An open label, multicenter, phase I/II study of belantamab mafodotin in combination with Kd for the treatment of relapsed myeloma patients, refractory to lenalidomide

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion PETHEMA

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

23 Nov 2021 → ongoing

Decision date (initial)

2024-10-18

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

PETHEMA Foundation

External identifiers

EU CT number

2024-517006-28-00

EudraCT number

2021-002125-15

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Dose response, Efficacy

Lead-in phase: To determine the maximum tolerated dose, and the recommended phase 2 dose of belantamab mafodotin in combination with carfilzomib and dexamethasone.
Expansion phase:
To evaluate the efficacy in terms of complete response rate and rates of minimal residual negativity after 12 months of therapy with belantamab mafodotin combined with carfilzomib and dexamethasone.
To evaluate safety and tolerability of the combination of belantamab mafodotin plus carfilzomib and dexamethasone.

Secondary objectives 5

1. To determine time to event data of the combinations: Progression-free survival, progression-free survival at 12 months, duration of response, time to response, and overall survival. SO2: Evaluate deepening of response during continuous therapy at 12, and 24 months. SO3: Evaluate sustained MRD rate at 1 and 2 years. SO4: Evaluate the rate of conversion from MRD positivity to MRD negativity during the treatment (yearly). SO5: To assess the safety of the combination of belantamab mafodotin + Kd, as well as the incidence of corneal and ophthalmologic adverse events.
2. Evaluate deepening of response during continuous therapy at 12, and 24 months.
3. Evaluate sustained MRD rate at 1 and 2 years.
4. Evaluate the rate of conversion from MRD positivity to MRD negativity during the treatment (yearly).
5. To assess the safety of the combination of belantamab mafodotin + Kd, as well as the incidence of corneal and ophthalmologic adverse events.

Conditions and MedDRA coding

Multiple myeloma

Study design 1 period

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 13

1. Patient is, in the investigator’s opinion, willing and able to comply with the protocol requirements.
2. Patient has given voluntary written informed consent before performance of any study-related procedure nor part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care.
3. Relapse multiple myeloma patients that have received at least 1 and no more than 3 prior lines of therapy. Induction, intensification with high-dose melphalan and stem cell transplant and maintenance is considered one line of treatment.
4. Patients must be refractory to lenalidomide. Refractoriness is defined as progression while receiving lenalidomide or in the first 60 days after the last dose of lenalidomide. Refractoriness would be defined regardless of the dose of lenalidomide received, and the schedule or whether it was given alone or in combination.
5. Patients can have received prior treatment with proteasome inhibitors. Patients with prior bortezomib treatment are eligible regardless of refractory status. Prior carfilzomib treatment is allowed, provided that the patients achieve at least a partial response to prior carfilzomib, and that there is a treatment free interval of at least 6 months.
6. Participant must have a measurable secretory disease defined as either serum monoclonal protein of ≥ 0,5 g/dl or urine monoclonal (light chain) protein ≥ 200 mg/24 h. For patients whose disease is only measurable by serum FLC, the involved FLC should be ≥ 100mg/L (10mg/dl), with an abnormal serum FLC ratio.
7. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
8. Participant must be ≥ 18 years of age.
9. Participant must have adequate organ function, defined in table 6
10. Female participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
11. Male participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
12. All prior treatment-related toxicities (defined by National Cancer Institute- Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.0 must be ≤ Grade 1 at the time of enrolment except for alopecia.
13. Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent.

Exclusion criteria 32

1. Participant has a diagnosis of primary amyloidosis, monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), plasma cell leukemia or active POEMS syndrome at the time of screening.
2. Participant has invasive malignancies other than disease under study, unless the second malignancy has been medically stable for at least 2 years and, in the opinion of the principal investigators, will not affect the evaluation of the effects of clinical trial treatments on the currently targeted malignancy.
3. Participants with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction.
4. Participant has meningeal involvement of multiple myeloma.
5. Pregnant or breastfeeding females.
6. Participant is simultaneously enrolled in other interventional clinical trial.
7. Participant has used a systemic anti-myeloma drug within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug.
8. Participant has used an investigational drug within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug.
9. Prior treatment with a monoclonal antibody against MM within 30 days of receiving the first dose of study drug.
10. Participant has received prior treatment with anti-BCMA agents.
11. Received plasmapheresis within 7 days prior to the first dose of study drug.
12. Participant has received prior radiotherapy within 2 weeks of start of study therapy.
13. 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.
14. Participant has a known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to belantamab mafodotin or drugs chemically related to belantamab mafodotin, or any of the components of the study treatment.
15. Participant has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other monoclonal antibodies.
16. Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
17. Participant has current corneal epithelial disease except mild punctate keratopathy.
18. Participant has peripheral neuropathy or neuropathic pain grade ≥2, as defined by the National Cancer Institute Terminology Criteria for Adverse Events (NCI CTCAE) Version 4.0
19. Participant evidence of cardiovascular risk including any of the following: - QTcF interval QTcF > 480 msec (the QT interval values must be corrected for heart rate by Fridericia’s formula [QTcF]) - Evidence of current clinically significant uncontrolled arrhythmias, including clinically significant ECG abnormalities such as 2nd degree (Type II) or 3rd degree atrioventricular (AV) block. - History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within six months of Screening.- Class III or IV heart failure as defined by the New York Heart Association functional classification system [NYHA, 1994] - Uncontrolled hypertension, defined as an average systolic blood pressure ≥ 160 mmHg or diastolic ≥ 100 mmHg despite optimal treatment.
20. Participant has current unstable liver or biliary disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis.
21. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect patient’s safety). Participants with isolated proteinuria resulting from MM are eligible, provided they fulfil inclusion criteria.
22. Evidence of active mucosal or internal bleeding.
23. Use of contact lenses while participating in this study.
24. Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
25. Uncontrolled endocrine diseases (i.e. diabetes mellitus, hypothyroidism or hyperthyroidism) (i.e. requiring relevant changes in medication within the last month, or hospital admission within the last 3 months).
26. Patients with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
27. Patients with severe chronic obstructive pulmonary disease (COPD) or asthma with forced expiratory volume in the first minute (FEV1) less than 50%.
28. History of interstitial lung disease or ongoing interstitial lung disease.
29. Participant has an active infection requiring antibiotic, antiviral, or antifungal treatment
30. Participant has known HIV infection
31. Participant has presence of hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb at screening or within 3 months prior to first dose of study treatment.
32. Participant has 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 10

1. Phase 1: Recommended phase 2 dose (RP2D)
2. Phase 2: Overall Response Rate (ORR), defined as the percentage of participants with a confirmed partial response (PR) or better (PR, VGPR, CR, sCR).
3. Phase 2: Complete Response Rate (CRR), defined as the percentage of participants with a confirmed complete response (CR) or better (stringent complete response (CR, sCR)).
4. Phase 2: Minimal Residual Disease (MRD) negativity rate, defined as the percentage of participants who are MRD negative by next-generation flow cytometry (NGF). MRD will be evaluated at the time of CR/VGPR, and in all patients at month 12, 18, and 24, and yearly thereafter.
5. Phase 2: Analysis of efficacy endpoints will be based on derived confirmed response according to International Myeloma Working Group (IMWG)
6. Phase 2: Incidence of deaths and primary cause of death.
7. Phase 2: Data for vital signs
8. Phase 2: Incidence of adverse events (AEs).
9. Phase 2: Changes in laboratory analyses from the hematology and blood chemistry panel
10. Phase 2: Ocular findings on ophthalmic exam

Secondary endpoints 9

1. Duration of Response (DoR), defined as the time from first documented evidence of PR or better until progressive disease (PD) or death due to PD among participants who achieved PR or better
2. Progression-Free Survival (PFS), defined as the time from the start of treatment until the earliest date of documented disease progression or death due to any cause.
3. Progression-Free Survival at 12 months.
4. Time to Response (TTR), defined as the time from the start of treatment and the first documented evidence of response (PR or better) among participants who achieve confirmed PR or better
5. Overall Survival (OS), defined as the time from the start of treatment until the date of death due to any cause
6. Percentage of patients upgrading the response category (i.e. percentage of patients converting from partial response to VGPR, etc.)
7. Percentage of patients achieving minimal residual disease negativity using EuroFlow Panel with a sensitivity of 10-6.
8. Percentage of patients converting from positive MRD to undetectable MRD following EuroFlow panel with a sensitivity of 10-6
9. Incidence of Treatment related adverse events Percentage of patients discontinuing therapy due to AEs. • Percentage of patients requiring dose modifications.

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion PETHEMA

Sponsor organisation

Fundacion PETHEMA

Address

Calle Del Professor Martin Lagos Sn

City

Madrid

Postcode

28040

Country

Spain

Scientific contact point

Organisation

Fundacion PETHEMA

Contact name

Dr Juan José Lahuerta

Public contact point

Organisation

Fundacion PETHEMA

Contact name

Dr Juan José Lahuerta

Third parties 4

Locations

1 EU/EEA country · 15 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 4 files

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

Application history

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