Clinical trial NCT04126200: Platform Study of Belantamab Mafodotin as Monotherapy and in Combination With Anti-cancer Treatments in Participants With Relapsed/Refractory Multiple Myeloma (RRMM)
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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Multiple Myeloma
Keywords: Belantamab mafodotin
GSK2857916
GSK3174998
Feladilimab
Nirogacestat
Dostarlimab
Isatuximab
Lenalidomide
Dexamethasone
Pomalidomide
Platform study
Relapsed/Refractory Multiple Myeloma
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2019-10-15
Enrollment: 209
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.


Eligibility criteria: 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 immunomodulating 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 milligrams (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 deoxyribonucleic acid (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 6,7, and 8:

* Participants with contraception requirements specific to Sub-study 6, 7, and 8 respectively.
* Participants with platelets value for Adequate Organ System Function is ≥75 × 10\^9/L.

Inclusion Criteria Specific to Sub-study 8:

- In Japan, participants should reside in Japan and be Japanese as defined by having all biological Japanese grandparents. Similarly, in China, subjects should reside in China and be Chinese as defined by having all biological Chinese grandparents.

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.
* Participants with known human immunodeficiency virus (HIV) infection, unless the participant can meet all criteria: a) established anti-retroviral therapy for at least 4 weeks and HIV viral load\<400 copies/milliliter (mL) b) cluster of differentiation 4 plus (CD4+) T-cell (CD4+) counts \>= 350 cells/microliter (µL) c) No history of Acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections within the last 12 months in which case the participant would be eligible for CE Phase only.

For participants receiving nirogacestat, HIV drugs that are strong Cytochrome P450 3A4 (CYP3A4) inhibitors are prohibited. HIV drugs that are moderate CYP3A4 inhibitors, while permitted, should be co-administered with caution and must be accompanied by nirogacestat dose modifications.

Additional Exclusion Criteria for Sub-study 1 and 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, and 8:

* 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, 7, and 8:

* 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 and 8:

- 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.

Additional Exclusion Criteria for Sub-study 8:

* Pregnant or lactating female or female who are interrupting lactation.
* Previously diagnosed with interstitial lung disease or current complication of interstitial lung disease.

Primary outcomes:
measure: DE Phase: Number of participants achieving dose limiting toxicities (DLT)
timeFrame: Up to 12 months
measure: DE Phase: Number of participants with adverse events (AEs) and serious adverse events (SAEs)
timeFrame: Up to 12 months
measure: DE Phase: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis lab parameters
timeFrame: Up to 12 months
measure: CE Phase: Number of participants achieving Overall Response Rate (ORR)
timeFrame: Up to 36 months
Secondary outcomes:
measure: DE Phase: Number of participants achieving ORR
timeFrame: Up to 12 months
measure: CE Phase: Number of participants achieving Clinical Benefit Rate (CBR)
timeFrame: Up to 36 months
measure: DE Phase: Number of participants achieving Partial Response (PR)
timeFrame: Up to 12 months
measure: CE Phase: Number of participants achieving PR
timeFrame: Up to 36 months
measure: DE Phase: Number of participants achieving Very Good Partial Response (VGPR)
timeFrame: Up to 12 months
measure: CE Phase: Number of participants achieving VGPR
timeFrame: Up to 36 months
measure: DE Phase: Number of participants achieving Complete Response (CR)
timeFrame: Up to 12 months
measure: CE Phase: Number of participants achieving CR
timeFrame: Up to 36 months
measure: DE Phase: Number of participants achieving stringent Complete Response (sCR)
timeFrame: Up to 12 months
measure: CE Phase: Number of participants achieving sCR
timeFrame: Up to 36 months
measure: DE Phase: Belantamab mafodotin concentrations when administered in combination with anti-cancer treatments
timeFrame: Up to 12 months
measure: CE Phase: Belantamab mafodotin concentrations when administered in combination with anti-cancer treatments
timeFrame: Up to 36 months
measure: DE Phase: GSK3174998 concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: GSK3174998 concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Feladilimab concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Feladilimab concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Nirogacestat concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Nirogacestat concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Dostarlimab concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Dostarlimab concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Isatuximab concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Isatuximab concentration when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Concentration of anti-drug antibodies (ADAs) against belantamab mafodotin when administered in combination with anti-cancer treatments
timeFrame: Up to 12 months
measure: CE Phase: Concentration of ADAs against belantamab mafodotin when administered in combination with anti-cancer treatments
timeFrame: Up to 36 months
measure: DE Phase: Concentration of ADAs against GSK3174998 when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Concentration of ADAs against GSK3174998 when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Concentration of ADAs against feladilimab when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Concentration of ADAs against feladilimab when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Concentration of ADAs against dostarlimab when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Concentration of ADAs against dostarlimab when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Concentration of ADAs against isatuximab when administered in combination with belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Concentration of ADAs against isatuximab when administered in combination with belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Number of participants with adverse events of special interest (AESI) for belantamab mafodotin
timeFrame: Up to 12 months
measure: CE Phase: Number of participants with AESI for belantamab mafodotin
timeFrame: Up to 36 months
measure: DE Phase: Number of participants with AESI for GSK3174998
timeFrame: Up to 12 months
measure: CE Phase: Number of participants with AESI for GSK3174998
timeFrame: Up to 36 months
measure: DE Phase: Number of participants with AESI for Feladilimab
timeFrame: Up to 12 months
measure: CE Phase: Number of participants with AESI for Feladilimab
timeFrame: Up to 36 months
measure: DE Phase: Number of participants with AESI for Nirogacestat
timeFrame: Up to 12 months
measure: CE Phase: Number of participants with AESI for Nirogacestat
timeFrame: Up to 36 months
measure: DE Phase: Number of participants with AESI for Dostarlimab
timeFrame: Up to 12 months
measure: CE Phase: Number of participants with AESI for Dostarlimab
timeFrame: Up to 36 months
measure: DE Phase: Number of participants with AESI for Isatuximab
timeFrame: Up to 12 months
measure: CE Phase: Number of participants with AESI for Isatuximab
timeFrame: Up to 36 months
measure: DE Phase: Number of participants with abnormal ocular findings on ophthalmic examination
timeFrame: Up to 12 months
measure: CE Phase: Number of participants with abnormal ocular findings on ophthalmic examination
timeFrame: Up to 36 months
measure: CE Phase: Number of participants achieving Progression-free survival (PFS)
timeFrame: Up to 36 months
measure: CE Phase: Duration of response (DoR)
timeFrame: Up to 36 months
measure: CE Phase: Time to response (TTR)
timeFrame: Up to 36 months
measure: CE Phase: Number of participants achieving Overall survival (OS)
timeFrame: Up to 36 months
measure: CE Phase: Number of participants with AEs and SAEs
timeFrame: Up to 36 months
measure: CE Phase: Number of participants with AEs leading to discontinuation
timeFrame: Up to 36 months
measure: CE Phase: Number of participants with dose reduction or delay
timeFrame: Up to 36 months
measure: CE Phase: Number of participants with clinically significant changes in hematology, clinical chemistry and urinalysis lab parameters
timeFrame: Up to 36 months
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: GSK Investigational Site
state: Georgia
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Boston
country: United States
facility: GSK Investigational Site
state: Massachusetts
city: Grand Rapids
country: United States
facility: GSK Investigational Site
state: Michigan
city: Madison
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Fitzroy
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Melbourne
country: Australia
facility: GSK Investigational Site
state: Victoria
city: Porto Alegre
country: Brazil
facility: GSK Investigational Site
city: Salvador
country: Brazil
facility: GSK Investigational Site
city: SAo Paulo
country: Brazil
facility: GSK Investigational Site
city: Vancouver
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Halifax
country: Canada
facility: GSK Investigational Site
state: Nova Scotia
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Lille
country: France
facility: GSK Investigational Site
city: Villejuif Cedex
country: France
facility: GSK Investigational Site
city: Frankfurt
country: Germany
facility: GSK Investigational Site
city: Hamburg
country: Germany
facility: GSK Investigational Site
city: Kiel
country: Germany
facility: GSK Investigational Site
city: Leipzig
country: Germany
facility: GSK Investigational Site
city: Athens
country: Greece
facility: GSK Investigational Site
city: Incheon
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Ulsan
country: Korea, Republic of
facility: GSK Investigational Site
city: Ciudad de Mexico
country: Mexico
facility: GSK Investigational Site
city: Leeuwarden
country: Netherlands
facility: GSK Investigational Site
city: Utrecht
country: Netherlands
facility: GSK Investigational Site
city: Oslo
country: Norway
facility: GSK Investigational Site
city: Katowice
country: Poland
facility: GSK Investigational Site
city: Lublin
country: Poland
facility: GSK Investigational Site
city: Moscow
country: Russian Federation
facility: GSK Investigational Site
city: Badalona
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: Madrid
country: Spain
facility: GSK Investigational Site
city: PamplonaNavarra
country: Spain
facility: GSK Investigational Site
city: Pozuelo De AlarcOn Madr
country: Spain
facility: GSK Investigational Site
city: Falun
country: Sweden
facility: GSK Investigational Site
city: Stockholm
country: Sweden
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Hosoya H, Sidana S. Antibody-Based Treatment Approaches in Multiple Myeloma. Curr Hematol Malig Rep. 2021 Apr;16(2):183-191. doi: 10.1007/s11899-021-00624-6. Epub 2021 Mar 17.
citation: Nooka AK, Weisel K, van de Donk NW, Routledge D, Otero PR, Song K, Quach H, Callander N, Minnema MC, Trudel S, Jackson NA, Ahlers CM, Im E, Cheng S, Smith L, Hareth N, Ferron-Brady G, Brouch M, Montes de Oca R, Paul S, Holkova B, Gupta I, Kremer BE, Richardson P. Belantamab mafodotin in combination with novel agents in relapsed/refractory multiple myeloma: DREAMM-5 study design. Future Oncol. 2021 Jun;17(16):1987-2003. doi: 10.2217/fon-2020-1269. Epub 2021 Mar 8.