Belantamab Mafodotin, Cyclophosphamide, and Dexamethasone in Relapsed/Refractory Multiple Myeloma

• ClinicalTrials.gov Identifier: NCT04896658
• Recruitment Status: Recruiting
• First Posted: May 21, 2021
• Last Update Posted: February 1, 2022
• Sponsor: University of Maryland, Baltimore
• Information provided by (Responsible Party): Ashraf Badros, University of Maryland, Baltimore

Study Description

Brief Summary:

Evaluate the efficacy and safety of Belantamab Mafodotin, cyclophosphamide, and dexamethasone in patients with Relapsed/Refractory Multiple Myeloma

Condition or disease	Intervention/treatment	Phase
Relapsed/Refractory Multiple Myeloma	Drug: Belantamab Mafodotin, Cyclophosphamide and Dexamethasone	Phase 1; Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 64 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

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

Once tolerability of the highest planned dose is established, patients will be assessed for response rate. The arm with acceptable toxicity and best response will be further assessed in the expansion cohort.

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Belantamab Mafodotin, Cyclophosphamide and Dexamethasone in Relapsed/Refractory Multiple Myeloma
• Actual Study Start Date: January 1, 2022
• Estimated Primary Completion Date: March 1, 2023
• Estimated Study Completion Date: March 1, 2024

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A; 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.; 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.	Drug: Belantamab Mafodotin, Cyclophosphamide and Dexamethasone; Study drug
Experimental: Arm B; 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.; 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.	Drug: Belantamab Mafodotin, Cyclophosphamide and Dexamethasone; Study drug

Outcome Measures

Primary Outcome Measures :

1. Overall incidence and severity of AEs in Dose Escalation [ Time Frame: Up to 6 weeks ]
   Overall incidence and severity of Adverse Events
2. Response rate in Expansion Cohort [ Time Frame: Up to 12 weeks ]
   percentage of patients with confirmed partial response or better and time to disease progression in responding patients.

Secondary Outcome Measures :

1. Time to progression [ Time Frame: From date of randomization until the date of death from any cause, assessed up to 100 months ]
   Time till the disease progresses
2. Progression free survival [ Time Frame: From date of randomization until the date of death from any cause, assessed up to 100 months ]
   time for study drugs to control the disease
3. Overall survival [ Time Frame: From date of randomization until the date of death from any cause, assessed up to 100 months ]
   total life expectancy
4. Cytokine Profile Data [ Time Frame: At the start of Cycle 2, Day 1 (a cycle is 28 days) ]
   The following Human Essential Immune Response Pane will be assessed:IL-4, IL-2, CXCL10 (IP-10), IL-1β, TNF-α, CCL2 (MCP-1), IL-17A, IL-6, IL-10, IFN-γ, IL-12p70, TGF-β1 (Free Active), CXCL8 (IL-8).

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Contacts

Contact: Ashraf Badros, MB; ChB; 410) 328-1230; abadros@UMM.edu

Contact: Sunita Sunita; 410-328-8199; sphilip1@umm.edu

Locations

United States, Maryland

University of Maryland; Recruiting

Baltimore, Maryland, United States, 21201

Contact: Sunita Philip, MBBS 410-328-8199 sphilip1@umm.edu

Sponsors and Collaborators

University of Maryland, Baltimore

Investigators

• Principal Investigator: Ashraf Badros, MB; ChB; University of Maryland, Baltimore

More Information

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• Responsible Party: Ashraf Badros, Director of Multiple Myeloma Service, University of Maryland, Baltimore
• ClinicalTrials.gov Identifier: NCT04896658
• Other Study ID Numbers: 2060GCCC
• First Posted: May 21, 2021
• Last Update Posted: February 1, 2022
• Last Verified: January 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Ashraf Badros, University of Maryland, Baltimore:

Belantamab mafodotin; Relapsed/Refractory Multiple Myeloma; Maximum tolerated doses; Overall response rate; Overall survival; Dose limiting toxicities

Additional relevant MeSH terms:

Multiple Myeloma; Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Dexamethasone; Cyclophosphamide; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Myeloablative Agonists; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents