Phase I/II Study of Belantamab Mafodotin with Carfilzomib and Dexamethasone in Relapsed Multiple Myeloma Refractory to Lenalidomide

Trial ID: 2024-517006-28-00
Protocol: GEM-BELMA
Sponsor: Fundacion PETHEMA

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Diseases & Conditions

Plasma cell myeloma

Objectives

The primary objective of this study is to determine the **maximum tolerated dose** and the recommended phase 2 dose of belantamab mafodotin in combination with carfilzomib and dexamethasone for patients with **multiple myeloma** who are refractory to lenalidomide. This is clinically relevant as it aims to establish a safe and effective dosage regimen for this combination therapy, potentially offering a new treatment option for this patient population.

Secondary objectives include:

Determining time to event data such as progression-free survival, progression-free survival at 12 months, duration of response, time to response, and overall survival.
Evaluating the deepening of response during continuous therapy at 12 and 24 months.
Assessing the sustained minimal residual disease (MRD) rate at 1 and 2 years.
Evaluating the rate of conversion from MRD positivity to MRD negativity during treatment on a yearly basis.
Assessing the safety of the combination of belantamab mafodotin and Kd, including the incidence of corneal and ophthalmologic adverse events.

Participants

The clinical trial involves participants diagnosed with **multiple myeloma**, specifically those experiencing relapse after receiving at least one and no more than three prior lines of therapy. The study population includes both male and female subjects aged 18 years and older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. Participants must have adequate organ function and a measurable secretory disease. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria emphasize the ability to comply with protocol requirements and the necessity for prior treatment-related toxicities to be at or below Grade 1, except for alopecia. Participants must be refractory to lenalidomide and may have received prior treatment with proteasome inhibitors, including bortezomib and carfilzomib, under specific conditions. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed as an open-label, multicenter, phase I/II study to evaluate the combination of **belantamab mafodotin** with **carfilzomib** and dexamethasone for the treatment of patients with relapsed **multiple myeloma** who are refractory to lenalidomide. The trial aims to determine the maximum tolerated dose and the recommended phase 2 dose of belantamab mafodotin in the lead-in phase, while the expansion phase focuses on assessing the efficacy in terms of complete response rate and minimal residual disease negativity after 12 months of therapy. The study also evaluates the safety and tolerability of the drug combination.

The trial employs a non-randomized design, with participants receiving the investigational treatment in an open-label manner. The study is expected to run from November 23, 2021, to August 30, 2027. Participants will be involved in the study for a duration that includes multiple visits, starting with a screening visit to assess eligibility based on specific inclusion criteria, such as being refractory to lenalidomide and having received 1 to 3 prior lines of therapy. Follow-up visits will be conducted to monitor the participants' response to treatment, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, where final assessments will be made.

Participants are expected to remain in the study unless they experience unacceptable toxicity, disease progression, or choose to withdraw consent. The primary endpoints include determining the recommended phase 2 dose and evaluating the overall response rate, complete response rate, and minimal residual disease negativity rate. Secondary endpoints focus on the duration of response, progression-free survival, time to response, overall survival, and the incidence of treatment-related adverse events. The study is conducted in compliance with local regulations, and participants must provide written informed consent before any study-related procedures are performed.

Treatment

The clinical trial involves the administration of **CARFILZOMIB**, an experimental medication used in the treatment of relapsed myeloma patients who are refractory to lenalidomide. **CARFILZOMIB** is provided in the form of an injection and is administered via **intravenous use**. The specific dosage and frequency of administration are determined based on the trial phase and individual patient response. The medication is of chemical origin and is not formulated for pediatric use. Participant compliance with the administration schedule is monitored throughout the trial to ensure adherence to the protocol.

Another experimental medication used in this trial is **BELANTAMAB MAFODOTIN**, which is a solution for infusion. This medication is also administered intravenously. **BELANTAMAB MAFODOTIN** is classified as an antineoplastic agent and is a monoclonal antibody. The trial aims to determine the maximum tolerated dose and the recommended phase 2 dose of **BELANTAMAB MAFODOTIN** when used in combination with **CARFILZOMIB** and dexamethasone. The medication is not intended for pediatric use, and its administration is closely monitored to evaluate safety, tolerability, and efficacy in achieving complete response rates and minimal residual negativity after 12 months of therapy.

In addition to the experimental medications, the trial includes the use of dexamethasone, a standard-of-care therapy, as part of the treatment regimen. Dexamethasone is administered according to established clinical guidelines and is used to enhance the therapeutic effects of the experimental medications. The combination of **BELANTAMAB MAFODOTIN**, **CARFILZOMIB**, and dexamethasone is evaluated for its potential to improve treatment outcomes in patients with relapsed myeloma.

Efficacy

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoints for Phase 2 include the **Overall Response Rate (ORR)**, which is defined as the percentage of participants achieving a confirmed partial response or better, and the **Complete Response Rate (CRR)**, which measures the percentage of participants with a confirmed complete response or better. Additionally, the **Minimal Residual Disease (MRD) negativity rate** will be evaluated using next-generation flow cytometry at specific timepoints, including at the time of complete response or very good partial response, and at months 12, 18, and 24, with annual assessments thereafter.

Secondary endpoints will include the **Duration of Response (DoR)**, **Progression-Free Survival (PFS)**, and **Overall Survival (OS)**. The DoR is defined as the time from the first documented evidence of partial response or better until disease progression or death due to progressive disease. PFS is measured from the start of treatment until documented disease progression or death from any cause. OS is defined as the time from the start of treatment until death from any cause. Additional secondary endpoints include the percentage of patients achieving MRD negativity and the incidence of treatment-related adverse events.

Data collection will involve the use of validated scales and laboratory tests to ensure accurate and reliable measurement of these endpoints. The analysis of efficacy endpoints will be based on derived confirmed responses according to the International Myeloma Working Group (IMWG) criteria. The trial will also monitor changes in laboratory analyses, vital signs, and ocular findings through ophthalmic exams to assess safety and tolerability.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Patient is, in the investigator’s opinion, willing and able to comply with the protocol requirements.
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.
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.
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.
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.
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.
Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
Participant must be ≥ 18 years of age.
Participant must have adequate organ function, defined in table 6
Female participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
Male participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.
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.
Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent.

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Exclusion Criteria

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.
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.
Participants with curatively treated non-melanoma skin cancer may be enrolled without a 2-year restriction.
Participant has meningeal involvement of multiple myeloma.
Pregnant or breastfeeding females.
Participant is simultaneously enrolled in other interventional clinical trial.
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.
Participant has used an investigational drug within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug.
Prior treatment with a monoclonal antibody against MM within 30 days of receiving the first dose of study drug.
Participant has received prior treatment with anti-BCMA agents.
Received plasmapheresis within 7 days prior to the first dose of study drug.
Participant has received prior radiotherapy within 2 weeks of start of study therapy.
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.
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.
Participant has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other monoclonal antibodies.
Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
Participant has current corneal epithelial disease except mild punctate keratopathy.
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
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.
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.
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.
Evidence of active mucosal or internal bleeding.
Use of contact lenses while participating in this study.
Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
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).
Patients with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
Patients with severe chronic obstructive pulmonary disease (COPD) or asthma with forced expiratory volume in the first minute (FEV1) less than 50%.
History of interstitial lung disease or ongoing interstitial lung disease.
Participant has an active infection requiring antibiotic, antiviral, or antifungal treatment
Participant has known HIV infection
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.
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.