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An Open Label, Multicenter, Phase I/II Study of Belantamab Mafodotin in Combination With Kd for the Treatment of Relapsed Myeloma Patients, Refractory to Lenalidomide

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ClinicalTrials.gov Identifier: NCT05060627
Recruitment Status : Not yet recruiting
First Posted : September 29, 2021
Last Update Posted : September 29, 2021
Sponsor:
Collaborator:
Adknoma Health Research
Information provided by (Responsible Party):
PETHEMA Foundation

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.


Condition or disease Intervention/treatment Phase
Relapsed Multiple Myeloma Drug: Belantamab mafodotin Drug: Carfilzomib Drug: Dexamethasone Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: N/A
Intervention Model: Sequential Assignment
Intervention Model Description: 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.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open Label, Multicenter, Phase I/II Study of Belantamab Mafodotin in Combination With Kd for the Treatment of Relapsed Myeloma Patients, Refractory to Lenalidomide.
Estimated Study Start Date : September 30, 2021
Estimated Primary Completion Date : May 2024
Estimated Study Completion Date : May 30, 2028


Arm Intervention/treatment
Experimental: Belantamab-Mafodotin + Carfilzomib+ dexametasona

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

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

Drug: Carfilzomib

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


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




Primary Outcome Measures :
  1. Number of participants with adverse events (AEs) during the triplet-therapy in phase I. [ Time Frame: At the end of the first 4-week cycle following a 3+3 design. ]
    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.

  2. Overall Response Rate (ORR) [ Time Frame: 12 months. ]
    Percentage of participants with a confirmed partial response (PR) or better (PR, VGPR, CR, sCR).

  3. Minimal Residual Disease (MRD) negativity rate [ Time Frame: At the time of CR/VGPR, and in all patients at month 12, 18, and 24, and yearly thereafter. ]
    The percentage of participants who are MRD negative by next-generation flow cytometry (NGF).

  4. Complete Response Rate (CRR) [ Time Frame: 12 months. ]
    The percentage of participants with a confirmed complete response (CR) or better (stringent complete response (CR, sCR)).

  5. Incidence of deaths and primary cause of death. [ Time Frame: Throughout the study. Approximately 60 months. ]
    Frequency and percentage of deaths and primary cause of death.

  6. Incidence of adverse events (AEs). [ Time Frame: Throughout the study. Approximately 60 months. ]
    Frequency and percentage of AEs

  7. % of patients with changes in hematologic laboratory parameters [ Time Frame: Throughout the study. Approximately 60 months. ]
    Percentage of patients who present differences in hematologic laboratory parameters from baseline values .

  8. % of patients with changes in blood chemistry laboratory parameters [ Time Frame: Throughout the study. Approximately 60 months. ]
    Percentage of patients who present differences in blood chemistry panel from baseline values.

  9. Frequency of ocular findings on ophthalmic exam [ Time Frame: Throughout the study. Approximately 60 months. ]
    Ocular findings on ophthalmic exam


Secondary Outcome Measures :
  1. Duration of Response (DoR) [ Time Frame: Throughout the study. Approximately 60 months. ]
    Time from first documented evidence of PR or better until progressive disease (PD) or death due to PD among participants who achieved PR or better.

  2. Progression-Free Survival (PFS) [ Time Frame: Throughout the study. Approximately 60 months. ]
    Time from the start of treatment until the earliest date of documented disease progression or death due to any cause.

  3. Progression-Free Survival (PFS) at 12 months. [ Time Frame: 12 months ]
    Time from the start of treatment until the earliest date of documented disease progression or death due to any cause.

  4. Time to Response (TTR) [ Time Frame: Throughout the study. Approximately 60 months. ]
    Time from the start of treatment and the first documented evidence of response (PR or better) among participants who achieve confirmed PR or better.

  5. Overall Survival (OS) [ Time Frame: Throughout the study. Approximately 60 months. ]
    Time from the start of treatment until the date of death due to any cause

  6. Percentage of patients upgrading the response category [ Time Frame: At 12 and 24 months ]
    Percentage of patients upgrading/deepening the response (converting from partial response to VGPR, etc.)

  7. Percentage of patients achieving minimal residual disease negativity using EuroFlow Panel with a sensitivity of 10*(-6). [ Time Frame: At 12, 18 and 24 months ]
    Percentage of patients achieving minimal residual disease negativity using EuroFlow Panel with a sensitivity of 10*(-6)

  8. Percentage of patients converting from positive MRD to undetectable MRD following EuroFlow panel with a sensitivity of 10*(-6) [ Time Frame: At 12, 24, 36, 48 and 60 months. ]
    Percentage of patients converting from positive MRD to undetectable MRD following EuroFlow panel with a sensitivity of 10-6

  9. Incidence of Treatment related adverse events [ Time Frame: Throughout the study. Approximately 60 months. ]
    Frequency and percentage of Treatment related adverse events

  10. Percentage of patients discontinuing therapy due to AEs. [ Time Frame: Throughout the study. Approximately 60 months. ]
    Percentage of patients discontinuing therapy due to AEs.

  11. Percentage of patients requiring dose modifications. [ Time Frame: Throughout the study. Approximately 60 months. ]
    Percentage of patients requiring dose modifications.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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

Inclusion Criteria:

Participant must be able to understand the study procedures

  1. Patient is, in the investigator's opinion, willing and able to comply with the protocol requirements.
  2. 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.
  3. 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.
  4. 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.

  5. 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.
  6. 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.
  7. Participant must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
  8. Participant must be ≥ 18 years of age
  9. Participant must have adequate organ function. Laboratory values that define adequate organ function for inclusion in study are as follow:

    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%

  10. 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
    • Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), preferably with low user dependency, during the intervention period and for at least 4 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.

    A WOCBP must have a negative highly sensitive serum pregnancy test (as required by local regulations) within 72 hours before the first dose of study intervention.

    The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy.

    Nonchildbearing potential is defined as follows (by other than medical reasons):

    • ≥45 years of age and has not had menses for >1 year
    • Patients who have been amenorrhoeic for >2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
    • Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation.Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
  11. Male participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies.

    Male participants are eligible to participate if they agree to the following from the time of first dose of study until 6 months after the last dose of belantamab mafodotin to allow for clearance of any altered sperm:

    - Refrain from donating sperm

    PLUS either:

    • Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
    • Must agree to use contraception/barrier as detailed below:

      • Agree to use a male condom, even if they have undergone a successful vasectomy and female partner to use an additional highly effective contraceptive method with a failure rate of <1% per year when having sexual intercourse with a WOCBP (including pregnant females).
  12. 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
  13. Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent

Exclusion Criteria:

  1. 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.
  2. 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.
  3. Participant has meningeal involvement of multiple myeloma.
  4. Pregnant or breastfeeding females.
  5. Participant is simultaneously enrolled in other interventional clinical trial.
  6. 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.
  7. Participant has used an investigational drug within 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug.
  8. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drug.
  9. Participant has received prior treatment with anti-BCMA agents.
  10. Received plasmapheresis within 7 days prior to the first dose of study drug.
  11. 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.

  12. 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.
  13. Participant has a known immediate or delayed hypersensitivity reaction or idiosyncrasy to other molecular antibodies.
  14. Major surgery (except kyphoplasty) ≤ 4 weeks prior to initiating protocol therapy.
  15. Participant has current corneal epithelial disease except mild changes in corneal epithelium
  16. 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.
  17. 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.
  18. 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. Note: Stable chronic liver disease (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if otherwise meets entry criteria.
  19. 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.
  20. Evidence of active mucosal or internal bleeding.
  21. Use of contact lenses while participating in this study.
  22. Any serious medical condition or psychiatric illness that would interfere in understanding of the informed consent form.
  23. 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).
  24. Patients with acute diffuse infiltrative pulmonary disease and/or pericardial disease.
  25. Patients with severe chronic obstructive pulmonary disease (COPD) or asthma with forced expiratory volume in the first minute (FEV1) less than 50%.
  26. History of interstitial lung disease or ongoing interstitial lung disease. aa. Participant has an active infection requiring antibiotic, antiviral, or antifungal treatment bb. Participant has known HIV infection cc. 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.

dd. 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.

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.

Note: Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05060627


Contacts
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Contact: Carmen López-Carrero 0034 699 835 437 carmen@fundacionpethema.es
Contact: Roberto Maldonado 0034 683 15 66 87 roberto.maldonado@fundacionpethema.es

Locations
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Spain
Hospital Germans Trias i Pujol (ICO BADALONA)
Badalona, Spain
Contact: Albert Oriol Rocafiguera         
Principal Investigator: Albert Oriol Rocafiguera         
Hospital Clinic
Barcelona, Spain
Contact: Laura Rosiñol         
Principal Investigator: Laura Rosiñol         
ICO Hospitalet
Bellvitge, Spain
Contact: Anna Sureda         
Principal Investigator: Anna S         
H. Gregorio Marañón
Madrid, Spain
Contact: Cristina Encinas         
Principal Investigator: Cristina Encinas         
Hospital Universitario 12 de Octubre
Madrid, Spain
Contact: Joaquín Martínez         
Principal Investigator: Joaquín Martínez         
H. Morales Meseguer
Murcia, Spain
Contact: Felipe de Arriba         
Principal Investigator: Felipe de Arriba         
HUCA
Oviedo, Spain
Contact: Mª Pilar González Rodríguez         
Principal Investigator: Mª Pilar González Rodríguez         
H. Son Llatzer
Palma De Mallorca, Spain
Contact: Joan Bargay         
Principal Investigator: Joan Bargay         
Clínica Universidad de Navarra (CUN)
Pamplona, Spain
Contact: Paula Rodríguez         
Principal Investigator: Paula Rodríguez         
Hospital Universitario de Salamanca
Salamanca, Spain
Contact: Mariví Mateos         
Principal Investigator: Mariví Mateos         
H. Universitario de Canarias
Santa Cruz De Tenerife, Spain
Contact: Miguel Teodoro Hernández García         
Principal Investigator: Miguel Teodoro Hernández García         
H. Universitario Marqués de Valdecilla
Santander, Spain
Contact: Enrique Ocio         
Principal Investigator: Enrique Ocio         
Complejo Hospitalario Santiago (CHUS)
Santiago De Compostela, Spain
Contact: Marta Sonia González Pérez         
Principal Investigator: Marta Sonia González Pérez         
Complejo Hospitalario Virgen del Rocío
Sevilla, Spain
Contact: Estrella Carrillo         
Principal Investigator: Estrella Carrillo         
H.U. La Fe
Valencia, Spain
Contact: Javier de la Rubia         
Principal Investigator: Javier de la Rubia         
Sponsors and Collaborators
PETHEMA Foundation
Adknoma Health Research
Investigators
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Study Chair: 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
Publications:

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Responsible Party: PETHEMA Foundation
ClinicalTrials.gov Identifier: NCT05060627    
Other Study ID Numbers: GEM-BELMA
2021-002125-15 ( EudraCT Number )
First Posted: September 29, 2021    Key Record Dates
Last Update Posted: September 29, 2021
Last Verified: September 2021

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by PETHEMA Foundation:
Relapsed multiple myeloma
Refractoriness to lenalidomide
Additional relevant MeSH terms:
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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
Anti-Inflammatory Agents
Antiemetics
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Gastrointestinal Agents
Glucocorticoids
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists
Antineoplastic Agents, Hormonal
Antineoplastic Agents