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

Relapsed/Refractory Multiple Myeloma Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04896658
• Other study ID #: 2060GCCC
• Status: Active, not recruiting
• Phase: Phase 1/Phase 2
• Start date: December 3, 2021
• Est. completion date: March 1, 2025

Study information

• Verified date: March 2024
• Source: University of Maryland, Baltimore
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 10
• Est. completion date: March 1, 2025
• Est. primary completion date: June 30, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell
• Relapsed/Refractory Multiple Myeloma

Intervention

Drug:
• Belantamab Mafodotin, Cyclophosphamide and Dexamethasone
Study drug

Locations

Country	Name	City	State
United States	University of Maryland	Baltimore	Maryland

Sponsors (1)

Lead Sponsor	Collaborator
University of Maryland, Baltimore

Country where clinical trial is conducted

United States, 

References & Publications (18)

Alley SC, Zhang X, Okeley NM, Anderson M, Law CL, Senter PD, Benjamin DR. The pharmacologic basis for antibody-auristatin conjugate activity. J Pharmacol Exp Ther. 2009 Sep;330(3):932-8. doi: 10.1124/jpet.109.155549. Epub 2009 Jun 4. — View Citation

Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, Moreau P, Dingli D, Cole C, Lonial S, Dimopoulos M, Stewart AK, Richter J, Vij R, Tuchman S, Raab MS, Weisel KC, Delforge M, Cornell RF, Kaminetzky D, Hoffman JE, Costa LJ, Parker TL, Levy M, Schreder M, Meuleman N, Frenzel L, Mohty M, Choquet S, Schiller G, Comenzo RL, Engelhardt M, Illmer T, Vlummens P, Doyen C, Facon T, Karlin L, Perrot A, Podar K, Kauffman MG, Shacham S, Li L, Tang S, Picklesimer C, Saint-Martin JR, Crochiere M, Chang H, Parekh S, Landesman Y, Shah J, Richardson PG, Jagannath S. Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma. N Engl J Med. 2019 Aug 22;381(8):727-738. doi: 10.1056/NEJMoa1903455. — View Citation

Dougherty BE, Nichols JJ, Nichols KK. Rasch analysis of the Ocular Surface Disease Index (OSDI). Invest Ophthalmol Vis Sci. 2011 Nov 7;52(12):8630-5. doi: 10.1167/iovs.11-8027. — View Citation

Gandhi UH, Cornell RF, Lakshman A, Gahvari ZJ, McGehee E, Jagosky MH, Gupta R, Varnado W, Fiala MA, Chhabra S, Malek E, Mansour J, Paul B, Barnstead A, Kodali S, Neppalli A, Liedtke M, Narayana S, Godby KN, Kang Y, Kansagra A, Umyarova E, Scott EC, Hari P, Vij R, Usmani SZ, Callander NS, Kumar SK, Costa LJ. Outcomes of patients with multiple myeloma refractory to CD38-targeted monoclonal antibody therapy. Leukemia. 2019 Sep;33(9):2266-2275. doi: 10.1038/s41375-019-0435-7. Epub 2019 Mar 11. — View Citation

Heylmann D, Bauer M, Becker H, van Gool S, Bacher N, Steinbrink K, Kaina B. Human CD4+CD25+ regulatory T cells are sensitive to low dose cyclophosphamide: implications for the immune response. PLoS One. 2013 Dec 23;8(12):e83384. doi: 10.1371/journal.pone.0083384. eCollection 2013. — View Citation

Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, Lonial S, Blade J, Mateos MV, Dimopoulos M, Kastritis E, Boccadoro M, Orlowski R, Goldschmidt H, Spencer A, Hou J, Chng WJ, Usmani SZ, Zamagni E, Shimizu K, Jagannath S, Johnsen HE, Terpos E, Reiman A, Kyle RA, Sonneveld P, Richardson PG, McCarthy P, Ludwig H, Chen W, Cavo M, Harousseau JL, Lentzsch S, Hillengass J, Palumbo A, Orfao A, Rajkumar SV, Miguel JS, Avet-Loiseau H. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol. 2016 Aug;17(8):e328-e346. doi: 10.1016/S1470-2045(16)30206-6. — View Citation

Kumar SK, Lee JH, Lahuerta JJ, Morgan G, Richardson PG, Crowley J, Haessler J, Feather J, Hoering A, Moreau P, LeLeu X, Hulin C, Klein SK, Sonneveld P, Siegel D, Blade J, Goldschmidt H, Jagannath S, Miguel JS, Orlowski R, Palumbo A, Sezer O, Rajkumar SV, Durie BG; International Myeloma Working Group. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012 Jan;26(1):149-57. doi: 10.1038/leu.2011.196. Epub 2011 Jul 29. Erratum In: Leukemia. 2012 May;26(5):1153. Nari, Hareth [corrected to Nahi, Hareth]. — View Citation

Laurent SA, Hoffmann FS, Kuhn PH, Cheng Q, Chu Y, Schmidt-Supprian M, Hauck SM, Schuh E, Krumbholz M, Rubsamen H, Wanngren J, Khademi M, Olsson T, Alexander T, Hiepe F, Pfister HW, Weber F, Jenne D, Wekerle H, Hohlfeld R, Lichtenthaler SF, Meinl E. gamma-Secretase directly sheds the survival receptor BCMA from plasma cells. Nat Commun. 2015 Jun 11;6:7333. doi: 10.1038/ncomms8333. — View Citation

Lonial S, Lee HC, Badros A, Trudel S, Nooka AK, Chari A, Abdallah AO, Callander N, Lendvai N, Sborov D, Suvannasankha A, Weisel K, Karlin L, Libby E, Arnulf B, Facon T, Hulin C, Kortum KM, Rodriguez-Otero P, Usmani SZ, Hari P, Baz R, Quach H, Moreau P, Voorhees PM, Gupta I, Hoos A, Zhi E, Baron J, Piontek T, Lewis E, Jewell RC, Dettman EJ, Popat R, Esposti SD, Opalinska J, Richardson P, Cohen AD. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020 Feb;21(2):207-221. doi: 10.1016/S1470-2045(19)30788-0. Epub 2019 Dec 16. — View Citation

Macsai M, Nariani A, Gan H, Lassman A, Merrell R, Gomez E, et al. Corneal Toxicity of ABT-414 in Glioblastoma (GBM): Clinical Manifestations, Ophthalmological Findings and Management. Investigative Ophthalmology & Visual Science. 2016 Sep 26;57(12):269-269.

Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, Gross JA, Greipp PR, Jelinek DF. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004 Jan 15;103(2):689-94. doi: 10.1182/blood-2003-06-2043. Epub 2003 Sep 25. — View Citation

Pirogova OV, Moiseev IS, Surkova EA, Lapin SV, Bondarenko SN, Kulagin AD, Afanasyev BV. Profiles of pro-inflammatory cytokines in allogenic stem cell transplantation with post-transplant cyclophosphamide. Cytokine. 2017 Nov;99:148-153. doi: 10.1016/j.cyto.2017.08.016. Epub 2017 Sep 9. — View Citation

Roghanian A, Hu G, Fraser C, Singh M, Foxall RB, Meyer MJ, Lees E, Huet H, Glennie MJ, Beers SA, Lim SH, Ashton-Key M, Thirdborough SM, Cragg MS, Chen J. Cyclophosphamide Enhances Cancer Antibody Immunotherapy in the Resistant Bone Marrow Niche by Modulating Macrophage FcgammaR Expression. Cancer Immunol Res. 2019 Nov;7(11):1876-1890. doi: 10.1158/2326-6066.CIR-18-0835. Epub 2019 Aug 26. — View Citation

Sanchez E, Li M, Kitto A, Li J, Wang CS, Kirk DT, Yellin O, Nichols CM, Dreyer MP, Ahles CP, Robinson A, Madden E, Waterman GN, Swift RA, Bonavida B, Boccia R, Vescio RA, Crowley J, Chen H, Berenson JR. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival. Br J Haematol. 2012 Sep;158(6):727-38. doi: 10.1111/j.1365-2141.2012.09241.x. Epub 2012 Jul 18. — View Citation

Tai YT, Li XF, Breitkreutz I, Song W, Neri P, Catley L, Podar K, Hideshima T, Chauhan D, Raje N, Schlossman R, Richardson P, Munshi NC, Anderson KC. Role of B-cell-activating factor in adhesion and growth of human multiple myeloma cells in the bone marrow microenvironment. Cancer Res. 2006 Jul 1;66(13):6675-82. doi: 10.1158/0008-5472.CAN-06-0190. — View Citation

Thompson JA, Motzer RJ, Molina AM, Choueiri TK, Heath EI, Redman BG, Sangha RS, Ernst DS, Pili R, Kim SK, Reyno L, Wiseman A, Trave F, Anand B, Morrison K, Donate F, Kollmannsberger CK. Phase I Trials of Anti-ENPP3 Antibody-Drug Conjugates in Advanced Refractory Renal Cell Carcinomas. Clin Cancer Res. 2018 Sep 15;24(18):4399-4406. doi: 10.1158/1078-0432.CCR-18-0481. Epub 2018 May 30. — View Citation

Trudel S, Lendvai N, Popat R, Voorhees PM, Reeves B, Libby EN, Richardson PG, Anderson LD Jr, Sutherland HJ, Yong K, Hoos A, Gorczyca MM, Lahiri S, He Z, Austin DJ, Opalinska JB, Cohen AD. Targeting B-cell maturation antigen with GSK2857916 antibody-drug conjugate in relapsed or refractory multiple myeloma (BMA117159): a dose escalation and expansion phase 1 trial. Lancet Oncol. 2018 Dec;19(12):1641-1653. doi: 10.1016/S1470-2045(18)30576-X. Epub 2018 Nov 12. — View Citation

Xie J, He Y. Ontology-Based Vaccine Adverse Event Representation and Analysis. Adv Exp Med Biol. 2017;1028:89-103. doi: 10.1007/978-981-10-6041-0_6. — View Citation

* Note: There are 18 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Overall incidence and severity of AEs in Dose Escalation	Overall incidence and severity of Adverse Events	Up to 6 weeks
Primary	Response rate in Expansion Cohort	percentage of patients with confirmed partial response or better and time to disease progression in responding patients.	Up to 12 weeks
Secondary	Time to progression	Time till the disease progresses	From date of randomization until the date of death from any cause, assessed up to 100 months
Secondary	Progression free survival	time for study drugs to control the disease	From date of randomization until the date of death from any cause, assessed up to 100 months
Secondary	Overall survival	total life expectancy	From date of randomization until the date of death from any cause, assessed up to 100 months
Secondary	Cytokine Profile Data	The following Human Essential Immune Response Pane will be assessed:IL-4, IL-2, CXCL10 (IP-10), IL-1ß, TNF-a, CCL2 (MCP-1), IL-17A, IL-6, IL-10, IFN-?, IL-12p70, TGF-ß1 (Free Active), CXCL8 (IL-8).	At the start of Cycle 2, Day 1 (a cycle is 28 days)