	Germany	24105
18	GSK Investigational Site	Hamburg		Germany	20246
19	GSK Investigational Site	Athens		Greece	11528
20	GSK Investigational Site	Incheon		Korea, Republic of	21565
21	GSK Investigational Site	Seoul		Korea, Republic of	06351
22	GSK Investigational Site	Seoul		Korea, Republic of	06591
23	GSK Investigational Site	Seoul		Korea, Republic of	110-744
24	GSK Investigational Site	Ulsan		Korea, Republic of	44033
25	GSK Investigational Site	Dordrecht		Netherlands	3318 AT
26	GSK Investigational Site	Leeuwarden		Netherlands	8934 AD
27	GSK Investigational Site	Utrecht		Netherlands	3584 CX
28	GSK Investigational Site	Oslo		Norway	0450
29	GSK Investigational Site	Gdansk		Poland	80-214
30	GSK Investigational Site	Katowice		Poland	40-519
31	GSK Investigational Site	Lodz		Poland	93-513
32	GSK Investigational Site	Lublin		Poland	20-081
33	GSK Investigational Site	Moscow		Russian Federation	125284
34	GSK Investigational Site	St'Petersburg		Russian Federation	191024
35	GSK Investigational Site	Badalona		Spain	08916
36	GSK Investigational Site	Madrid		Spain	28027
37	GSK Investigational Site	Madrid		Spain	28040
38	GSK Investigational Site	Madrid		Spain	28041
39	GSK Investigational Site	Pamplona		Spain	31008
40	GSK Investigational Site	Pozuelo (Madrid)		Spain	28223
41	GSK Investigational Site	Falun		Sweden	SE-791 82
42	GSK Investigational Site	Stockholm		Sweden	SE-141 86