Study of Belantamab Mafodotin in Combination With Kd for the Treatment of Relapsed Myeloma Patients, Refractory to Lenalidomide

NCT05060627 | Recruiting Phase 1 DMC

• 2 other identifiers: GEM-BELMA2021-002125-15
• Study Type: interventional
• Target: 60
• Locations: 1 country
• Sites: 15

Brief Summary

This is a phase I-II open-label, multicenter, non-randomized study aiming to evaluate the efficacy and safety of belantamab mafodotin in combination with carfilzomib (Kyprolis®) and dexamethasone (Kd). Since this is the first time that this combination is being evaluated in a clinical trial, a first dose escalation part will be developed following the classic 3+3 design, to establish the maximum tolerated dose (MTD) of the combination. Once the MTD will be defined, a dose expansion phase will be open to recruit up to 60 patients. Patients will receive treatment with belantamab-mafodotin + Kd, until unacceptable toxicity, disease progression, patient withdrawal, loss to follow-up, end of study, or death.

Conditions

Relapsed Multiple Myeloma

Keywords

Relapsed multiple myeloma; Refractoriness to lenalidomide

Outcome Measures

Primary Outcomes (9)

• Number of participants with adverse events (AEs) during the triplet-therapy in phase I.

  To determine the maximum tolerated dose, and the recommended phase 2 dose of belantamab mafodotin in combination with carfilzomib and dexamethasone, number of participants with adverse events (AEs) during the triplet-therapy in phase 1 will be evaluated.

  At the end of the first 4-week cycle following a 3+3 design.

• Overall Response Rate (ORR)

  Percentage of participants with a confirmed partial response (PR) or better (PR, VGPR, CR, sCR).

  12 months.

• Minimal Residual Disease (MRD) negativity rate

  The percentage of participants who are MRD negative by next-generation flow cytometry (NGF).

  At the time of CR/VGPR, and in all patients at month 12, 18, and 24, and yearly thereafter.

• Complete Response Rate (CRR)

  The percentage of participants with a confirmed complete response (CR) or better (stringent complete response (CR, sCR)).

  12 months.

• Incidence of deaths and primary cause of death.

  Frequency and percentage of deaths and primary cause of death.

  Throughout the study. Approximately 60 months.

• Incidence of adverse events (AEs).

  Frequency and percentage of AEs

  Throughout the study. Approximately 60 months.

• % of patients with changes in hematologic laboratory parameters

  Percentage of patients who present differences in hematologic laboratory parameters from baseline values .

  Throughout the study. Approximately 60 months.

• % of patients with changes in blood chemistry laboratory parameters

  Percentage of patients who present differences in blood chemistry panel from baseline values.

  Throughout the study. Approximately 60 months.

• Frequency of ocular findings on ophthalmic exam

  Ocular findings on ophthalmic exam

  Throughout the study. Approximately 60 months.

Secondary Outcomes (11)

• Duration of Response (DoR)

  Throughout the study. Approximately 60 months.

• Progression-Free Survival (PFS)

  Throughout the study. Approximately 60 months.

• Progression-Free Survival (PFS) at 12 months.

  12 months

• Time to Response (TTR)

  Throughout the study. Approximately 60 months.

• Overall Survival (OS)

  Throughout the study. Approximately 60 months.

Study Arms (1)

Belantamab-Mafodotin + Carfilzomib+ dexametasona

EXPERIMENTAL

In the phase 1 of the study, aiming to establish the recommended phase 2 dose (RP2D), patients will be included following the classic 3 + 3 design. Once the DLT assessment period is completed and the MTD is defined, the recruitment will continue in the expansion phase 2. Combination treatment will be administered at the recommended Phase 2 dose (RP2D) based on the results of the phase 1 dose escalation part of the study: * Belantamab mafodotin on day 1 at the RP2D, every 8 weeks, intravenously (IV). * Carfilzomib will be given at the RP2D weekly IV on days: 1, 8, and 15 of every 4-week cycle (Q4W). * Dexamethasone will be given at the dose of 40 mg (or 20 mg if patient \> 75 years old) on days: 1, 8, 15 and 22 Q4W. From month 13 onwards carfilzomib treatment will be given on day 1 and 15 of every 4-weeks cycles. Belantamab will be given at the RP2D every 8 weeks and Dexamethasone 40mg on days 1, 8, and 15 of every 4-week cycle.

Drug: Belantamab mafodotin; Drug: Carfilzomib; Drug: Dexamethasone

Interventions

Belantamab mafodotin DRUG

In phase 1: * Dose level -1: Belantamab-Mafodotin 1.9 mg/kg day 1, Q8W * Dose level 1,2,3: Belantamab-Mafodotin 2.5 mg/kg day 1, Q8W In phase 2: maximum tolerated dose (MTD) of the combination

Belantamab-Mafodotin + Carfilzomib+ dexametasona

Carfilzomib DRUG

In phase 1: * Dose level -1, 1: Carfilzomib 20/45 mg/m2 days 1, 8, and 15, Q4W. * Dose level 2: Carfilzomib 20/56 mg/m2 on days 1, 8, and 15, Q4W * Dose level 3: Carfilzomib 20/70 mg/m2 on days 1, 8, and 15, Q4W. In phase 2: maximum tolerated dose (MTD) of the combination

Belantamab-Mafodotin + Carfilzomib+ dexametasona

Dexamethasone DRUG

Description: Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients \> 75 years old., Q4W

Belantamab-Mafodotin + Carfilzomib+ dexametasona

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant must be able to understand the study procedures
• 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 ≥ 10mg/L (100 mg/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
• HEMATOLOGIC Absolute neutrophil count (ANC) ≥1.5 X 109/L Hemoglobin ≥8.0 g/dL (prior red blood cell (RBC) transfusion or recombinant human erythropoietin use is permitted) Platelets ≥75 x 109/L for subjects in whom \<50% of bone marrow nucleated cells are plasma cells; otherwise platelet count \>50 × 10\*9/L (prior platelet transfusion is permitted up to 7 days before the screening phase) Calcium corrected serum calcium \<14 mg/dL (\<3.5 mmol/L); or free ionized calcium \<6.5 mg/dL (\<1.6 mmol/L); HEPATIC Total bilirubin ≤1.5X ULN (Isolated bilirubin ≥1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%) ALT ≤2.5 X ULN AST ≤2.5 X ULN
• RENAL eGFRa ≥40 mL/min/ 1.73 m2 Spot urine (albumin/creatinine ratios) \<500 mg/g (56 mg/mmol) OR Negative/trace (if ≥1+ only eligible if confirmed ≥ 500 mg/g (56 mg/mmol) by albumin/creatinine ratio (spot urine from first void) Urine Dipstick
• CARDIAC LVEF (echo) ≥ 40%
• Female participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a woman of childbearing potential (WOCBP) OR

You may not qualify if:

• 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 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 molecular antibodies.
• Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.

Sponsors & Collaborators

• PETHEMA Foundation: lead
• Adknoma Health Research: collaborator

Study Sites (15)

Hospital Germans Trias i Pujol (ICO BADALONA)

Badalona, Spain

RECRUITING

Hospital Clinic

Barcelona, Spain

NOT YET RECRUITING

ICO Hospitalet

Bellvitge, Spain

RECRUITING

H. Gregorio Marañón

Madrid, Spain

NOT YET RECRUITING

Hospital Universitario 12 de Octubre

Madrid, Spain

NOT YET RECRUITING

H. Morales Meseguer

Murcia, Spain

RECRUITING

HUCA

Oviedo, Spain

RECRUITING

H. Son Llatzer

Palma de Mallorca, Spain

RECRUITING

Clínica Universidad de Navarra (CUN)

Pamplona, Spain

RECRUITING

Hospital Universitario de Salamanca

Salamanca, Spain

RECRUITING

H. Universitario de Canarias

Santa Cruz de Tenerife, Spain

NOT YET RECRUITING

H. Universitario Marqués de Valdecilla

Santander, Spain

NOT YET RECRUITING

Complejo Hospitalario Santiago (CHUS)

Santiago de Compostela, Spain

RECRUITING

Complejo Hospitalario Virgen del Rocío

Seville, Spain

RECRUITING

H.U. La Fe

Valencia, Spain

RECRUITING

Related Publications (10)

• Berenson JR, Cartmell A, Bessudo A, Lyons RM, Harb W, Tzachanis D, Agajanian R, Boccia R, Coleman M, Moss RA, Rifkin RM, Patel P, Dixon S, Ou Y, Anderl J, Aggarwal S, Berdeja JG. CHAMPION-1: a phase 1/2 study of once-weekly carfilzomib and dexamethasone for relapsed or refractory multiple myeloma. Blood. 2016 Jun 30;127(26):3360-8. doi: 10.1182/blood-2015-11-683854. Epub 2016 May 12.

  PMID: 27207788 BACKGROUND

• Chari A, Martinez-Lopez J, Mateos MV, Blade J, Benboubker L, Oriol A, Arnulf B, Rodriguez-Otero P, Pineiro L, Jakubowiak A, de Boer C, Wang J, Clemens PL, Ukropec J, Schecter J, Lonial S, Moreau P. Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma. Blood. 2019 Aug 1;134(5):421-431. doi: 10.1182/blood.2019000722. Epub 2019 May 21.

  PMID: 31113777 BACKGROUND

• Cowan AJ, Allen C, Barac A, Basaleem H, Bensenor I, Curado MP, Foreman K, Gupta R, Harvey J, Hosgood HD, Jakovljevic M, Khader Y, Linn S, Lad D, Mantovani L, Nong VM, Mokdad A, Naghavi M, Postma M, Roshandel G, Shackelford K, Sisay M, Nguyen CT, Tran TT, Xuan BT, Ukwaja KN, Vollset SE, Weiderpass E, Libby EN, Fitzmaurice C. Global Burden of Multiple Myeloma: A Systematic Analysis for the Global Burden of Disease Study 2016. JAMA Oncol. 2018 Sep 1;4(9):1221-1227. doi: 10.1001/jamaoncol.2018.2128.

  PMID: 29800065 BACKGROUND

• Dimopoulos MA, Moreau P, Palumbo A, Joshua D, Pour L, Hajek R, Facon T, Ludwig H, Oriol A, Goldschmidt H, Rosinol L, Straub J, Suvorov A, Araujo C, Rimashevskaya E, Pika T, Gaidano G, Weisel K, Goranova-Marinova V, Schwarer A, Minuk L, Masszi T, Karamanesht I, Offidani M, Hungria V, Spencer A, Orlowski RZ, Gillenwater HH, Mohamed N, Feng S, Chng WJ; ENDEAVOR Investigators. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016 Jan;17(1):27-38. doi: 10.1016/S1470-2045(15)00464-7. Epub 2015 Dec 5.

  PMID: 26671818 BACKGROUND

• 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.

  PMID: 31859245 BACKGROUND

• O'Connor OA, Stewart AK, Vallone M, Molineaux CJ, Kunkel LA, Gerecitano JF, Orlowski RZ. A phase 1 dose escalation study of the safety and pharmacokinetics of the novel proteasome inhibitor carfilzomib (PR-171) in patients with hematologic malignancies. Clin Cancer Res. 2009 Nov 15;15(22):7085-91. doi: 10.1158/1078-0432.CCR-09-0822. Epub 2009 Nov 10.

  PMID: 19903785 BACKGROUND

• Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, Trudel S, Kukreti V, Bahlis N, Alsina M, Chanan-Khan A, Buadi F, Reu FJ, Somlo G, Zonder J, Song K, Stewart AK, Stadtmauer E, Kunkel L, Wear S, Wong AF, Orlowski RZ, Jagannath S. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012 Oct 4;120(14):2817-25. doi: 10.1182/blood-2012-05-425934. Epub 2012 Jul 25.

  PMID: 22833546 BACKGROUND

• 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.

  PMID: 30442502 BACKGROUND

• Trudel S, Lendvai N, Popat R, Voorhees PM, Reeves B, Libby EN, Richardson PG, Hoos A, Gupta I, Bragulat V, He Z, Opalinska JB, Cohen AD. Antibody-drug conjugate, GSK2857916, in relapsed/refractory multiple myeloma: an update on safety and efficacy from dose expansion phase I study. Blood Cancer J. 2019 Mar 20;9(4):37. doi: 10.1038/s41408-019-0196-6.

  PMID: 30894515 BACKGROUND

• Vij R, Siegel DS, Jagannath S, Jakubowiak AJ, Stewart AK, McDonagh K, Bahlis N, Belch A, Kunkel LA, Wear S, Wong AF, Wang M. An open-label, single-arm, phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory multiple myeloma who have been previously treated with bortezomib. Br J Haematol. 2012 Sep;158(6):739-48. doi: 10.1111/j.1365-2141.2012.09232.x. Epub 2012 Jul 30.

  PMID: 22845873 BACKGROUND

MeSH Terms

Conditions

Multiple Myeloma

Interventions

belantamab mafodotin; carfilzomib; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Paula Rodríguez Otero

  Clínica Universidad de Navarra

  STUDY CHAIR

• María-Victoria Mateos

  University of Salamanca

  STUDY CHAIR

• Jesús San Miguel Izquierdo

  Clínica Universidad de Navarra

  STUDY CHAIR

Central Study Contacts

Carmen López-Carrero

CONTACT

0034 699 835 437; carmen@fundacionpethema.es

Roberto Maldonado

CONTACT

0034 683 15 66 87; roberto.maldonado@fundacionpethema.es

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: A phase I classic 3+3 design, to establish the maximum tolerated dose (MTD) of the combination. Once the MTD will be defined, a dose expansion phase II will be open to recruit up to 60 patients.

Study Record Dates

• First Submitted: September 17, 2021
• First Posted: September 29, 2021
• Study Start: December 20, 2021
• Primary Completion: May 1, 2024
• Study Completion (Estimated): May 30, 2028
• Last Updated: September 8, 2022

Record last verified: 2022-09

Locations

ES (15)