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

Study Purpose

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.

Recruitment Criteria

Accepts Healthy Volunteers

Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms

No
Study Type

An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes.


An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes.


Searching Both is inclusive of interventional and observational studies.

Interventional
Eligible Ages 18 Years and Over
Gender All
More Inclusion & Exclusion 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performance of any study-related procedure nor part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to their future medical care. 3.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.

Trial Details

Trial ID:

This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.

NCT05060627
Phase

Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.

Phase 1/Phase 2
Lead Sponsor

The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.

PETHEMA Foundation
Principal Investigator

The person who is responsible for the scientific and technical direction of the entire clinical study.

Paula Rodríguez OteroMaría-Victoria MateosJesús San Miguel Izquierdo
Principal Investigator Affiliation Clínica Universidad de NavarraUniversity of SalamancaClínica Universidad de Navarra
Agency Class

Category of organization(s) involved as sponsor (and collaborator) supporting the trial.

Other, Industry
Overall Status Recruiting
Countries Spain
Conditions

The disease, disorder, syndrome, illness, or injury that is being studied.

Relapsed Multiple Myeloma
Additional Details

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. The study comprises the following phases: Phase 1 (Lead-in): 3+3 Dose escalation. 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. Dose levels will be as follows: Dose level -1.

  • - Belantamab-Mafodotin 1.9 mg/kg day 1, Q8W.
  • - Carfilzomib 20/45 mg/m2 on days 1, 8, and 15, Q4W.
  • - Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients > 75 years old, Q4W Dose level 1.
  • - Belantamab-Mafodotin 2.5 mg/kg day 1, Q8W.
  • - Carfilzomib 20/45 mg/m2 days 1, 8, and 15, Q4W.
  • - Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients > 75 years old.
, Q4W Dose level 2.
  • - Belantamab-Mafodotin 2.5 mg/kg on day 1, Q8W.
  • - Carfilzomib 20/56 mg/m2 on days 1, 8, and 15, Q4W.
  • - Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients > 75 years old, Q4W.
Dose level 3.
  • - Belantamab-Mafodotin 2.5 mg/kg on day 1, every 4 weeks (Q8W) - Carfilzomib 20/70 mg/m2 on days 1, 8, and 15, Q4W.
  • - Dexamethasone 40 mg weekly (days 1, 8, 15 and 22) or 20 mg in patients > 75 years old.
, Q4W. The rules applied for the Lead-in phase are as follows: 1. An initial cohort of 3 subjects is enrolled at the first dose level (DL1). 2. If 1/3 subjects develop a DLT, 3 additional patients will be included at the same dose level (DL1) 3. If 0/3 subjects develop a DLT, 3 additional patients will be included at the next dose level (DL2, dose level 2). 4. If 1/3 subjects develop a DLT, 3 additional patients will be included at the same dose level (DL2, dose level 2). 5. If 0 of the 3 new subjects develops a DLT (for a total of 0-1/6 patients with a DLT at this dose level), 3 new subjects will be included in DL3 (dose level 3). 6. If 1 of the 3 new subjects develops a DLT (for a total of 0-1/6 patients with a DLT at this dose level), 3 new subjects will be included at the same dose level (DL3, dose level 3) 7. If 0 out of the 3 new subjects develops a DLT, 3 additional subjects will be included in the same dose level. If 0-1 out of 6 patients developed a DLT, this dose will be considered the maximum tolerated dose (MTD) and will be explored in the expansion phase (phase 2). 8. If ≥2/3 subjects develop a DLT, dose level will be de-escalated (previous dose level) with the same rules as described above. Dose limiting toxicities (DLTs) will be evaluated during the DLT evaluation period. The DLT evaluation period will be defined as the first 4-weeks treatment cycle for each cohort. Patients participating in the Lead-In-Phase must undergo a complete ophthalmologic examination at the end of the DLT evaluation period (4-weeks) and before starting Cycle 2. Subjects will be considered evaluable for the assessment of DLT if they:
  • - Received at least 1 dose of belantamab mafodotin + Kd and experience a DLT, OR.
  • - Received at least 1 dose of belantamab mafodotin, 3 doses of Carfilzomib and 3 doses of Dexamethasone and complete the safety follow-up through the end of the DLT evaluation period.
Non-evaluable subjects will be replaced. Phase 2 (Expansion Phase, n= up to 60 patients) Combination treatment will be administered at the 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. The trial has the following objectives: Primary objectives (PO): Phase 1 PO1: To determine the maximum tolerated dose, and the recommended phase 2 dose of belantamab mafodotin in combination with carfilzomib and dexamethasone. Phase 2 PO2: To evaluate the efficacy in terms of complete response rate and rates of minimal residual negativity after 12 months of therapy with belantamab mafodotin combined with carfilzomib and dexamethasone. PO3: To evaluate safety and tolerability of the combination of belantamab mafodotin plus carfilzomib and dexamethasone. Secondary Objectives (SO): SO1: To determine time to event data of the combinations: Progression-free survival, progression-free survival at 12 months, duration of response, time to response, and overall survival. SO2: Evaluate deepening of response during continuous therapy at 12, and 24 months. SO3: Evaluate sustained MRD rate at 1 and 2 years. SO4: Evaluate the rate of conversion from MRD positivity to MRD negativity during the treatment (yearly). SO5: To assess the safety of the combination of belantamab mafodotin + Kd, as well as the incidence of corneal and ophthalmologic adverse events.

Arms & Interventions

Arms

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.

Interventions

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

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

International Sites

Badalona, Spain

Status

Not yet recruiting

Address

Hospital Germans Trias i Pujol (ICO BADALONA)

Badalona, ,

Site Contact

Albert Oriol Rocafiguera

carmen@fundacionpethema.es

0034 699 835 437

Hospital Clinic, Barcelona, Spain

Status

Not yet recruiting

Address

Hospital Clinic

Barcelona, ,

Site Contact

Laura Rosiñol

carmen@fundacionpethema.es

0034 699 835 437

ICO Hospitalet, Bellvitge, Spain

Status

Recruiting

Address

ICO Hospitalet

Bellvitge, ,

Site Contact

Anna Sureda

carmen@fundacionpethema.es

0034 699 835 437

H. Gregorio Marañón, Madrid, Spain

Status

Not yet recruiting

Address

H. Gregorio Marañón

Madrid, ,

Site Contact

Cristina Encinas

carmen@fundacionpethema.es

0034 699 835 437

Hospital Universitario 12 de Octubre, Madrid, Spain

Status

Not yet recruiting

Address

Hospital Universitario 12 de Octubre

Madrid, ,

Site Contact

Joaquín Martínez

carmen@fundacionpethema.es

0034 699 835 437

H. Morales Meseguer, Murcia, Spain

Status

Not yet recruiting

Address

H. Morales Meseguer

Murcia, ,

Site Contact

Felipe de Arriba

carmen@fundacionpethema.es

0034 699 835 437

HUCA, Oviedo, Spain

Status

Not yet recruiting

Address

HUCA

Oviedo, ,

Site Contact

Mª Pilar González Rodríguez

carmen@fundacionpethema.es

0034 699 835 437

H. Son Llatzer, Palma De Mallorca, Spain

Status

Recruiting

Address

H. Son Llatzer

Palma De Mallorca, ,

Site Contact

Joan Bargay

carmen@fundacionpethema.es

0034 699 835 437

Clínica Universidad de Navarra (CUN), Pamplona, Spain

Status

Recruiting

Address

Clínica Universidad de Navarra (CUN)

Pamplona, ,

Site Contact

Paula Rodríguez

carmen@fundacionpethema.es

0034 699 835 437

Hospital Universitario de Salamanca, Salamanca, Spain

Status

Not yet recruiting

Address

Hospital Universitario de Salamanca

Salamanca, ,

Site Contact

Mariví Mateos

carmen@fundacionpethema.es

0034 699 835 437

H. Universitario de Canarias, Santa Cruz De Tenerife, Spain

Status

Not yet recruiting

Address

H. Universitario de Canarias

Santa Cruz De Tenerife, ,

Site Contact

Miguel Teodoro Hernández García

carmen@fundacionpethema.es

0034 699 835 437

H. Universitario Marqués de Valdecilla, Santander, Spain

Status

Not yet recruiting

Address

H. Universitario Marqués de Valdecilla

Santander, ,

Site Contact

Enrique Ocio

carmen@fundacionpethema.es

0034 699 835 437

Complejo Hospitalario Santiago (CHUS), Santiago De Compostela, Spain

Status

Recruiting

Address

Complejo Hospitalario Santiago (CHUS)

Santiago De Compostela, ,

Site Contact

Marta Sonia González Pérez

carmen@fundacionpethema.es

0034 699 835 437

Complejo Hospitalario Virgen del Rocío, Sevilla, Spain

Status

Not yet recruiting

Address

Complejo Hospitalario Virgen del Rocío

Sevilla, ,

Site Contact

Estrella Carrillo

carmen@fundacionpethema.es

0034 699 835 437

H.U. La Fe, Valencia, Spain

Status

Not yet recruiting

Address

H.U. La Fe

Valencia, ,

Site Contact

Javier de la Rubia

carmen@fundacionpethema.es

0034 699 835 437