Phase III study of GSK2857916, bortezomib, and dexamethasone versus daratumumab, bortezomib, and dexamethasone in participants with relapsed/refractory multiple myeloma (DREAMM 7)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Glaxosmithkline Research & Development Limited

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

15 May 2020 → ongoing

Decision date (initial)

2024-06-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

No

External identifiers

EU CT number

2023-510537-28-00

EudraCT number

2018-003993-29

ClinicalTrials.gov

NCT04246047

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

The primary objective of this study is to compare the efficacy of belantamab mafodotin in combination with bortezomib and dexamethasone (bor/dex) with that of daratumumab in combination with bor/dex in participants with relapsed refractory multiple myeloma in terms of progression-free survival

Secondary objectives 7

1. To compare the efficacy of belantamab mafodotin in combination with bortezomib and dexamethasone with that of daratumumab in combination with bortezomib and dexamethasone in participants with relapsed refractory multiple myeloma in terms of overall survival, duration of response and minimal residual disease.
2. To further assess the efficacy of belantamab mafodotin in combination with bortezomib and dexamethasone with that of daratumumab in combination with bortezomib and dexamethasone in terms of other efficacy outcomes in participants with relapsed refractory multiple myeloma
3. To evaluate the safety and tolerability of belantamab mafodotin when administered in combination with bortezomib and dexamethasone
4. To further describe the exposure to belantamab mafodotin when administered in combination with bortezomib and dexamethasone
5. To assess anti-drug antibodies (ADAs) against belantamab mafodotin
6. To evaluate the safety and tolerability of belantamab mafodotin based on self-reported symptomatic adverse effects when administered in combination with bortezomib and dexamethasone
7. To evaluate and compare changes in symptoms and health-related quality of life (HRQOL) as measured by EORTC QLQ-C30 and EORTC IL52

Conditions and MedDRA coding

Multiple Myeloma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 11

1. Capable of giving signed informed consent as described in protocol section 10.1.3 which includes compliance with the requirements and restrictions listed in the informed consent form and in the protocol.
2. Male or female, 18 years or older (at the time consent is obtained)
3. Confirmed diagnosis of multiple myeloma as defined by the IMWG criteria [Rajkumar, 2014].
4. Previously treated with at least 1 prior line of multiple myeloma therapy, and must have documented disease progression during or after their most recent therapy. "
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2
6. Participants with a history of autologous SCT are eligible for study participation provided the following are met: a. Autologous stem cell transplant was >100 days prior to initiating study treatment, and b. No active bacterial, viral, or fungal infection(s) present."
7. Must have at least ONE aspect of measurable disease, defined as one the following: a. Urine M-protein excretion ≥200 mg/24h, 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). "
8. All prior treatment-related toxicities, defined by NCI-CTCAE v5.0, must be ≤ Grade 1 at the time of enrollment, except for alopecia."
9. Adequate organ system functions as defined by the following laboratory assessments: Absolute Neutrophil Count: ≥1.0 x 10^9/L Hemoglobin: ≥ 8.0g/dL Platelets: ≥75x109^/L Total bilirubin: ≤1.5xULN; (Isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin is <35%) Alanine aminotransferase: ≤2.5xULN eGFR: ≥30 mL/min/1.73 m2 Urine dipstick for protein: Negative/trace [if ≥1+, only eligible if confirmed ≤500 mg/g (56 mg/mmol) by albumin/creatinine ratio (spot urine from first void)] OR Albumin/creatinine ratio (from spot urine): ≤500 mg/g (56 mg/mmol) "
10. Female Participants: Contraceptive use by women should be consistent with local regulations regarding 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 OR Is a woman of childbearing potential and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency during the intervention period and for 4 months after the last dose of belantamab mafodotin, 3 months from the last dose of daratumumab, and 7 months from the last dose of bortezomib, whichever is longer, 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 intervention. Women of childbearing potential must have a negative highly sensitive serum pregnancy test within 72 hours of dosing on C1D1. Additional requirements for pregnancy testing during and after study intervention are provided in Section 10.3 and the SoA of the protocol. 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. "
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 the following from the time of first dose of study until 6 months after the last dose of belantamab mafodotin, and 4 months from the last dose of bortezomib, 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, 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 child bearing potential (including pregnant females)"

Exclusion criteria 24

1. Intolerant to daratumumab
2. Prior allogenic stem cell transplant. Participants who have undergone syngeneic transplant are allowed only if no history of GvHD"
3. 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 all inclusion criteria are met "
4. Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with participant’s safety, obtaining informed consent or compliance to the study procedures "
5. Evidence of active mucosal or internal bleeding"
6. Cirrhosis or current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, esophageal or gastric varices, persistent jaundice. NOTE: stable non-cirrhotic chronic liver disease(including Gilbert’s syndrome or asymptomatic gallstones) is acceptable provided all inclusion criteria are met"
7. Any major surgery within 4 weeks prior to the first dose of study drug. Exception allowed for bone stabilizing surgery in consultation with medical monitor"
8. Refractory to daratumumab or any other anti-CD38 therapy (defined as progressive disease during treatment with anti-CD38 therapy, or within 60 days of completing that treatment) "
9. Intolerant to bortezomib, or refractory to bortezomib (defined as progressive disease during treatment with a bortezomib-containing regimen of 1.3 mg/m2 twice weekly, or within 60 days of completing that treatment). Participants with progressive disease during treatment with a weekly bortezomib regimen are allowed."
10. Ongoing Grade 2 or higher peripheral neuropathy or neuropathic pain
11. Prior treatment with anti-BCMA therapy"
12. 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"
13. Plasmapheresis within 7 days prior to the first dose of study drug"
14. Has received radiotherapy to a large pelvic area. Bridging radiotherapy is allowed. NOTE: Disease assessment should be repeated if RT is done prior to first dose of study drug within screening window"
15. Previous or concurrent malignancies other than multiple myeloma, 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"
16. Evidence of cardiovascular risk including any of the following: a. Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including second degree (Mobitz Type II) or third degree atrioventricular (AV) block b. History of myocardial infarction, acute coronary syndromes, 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 d. Uncontrolled hypertension "
17. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, daratumumab, bortezomib, boron or mannitol or any components of the study treatment"
18. Active infection requiring treatment"
19. Known HIV infection, unless the participant can meet all of the following criteria: • Established anti-retroviral therapy 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 Note: consideration must be given to ART and prophylactic antimicrobials that may have a drug-drug interaction and/or overlapping toxicities with belantamab mafodotin or other combination products as relevant (see protocol Section 6.5.2) "
20. Patients with Hepatitis B unless the following criteria can be met: Serology: HBcAb+, HbsAg-: At Screening: • HBV DNA undetectable During the study: • Monitoring per protocol (Table 18) • Antiviral treatment instituted if HBV DNA becomes detectable Serology: HBsAg+ at screen or within 3 months prior to first dose: • HBV DNA undetectable at Screening • Highly effective antiviral treatment started at least 4 weeks prior to first dose of study treatment • Baseline imaging per protocol at Screening • Participants with cirrhosis at Screening are excluded During the study: • Antiviral treatment maintained throughout study treatment • Monitoring and management per protocol (Table 18)"
21. 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: • RNA test negative • Successful anti-viral treatment (usually 8 weeks duration) is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks. "
22. Current corneal epithelial disease except for mild punctate keratopathy "
23. Intolerance or contraindications to anti-viral prophylaxis."
24. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukaemia at the time of screening."

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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

Secondary endpoints 16

1. Overall Survival (OS), defined as the time from the date of randomization until the date of death due to any cause
2. Duration of Response (DoR), defined as the time from first documented evidence of PR or better until progressive disease (PD) or death due to any cause
3. Minimal Residual Disease (MRD) negativity rate, defined as the percentage of participants who are MRD negative by next-generation sequencing (NGS)
4. Complete Response Rate (CRR), defined as the percentage of participants with a confirmed complete response (CR) or better
5. Overall Response Rate (ORR), defined as the percentage of participants with a confirmed partial response (PR) or better
6. Clinical Benefit Rate (CBR), defined as the percentage of participants with a confirmed minimal response (MR) or better per IMWG
7. 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
8. 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
9. PFS2, defined as time from randomization to disease progression after initiation of new anti-myeloma therapy or death from any cause, whichever is earlier.
10. If disease progression after new anti-myeloma therapy cannot be measured, a PFS event is defined as the date of discontinuation of new anti-myeloma therapy, or death from any cause, whichever is earlier
11. Incidence of adverse events (AEs) and changes in laboratory parameters
12. Ocular findings on ophthalmic exam
13. Plasma concentrations of belantamab mafodotin, and cys-mcMMAF
14. Incidence and titers of ADAs against belantamab mafodotin
15. Maximum post-baseline PRO-CTCAE score for each item attribute
16. Change from baseline in HRQOL as measured by EORTC QLQ-C30 and EORTC IL52 (disease symptoms domain from the EORTC QLQ-MY20)

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Comparator 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Glaxosmithkline Research & Development Limited

Sponsor organisation

Glaxosmithkline Research & Development Limited

Address

G S K House, 980 Great West Road 980 Great West Road

City

Brentford

Postcode

TW8 9GS

Country

United Kingdom

Scientific contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Public contact point

Organisation

Glaxosmithkline Research & Development Limited

Contact name

EU GSK Clinical Trials Call Center

Third parties 27

Locations

9 EU/EEA countries · 39 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 216 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

8 submissions — initial application plus substantial / non-substantial modifications