Belantamab Mafodotin in combination with Daratumumab, Lenalidomide and Dexamethasone for the treatment of patients with newly diagnosed multiple myeloma transplant ineligible

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Hellenic Society Of Hematology

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

31 Mar 2022 → ongoing

Decision date (initial)

2024-09-23

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

GlaxoSmithKline Research and Development Limited

External identifiers

EU CT number

2024-515634-32-00

EudraCT number

2021-006792-42

ClinicalTrials.gov

NCT05280275

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Dose response, Efficacy, Safety, Pharmacokinetic, Therapy

Part 1 – Dose finding
To determine the safety and tolerability of belantamab mafodotin in combination with daratumumab, lenalidomide, and dexamethasone to establish a recommended dose for participants with TI NDMM.
Part 2 – Dose expansion
To further evaluate the safety and determine the preliminary clinical activity of belantamab mafodotin RP2D in combination with daratumumab, lenalidomide, and dexamethasone.

Secondary objectives 5

1. To evaluate the effect of combining belantamab mafodotin with daratumumab, lenalidomide, and dexamethasone.
2. Assess the efficacy of belantamab mafodotin in combination with daratumumab, lenalidomide, and dexamethasone in TI NDMM.
3. Evaluate alternate corneal AE management approaches using visual acuity changes for belantamab mafodotin dose modifications.
4. To further characterize the pharmacokinetic (PK) profile of belantamab mafodotin when administered in combination with daratumumab, lenalidomide, and dexamethasone
5. To evaluate symptomatic AEs measured by the Ocular Surface Disease Index (OSDI) questionnaire as documented by the investigator.

Conditions and MedDRA coding

newly diagnosed multiple myeloma

Study design 2 periods

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 9

1. 1.Age ≥ 18 years
2. 2.Monoclonal plasma cells in the BM ≥10% or presence of a biopsy proven plasmacytoma and documented MM satisfying at least 1 of the CRAB criteria: -Hypercalcemia:serum calcium >0.25 mmol/L higher than ULN or >2.75 mmol/L. - Renal insufficiency:CrCl <40mL/min or serum creatinine >177 μmol/L. -Anemia: hemoglobin >2 g/dL below the lower limit of normal or hemoglobin <10 g/dL. - Bone lesions: 1 or more osteolytic lesions on skeletal radiography, CT or PET-CT OR Biomarkers of Malignancy: - Clonal BM plasma cell ≥60% - Involved: uninvolved serum FLC ratio ≥100 - More than 1 focal lesion on MRI studies
3. 3.Must have at least 1 aspect of measurable disease, defined as one of the below Urine M-protein excretion ≥200 mg/24 hours or Serum M-protein concentration ≥0.5 g/dL or Serum FLC assay: involved FLC level ≥10 mg/dL and an abnormal serum FLC ratio <0.26 or >1.65
4. 4.Not a candidate for high-dose chemotherapy with ASCT due to the presence of significant comorbid condition(s) that are likely to have a negative impact on tolerability of high dose chemotherapy with stem cell transplantation. The participants will be assessed by the IMWG frailty index that is recommended by ESMO guidelines. Participants with IMWG frailty index score 1 or 2 will be considered transplant ineligible
5. 5.ECOG performance status: 0–2
6. 6.Adequate organ system function as defined by the below laboratory assessments. oANC ≥1.25 X 109/L; GCSF use within the past 14 days is NOT permitted Hemoglobin ≥ 8.0 g/dL; transfusions within the past 14 days are NOT permitted PLT ≥ 50 x 109/L if BM is >50% involved in myeloma. Otherwise ≥75 x 109/L; transfusions within the past 14 days are NOT allowed to reach this level Total bilirubin ≤1.5xULN ALT ≤ 2.5xULN eGFR ≥30 mL/min/1.73 m2 Spot urine < 500 mg/g (56 mg/mmol) OR Urine Dipstick: Negative trace; if ≥ 1+ only eligible if confirmed < 500 mg/g [56 mg/mmol] by albumin/creatinine ratio
7. 7.Female participants are eligible to participate if she is not pregnant or breastfeeding and at least 1 of the following conditions applies: Is not a WOCBP defined as follows: a.Age≥ 45 years with no menses for > 1 year b.Participants who have been amenorrhoeic for < 2 years without a history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation c.Post-hysterectomy, post-bilateral oophorectomy or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure. OR •Is a WOCBP and using 2 methods of reliable birth control, beginning 4 weeks before initiating treatment with lenalidomide, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of lenalidomide treatment. Thereafter, WOCBP must use 1 method of reliable birth control that is highly effective for a further 4 months following discontinuation of belantamab mafodotin or 3 months following the discontinuation of daratumumab. WOCBP must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during treatment, during dose interruptions and for 28-days following the last dose of lenalidomide or 3 months following discontinuation of daratumumab treatment or 4 months following discontinuation of belantamab mafodotin treatment whichever is longer. A WOCBP must have 2 negative pregnancy tests before therapy initiation. The 1st test should be performed within 10-14 days and the 2nd test within 24h before the start of lenalidomide therapy. The participant should not receive lenalidomide until the investigator has verified that the results of these tests are negative and evaluate the effectiveness of the contraceptive method in relation to the 1st dose of study treatment. The investigator is responsible for reviewing the medical and menstrual history and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy
8. 8.Male participants are eligible to participate if they agree to the following during the intervention period and until 28 days after the last dose of lenalidomide or 3 months following the discontinuation of daratumumab or 6 months after the last dose of belantamab mafodotin whichever is longer 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 and agree to remain abstinent OR •Must agree to use contraception/barrier as below: Agree to use a male condom and female partner to use an additional highly effective contraceptive method with a failure rate of <1% per year as when having sexual intercourse with a woman of childbearing potential •Participants must be able to understand the study procedures and agree to participate in the study by providing written ICF
9. 9. Participants must be able to understand the study procedures and agree to participate in the study by providing written informed consent.

Exclusion criteria 28

1. 1.Prior systemic therapy for MM or SMM.
2. 2.Peripheral neuropathy or neuropathic pain Grade 2 or higher, as defined by the NCI CTCAE Version 5
3. 3. Major surgery within 4 weeks before the first dose of study drug.
4. 4.Presence of active renal condition. Participants with isolated proteinuria resulting from MM are eligible, provided that they fulfil the other inclusion criteria.
5. 5.Any serious and/or unstable pre-existing medical or psychiatric disorder, or other conditions (including laboratory abnormalities) that could interfere with participant's safety, obtaining informed consent or compliance to the study procedures.
6. 6.Evidence of active mucosal or internal bleeding uncontrolled by local therapy and not explained by reversible coagulopathy
7. 7.Current active unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
8. 8.Participants with previous or concurrent malignancies other than MM are excluded. Exceptions are surgically treated cervical carcinoma in situ, or any other malignancy that 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.
9. 9.Evidence of cardiovascular risk including any of the following: •Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities, second degree or third degree AV block. •Screening 12-lead ECG showing a baseline QT interval >470 msec •History of myocardial infarction, acute coronary syndromes, coronary angioplasty or stenting or bypass grafting within 3 months of Screening. •Class III or IV heart failure as defined by the New York Heart Association functional classification system. •Uncontrolled hypertension.
10. 10.Participant has known COPD
11. 11.Active infection requiring treatment.
12. 12.Known HIV infection, unless the participant can meet all of the following criteria: •Established ART for at least 4 weeks and HIV viral load <400 copies/mL. •CD4+ T-cell (CD4+) count ≥350 cells/uL. •No history of AIDS-defining opportunistic infections within the last 12 months.
13. 13.To be seropositive for hepatitis B at screening or within 3 months prior to first dose of study treatment.
14. 14.Positive hepatitis C antibody test result or positive hepatitis C RNA test result at screening or within 3 months before the first dose of study treatment unless the participant can meet the following criteria: •RNA test negative •Successful anti-viral treatment is required, followed by a negative HCV RNA test after a washout period of at least 4 weeks.
15. 15.Current corneal epithelial disease except for mild punctate keratopathy.
16. 16.Intolerance or contraindications to anti-viral prophylaxis.
17. 17.Unable to tolerate antithrombotic prophylaxis.
18. 18.Active or history of venous thromboembolism within past 3 months.
19. 19.AL amyloidosis (light chain amyloidosis), active POEMS syndrome or active plasma cell leukemia at the time of screening.
20. 20.Exhibiting clinical signs of or with a known history of meningeal or central nervous system involvement by MM.
21. 21.Known intolerance or immediate or delayed hypersensitivity reaction or idiosyncratic reaction to: drugs chemically related to belantamab mafodotin, or any of the components of the study treatment; daratumumab SC or to any of its excipients; or infused protein products, sucrose, histidine, and polysorbate 80.
22. 22.Use of an investigational drug within 14 days or 5 half-lives (whichever is longer) preceding the first dose of study drug.
23. 23.Plasmapheresis within 7 days before the first dose of study drug.
24. 24.Participants with uncontrolled skin disease.
25. 25.Participants with concomitant administration of a strong or moderate CYP3A4 inhibitor or inducer
26. 26.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 to the study procedures.
27. 27.Participant must not have received a live or live-attenuated vaccine within 30 days prior to first dose of belantamab mafodotin.
28. 28.Participant should not use contact lenses while receiving belantamab mafodotin.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The description of the primary endpoint exceeds the number of allowed characters in this field. Please refer to the protocol enclosed in this application

Secondary endpoints 14

1. •Lenalidomide RDI; DLT evaluable population, safety population
2. •Cumulative belantamab mafodotin dose of (DLT evaluable population, safety population) administered in combination with daratumumab, lenalidomide and dexamethasone. The total dose for each participant will be calculated as the sum of all administrated doses
3. •ORR and 95% CI as per IMWG by Investigator Assessment (ITT population) Part 1 only
4. •VGPR+ and 95% CI as per IMWG by Investigator Assessment (ITT population) Part 1 only
5. •TTR as per IMWG by Investigator Assessment (ITT population)
6. •DoR as per IMWG by Investigator Assessment (ITT population). The median DoR will be presented along with the respective 95% CIs and the 1st and 3rd quartiles.
7. •CRR as per IMWG by Investigator Assessment (ITT population).The denominator will be the total number of participants in each population, cohort and group respectively.
8. •MRD negativity rate (ITT population). The denominator will be the total number of participants in each population, cohort and Group respectively.
9. •PFS as per IMWG by Investigator Assessment (ITT population, Safety population). The median PFS will be analyzed with the Kaplan Meier method and presented along with the respective 95% CI and the 1st and 3rd quartiles.
10. •OS (ITT population, Safety population). The median OS will be analyzed using the Kaplan-Meier method and will be presented with the respective 95% CI and the 1st and 3rd quartiles.
11. •Number (%) of participants with abnormal ocular findings (DLT evaluable population, Safety population).
12. •PK analysis (PK population) Concentration-time data: linear and semi-logistic unique profiles of concentration-time and the mean and median profiles will be graphically represented for belantamab mafodotin. PK parameters: Concentration-time data can be presented, considering data from other studies and analyzed using a population PK analysis. Further, the Cmax and AUC will be calculated.
13. •Number of participants with changes from baseline and proportion of participants with within-participant meaningful change in self reported ocular symptoms and related impacts as measured by the OSDI questionnaire.
14. •Alternate corneal AE management: KVA events, dose holds, worst postbaseline BCVA and incidence of Grade 4 corneal findings will be descriptively summarized using frequencies and proportions. Exploratory Endpoints

Investigational products

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

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Hellenic Society Of Hematology

Sponsor organisation

Hellenic Society Of Hematology

Address

Kifissias Leoforos 27

City

Athens

Postcode

115 23

Country

Greece

Scientific contact point

Organisation

Hellenic Society Of Hematology

Contact name

Prof. Evangelos Terpos

Public contact point

Organisation

Hellenic Society Of Hematology

Contact name

Prof. Georgios Vasilopoulos

Third parties 12

Locations

1 EU/EEA country · 1 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 15 files

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

Application history

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