Relapsed/Refractory Multiple Myeloma
Conditions
Keywords
Belantamab mafodotin, Relapsed/Refractory Multiple Myeloma, Maximum tolerated doses, Overall response rate, Overall survival, Dose limiting toxicities
Brief summary
Evaluate the efficacy and safety of Belantamab Mafodotin, cyclophosphamide, and dexamethasone in patients with Relapsed/Refractory Multiple Myeloma
Detailed description
This is a Phase I/II, open-label study to evaluate the efficacy and safety of Belantamab Mafodotin, cyclophosphamide, and dexamethasone. In Phase I, the subjects will be assigned into two arms and there are two dose levels for Belantamab Mafodotin and there are two dose levels of cyclophosphamide in each arm. In Phase II, once tolerability of the highest planned dose is established, the patients will be assessed for response rate. The arm with acceptable toxicity and best response will be further assessed in the expansion cohort. Belantamab mafodotin was approved by the U.S. Food and Drug Administration (FDA) on Aug 5, 2020, for treating patients with relapsed/refractory multiple myeloma. Cyclophosphamide and dexamethasone are both approved by the FDA. But the combinations with these three drugs to treat people with relapsed/refractory multiple myeloma has not been approved by the FDA.
Interventions
DRUGBelantamab Mafodotin, Cyclophosphamide and Dexamethasone
Study drug
Sponsors
University of Maryland, Baltimore
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase I 1. Arm A (cycles repeated every 3 weeks) 1. Dose level 1: The subject will take 1.9 mg/kg of Belantamab Mafodotin, 300 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 of each 3 weeks cycles. 2. Dose level 2: The subject will take 1.9 mg/kg of Belantamab Mafodotin, 500 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 of each 3 weeks cycles. 2. Arm B (cycles repeated every 6 weeks) 1. Dose level 1: The subject will take 2.5 mg/kg of Belantamab Mafodotin, 300 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 of each 6 weeks cycles. 2. Dose level 2: The subject will take 2.5 mg/kg of Belantamab Mafodotin, 500 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 of each 6 weeks cycles. Phase II : Phase II was stopped with the FDA withdrawal of the drug approval and reluctance of patients to participate.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Histologically confirmed diagnosis of Refractory MM; failed at least 3 prior lines of anti-myeloma treatments, including an anti-CD38 antibody (e.g., daratumumab) alone or in combination, and is refractory to an IMiD (i.e., lenalidomide or pomalidomide), and to a proteasome inhibitor (e.g., bortezomib, ixazomib or carfilzomib). (Refractory myeloma is defined as disease that is nonresponsive while on primary or salvage therapy or progresses within 60 days of last therapy. Nonresponsive disease is defined as either failure to achieve at least minimal response or development of progressive disease (PD) while on therapy). 2. Has measurable disease with at least one of the following: 1. Serum M-protein ≥0.5 g/dL (≥ 5 g/L) 2. Urine M-protein ≥ 200 mg/24h 3. Serum FLC assay: Involved FLC level ≥10 mg/dL and an abnormal ratio (\<0.26 or \>1.65) 3. Provide signed written informed consent. 4. 18 years or older (at the time consent is obtained). 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. 6. Participants with a history of autologous stem cell transplant or Prior BCMA targeted therapy (e.g. CAR-T cells, BiTes) can enroll on the study provided that: 1. Therapy was \>100 days prior to study enrolment. 2. No active infection(s). 7. Adequate organ system function (as defined by inclusion criteria #7). 8. Female and Male patients: Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 9. Prior treatment-related toxicities must be ≤ Grade 1 except peripheral neuropathy (Grade-2).
Exclusion criteria
1. Systemic anti-myeloma therapy within ≤14 days or 5 half-lives, whichever is shorter, or plasmapheresis within 7 days prior to treatment. 2. Systemic treatment with high dose steroids (equivalent to ≥ 60 mg prednisone daily for ≥4 days) within the past 14 days. 3. Symptomatic amyloidosis, active CNS disease, active plasma cell leukemia at the time of screening. 4. Prior allogeneic stem cell transplant (SCT). NOTE - Participants who have undergone syngeneic transplant may be allowed if no history of GvHD. 5. Current corneal epithelial disease except mild punctate keratopathy. 6. Evidence of active bleeding. 7. Any major surgery within the last four weeks. 8. Presence of active renal condition (infection, dialysis); isolated proteinuria from MM is allowed provided participants fulfil the adequate organ system function criteria (as defined by inclusion criteria #7). 9. Any serious and/or unstable pre-existing medical, psychiatric disorder or lab abnormalities that affect patients' safety, obtaining informed consent or compliance with study procedures. 10. Current unstable liver disease defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable non-cirrhotic chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) is acceptable if participant otherwise meets entry criteria. 11. Other malignancies except for malignancy from which the patients have been disease-free \> 2 years. 12. Evidence of cardiovascular disease including any of the following: 1. Evidence of current clinically significant untreated arrhythmias, including clinically significant ECG abnormalities including second degree (Mobitz Type II) or third degree atrioventricular (AV) block. 2. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within 3 months of Screening. 3. Class III or IV heart failure as defined by the New York Heart Association functional classification system. 4. Uncontrolled hypertension. 13. Known immediate or delayed hypersensitivity reaction or idiosyncratic reaction to drugs chemically related to belantamab mafodotin, daratumumab, bortezomib, boron or mannitol or any other components of the study treatment. 14. Active infection requiring treatment. 15. Known HIV infection. 16. 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. Note: presence of Hep B surface antibody (HBsAb) indicating previous vaccination will not exclude a participant. 17. 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. NOTE: Participants with positive hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Hepatitis RNA testing is optional and participants with negative hepatitis C antibody test are not required to also undergo hepatitis C RNA testing. 18. Symptomatic amyloidosis, active POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma proliferative disorder, skin changes) or active plasma cell leukemia at the time of screening. 19. Pregnant or lactating female. 20. Concomitant administration of strong P-glycoprotein inhibitors and inhibitors of OATP will be avoided.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events in Dose Escalation | Up to 6 weeks | Overall incidence and severity of Adverse Events in Number of Participants with Adverse Events in Dose Escalation |
| Response Rate in Dose Escalation and Expansion Cohort | Up to 12 weeks | Number of Participants With response rate in Dose Escalation and Expansion Cohort. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Disease Progression | From date of randomization until the date of death from any cause, assessed up to 3 years | Number of participants with disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
| Number of Participants According to Best Response | From date of randomization until the date of death from any cause, assessed up to 3 years | Best Response (Not including Overall Survival (OS) response) |
| Overall Survival | From date of randomization until the date of death from any cause, assessed up to 3 years | Number of patients with overall survival response |
Other
| Measure | Time frame | Description |
|---|---|---|
| Cytokine Profile Data | From date of randomization until the date of death from any cause, assessed up to 3 years | The cytokines were exploratory data, and were done on few patients, data is not conclusive to establish a reasonable ink with toxicity. Therefore, this endpoint cannot be provided. |
Countries
United States
Participant flow
Recruitment details
Dates of the recruitment period: 12/03/2021- 01/08/2024 Types of location: UMGCCC outpatient clinic
Pre-assignment details
Reasons for exclusion- history of GvHD; wears scleral lenses, Patient withdrew consent, No Measurable Disease, Inadequate organ system function, Current unstable liver disease
Participants by arm
| Arm | Count |
|---|---|
| Phase I: Arm A - Dose Level 1 (1) Dose level 1: The subject will take 1.9 mg/kg of Belantamab Mafodotin, 300 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 of each 3 weeks cycles.
Belantamab Mafodotin, Cyclophosphamide and Dexamethasone: Study drug | 3 |
| Phase I: Arm A - Dose Level 2 (2) Dose level 2: The subject will take 1.9 mg/kg of Belantamab Mafodotin, 500 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 each 3 weeks cycles.
Belantamab Mafodotin, Cyclophosphamide and Dexamethasone: Study drug | 0 |
| Phase I: Arm B - Dose Level 1 (1) Dose level 1: The subject will take 2.5 mg/kg of Belantamab Mafodotin, 300 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 of each 6 weeks cycles.
Belantamab Mafodotin, Cyclophosphamide and Dexamethasone: Study drug | 3 |
| Phase I: Arm B - Dose Level 2 (2) Dose level 2: The subject will take 2.5 mg/kg of Belantamab Mafodotin, 500 mg of Cyclophosphamide, and 40 mg of Dexamethasone on day 1 each 6 weeks cycles.
Belantamab Mafodotin, Cyclophosphamide and Dexamethasone: Study drug | 4 |
| Total | 10 |
Baseline characteristics
| Characteristic | Phase I: Arm A - Dose Level 1 | Phase I: Arm A - Dose Level 2 | Phase I: Arm B - Dose Level 1 | Phase I: Arm B - Dose Level 2 | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 3 Participants | 3 Participants | 9 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 0 Participants | 3 Participants | 2 Participants | 6 Participants |
| Region of Enrollment United States | 3 participants | — | 3 participants | 4 participants | 10 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants | 1 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 0 / 0 | 0 / 3 | 1 / 4 |
| other Total, other adverse events | 3 / 3 | 0 / 0 | 3 / 3 | 4 / 4 |
| serious Total, serious adverse events | 0 / 3 | 0 / 0 | 2 / 3 | 2 / 4 |
Outcome results
Primary
Number of Participants With Adverse Events in Dose Escalation
Overall incidence and severity of Adverse Events in Number of Participants with Adverse Events in Dose Escalation
Time frame: Up to 6 weeks
Population: 3 patients were enrolled in Arm A, Dose Level 1. Arm A was closed due to AEs and no patients enrolled in Arm A, Dose Level 2 3 patients were enrolled in Arm B, Dose Level 1. Then 4 new patients were enrolled in Arm B, Dose Level 2.~Part 2 was stopped with the FDA withdrawal of the drug approval and reluctance of patients to participate.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Dose Level 1 | Number of Participants With Adverse Events in Dose Escalation | 3 Participants |
| Arm A - Dose Level 2 | Number of Participants With Adverse Events in Dose Escalation | 0 Participants |
| Arm B - Dose Level 1 | Number of Participants With Adverse Events in Dose Escalation | 3 Participants |
| Arm B - Dose Level 2 | Number of Participants With Adverse Events in Dose Escalation | 4 Participants |
Primary
Response Rate in Dose Escalation and Expansion Cohort
Number of Participants With response rate in Dose Escalation and Expansion Cohort. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: Up to 12 weeks
Population: Phase II of the expansion cohort was stopped with the FDA withdrawal of the drug approval and reluctance of patients to participate. 0 patients were enrolled in the Phase II expansion Cohort, therefore, there is no data to report in the data table.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Dose Level 1 | Response Rate in Dose Escalation and Expansion Cohort | 3 Participants |
| Arm A - Dose Level 2 | Response Rate in Dose Escalation and Expansion Cohort | 0 Participants |
| Arm B - Dose Level 1 | Response Rate in Dose Escalation and Expansion Cohort | 3 Participants |
| Arm B - Dose Level 2 | Response Rate in Dose Escalation and Expansion Cohort | 4 Participants |
| Phase II : Expansion Cohort | Response Rate in Dose Escalation and Expansion Cohort | 0 Participants |
Secondary
Number of Participants According to Best Response
Best Response (Not including Overall Survival (OS) response)
Time frame: From date of randomization until the date of death from any cause, assessed up to 3 years
Population: Phase II of the expansion cohort was stopped with the FDA withdrawal of the drug approval and reluctance of patients to participate. 0 patients were enrolled in the Phase II expansion Cohort, therefore, there is no data to report in the data table.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A - Dose Level 1 | Number of Participants According to Best Response | Stable Disease (SD) | 1 Participants |
| Arm A - Dose Level 1 | Number of Participants According to Best Response | Very good partial response (VGPR) | 0 Participants |
| Arm A - Dose Level 1 | Number of Participants According to Best Response | Partial Response (PR) | 2 Participants |
| Arm A - Dose Level 2 | Number of Participants According to Best Response | Partial Response (PR) | 0 Participants |
| Arm A - Dose Level 2 | Number of Participants According to Best Response | Stable Disease (SD) | 0 Participants |
| Arm A - Dose Level 2 | Number of Participants According to Best Response | Very good partial response (VGPR) | 0 Participants |
| Arm B - Dose Level 1 | Number of Participants According to Best Response | Partial Response (PR) | 1 Participants |
| Arm B - Dose Level 1 | Number of Participants According to Best Response | Stable Disease (SD) | 2 Participants |
| Arm B - Dose Level 1 | Number of Participants According to Best Response | Very good partial response (VGPR) | 0 Participants |
| Arm B - Dose Level 2 | Number of Participants According to Best Response | Stable Disease (SD) | 2 Participants |
| Arm B - Dose Level 2 | Number of Participants According to Best Response | Very good partial response (VGPR) | 1 Participants |
| Arm B - Dose Level 2 | Number of Participants According to Best Response | Partial Response (PR) | 1 Participants |
| Phase II : Expansion Cohort | Number of Participants According to Best Response | Partial Response (PR) | 0 Participants |
| Phase II : Expansion Cohort | Number of Participants According to Best Response | Stable Disease (SD) | 0 Participants |
| Phase II : Expansion Cohort | Number of Participants According to Best Response | Very good partial response (VGPR) | 0 Participants |
Secondary
Number of Participants With Disease Progression
Number of participants with disease progression. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: From date of randomization until the date of death from any cause, assessed up to 3 years
Population: Phase II of the expansion cohort was stopped with the FDA withdrawal of the drug approval and reluctance of patients to participate. 0 patients were enrolled in the Phase II expansion Cohort, therefore, there is no data to report in the data table.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Dose Level 1 | Number of Participants With Disease Progression | 0 Participants |
| Arm A - Dose Level 2 | Number of Participants With Disease Progression | 0 Participants |
| Arm B - Dose Level 1 | Number of Participants With Disease Progression | 1 Participants |
| Arm B - Dose Level 2 | Number of Participants With Disease Progression | 3 Participants |
| Phase II : Expansion Cohort | Number of Participants With Disease Progression | 0 Participants |
Secondary
Overall Survival
Number of patients with overall survival response
Time frame: From date of randomization until the date of death from any cause, assessed up to 3 years
Population: Phase II of the expansion cohort was stopped with the FDA withdrawal of the drug approval and reluctance of patients to participate. 0 patients were enrolled in the Phase II expansion Cohort, therefore, there is no data to report in the data table.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A - Dose Level 1 | Overall Survival | 2 Participants |
| Arm A - Dose Level 2 | Overall Survival | 0 Participants |
| Arm B - Dose Level 1 | Overall Survival | 3 Participants |
| Arm B - Dose Level 2 | Overall Survival | 3 Participants |
| Phase II : Expansion Cohort | Overall Survival | 0 Participants |
Other Pre-specified
Cytokine Profile Data
The cytokines were exploratory data, and were done on few patients, data is not conclusive to establish a reasonable ink with toxicity. Therefore, this endpoint cannot be provided.
Time frame: From date of randomization until the date of death from any cause, assessed up to 3 years