Clinical Trials /

Study of Carfilzomib, Lenalidomide, Dexamethasone and Belantamab Mafodotin in Multiple Myeloma

NCT04822337

Description:

This research study is being done to learn if the study drug belantamab mafodotin, in combination with other standard medications, can improve multiple myeloma. This study will also help determine what effects, good and/or bad, this combination of study drugs have on subjects and their cancer, and to evaluate the overall response to this study treatment combination.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of Carfilzomib, Lenalidomide, Dexamethasone and Belantamab Mafodotin in Multiple Myeloma
  • Official Title: A Phase I/II Study of Carfilzomib, Lenalidomide, Dexamethasone and the Anti-B-Cell Maturation Antigen (BCMA) Antibody Drug Conjugate Belantamab Mafodotin in Multiple Myeloma

Clinical Trial IDs

  • ORG STUDY ID: LCI-HEM-NDMYE-KRDB-001
  • SECONDARY ID: 00050160
  • NCT ID: NCT04822337

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
Carfilzomib, Lenalidomide, Dexamethasone, Belantamab MafodotinPhase I

Purpose

This research study is being done to learn if the study drug belantamab mafodotin, in combination with other standard medications, can improve multiple myeloma. This study will also help determine what effects, good and/or bad, this combination of study drugs have on subjects and their cancer, and to evaluate the overall response to this study treatment combination.

Detailed Description

      This is a phase I dose escalation and expansion study in RMM and RRMM followed by a single
      arm phase II expansion in high risk, NDMM. The phase I portion of the protocol will utilize a
      standard 3+3 dose escalation design to determine the maximum tolerated dose (MTD) and RP2D of
      the KRd-belantamab mafodotin combination. The phase II portion of the trial is a two-stage
      design that will assess the efficacy and safety of the combination in newly diagnosed,
      high-risk MM patients.
    

Trial Arms

NameTypeDescriptionInterventions
Phase IExperimentalCarfilzomib, Lenalidomide, Dexamethasone, Belantamab Mafodotin
  • Carfilzomib, Lenalidomide, Dexamethasone, Belantamab Mafodotin
Phase IIExperimentalCarfilzomib, Lenalidomide, Dexamethasone, Belantamab Mafodotin
  • Carfilzomib, Lenalidomide, Dexamethasone, Belantamab Mafodotin

Eligibility Criteria

        INCLUSION CRITERIA for all subjects:

          1. Written informed consent and HIPAA authorization for release of personal health
             information. NOTE: HIPAA authorization may be included in the informed consent or
             obtained separately.

          2. Age greater than or equal to 18 years at the time of consent. Because no dosing or
             adverse event data are currently available on the use of belantamab mafodotin as a
             single agent or in combination with KRd in subjects less than 18 years of age,
             children are excluded from this study.

          3. ECOG Performance Status of less than or equal to 2

          4. Demonstrate adequate organ function

          5. Adequate cardiac function as defined by a greater than 40% left ventricular ejection
             fraction (LVEF) by ECHO, cardiac MRI or MUGA

               1. Note for patients in phase II: if a cycle of pre-study induction therapy
                  containing a PI or anthracycline was administered, assessment of the LVEF must be
                  repeated.

          6. For those with symptomatic pulmonary disease with Grade 2 or higher symptoms (e.g.
             COPD, asthma) or other signs / symptoms of pulmonary disease, adequate pulmonary
             function as defined by a FEV1 greater than or equal to 50% of predicted and DLCO/VA
             greater than or equal to 50% of predicted

          7. Females of childbearing potential (FCBP) must have two negative serum pregnancy tests
             during screening: the first within 10-14 days prior to first dose of study treatment
             and the second within 24 hours prior to first dose of study treatment. NOTE: Females
             are considered of childbearing potential unless they are surgically sterile (have
             undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), are
             amenorrhoeic for less than 2 years without history of a hysterectomy and oophorectomy
             must have a follicle stimulating hormone value in the postmenopausal range upon
             screening evaluation; or are postmenopausal (at least 12 consecutive months with no
             menses without an alternative medical cause).

          8. FCBP must be willing to use 2 effective contraceptive methods or abstinence starting
             from the time of informed consent, while on belantamab mafodotin and lenalidomide. If
             either drug is discontinued, 2 effective forms of contraception should be continued
             until at least 4 weeks after the last dose of lenalidomide, and 1 form of effective
             contraception should be continued until 4 months post last dose of belantamab
             mafodotin. FCBP should use effective contraception or abstinence from consent until 30
             days after last treatment with carfilzomib, and males with a partner of childbearing
             potential must use effective contraception or abstinence for at least 90 days post
             last dose of carfilzomib.

          9. Male subjects must agree to the following from the first dose of study treatment until
             6 months after the last dose of belantamab mafodotin, to allow for clearance of
             altered sperm:

               1. Refrain from donating sperm

                  PLUS either:

               2. 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

               3. Must agree to use effective contraception/barrier as detailed below:

                  Agree to use a male condom, even if they have undergone a successful vasectomy,
                  and female partner of reproductive potential to use an additional highly
                  effective contraceptive method with a failure rate of less than 1% per year

         10. FCBP must agree not to donate eggs (ova, oocytes) for the purpose of reproduction
             during the intervention period and for at least 4 months after the last dose of study
             intervention belantamab mafodotin, at least 30 days after the last dose of
             carfilzomib, and at least 4 weeks after the last dose of lenalidomide.

         11. As determined by the enrolling physician, ability of the subject to understand and
             adhere with study procedures for the entire length of the study

         12. Ability to swallow oral medications

         13. Willing to refrain from using contact lenses while participating in this study

        INCLUSION CRITERIA - Phase I treatment for Relapsed or Relapsed/Refractory MM:

          1. Subjects with Relapsed or Relapsed/Refractory MM who have had 1-3 lines of prior
             therapy.

               1. Refractory is defined as less than 25% reduction in M-protein or progression of
                  disease during treatment or within 60 days after cessation of treatment

               2. A line of therapy is defined as one or more cycles of a planned treatment
                  program.

             This may consist of one or more planned cycles of single-agent therapy or combination
             therapy, as well as a sequence of treatments administered in a planned manner. A new
             line of therapy starts when a planned course of therapy is modified to include other
             treatment agents (alone or in combination) as a result of disease progression,
             relapse, or toxicity. A new line of therapy also starts when a planned period of
             observation off therapy is interrupted by a need for additional treatment for the
             disease.

          2. Subjects must have measurable disease, at diagnosis, as defined by at least one of the
             following:

               1. Serum monoclonal protein level greater than or equal to 0.5 g/dL

               2. 24-hour urinary M-protein greater than or equal to 200 mg

               3. Involved free light chain level greater than or equal to 10 mg/dL, along with an
                  abnormal free light chain ratio.

          3. Subject must have not progressed on full dose lenalidomide previously (25 mg on days
             1-21 of a 28-day cycle or its dosing equivalent based on renal function at the time of
             progression)

        INCLUSION CRITERIA - Phase II treatment for high-risk newly diagnosed MM:

        1. Active, newly diagnosed multiple myeloma with CRAB features or a myeloma-defining event
        per the IMWG 2014 criteria. Note: It is acceptable to include subjects who have had one
        cycle of emergent treatment for multiple myeloma.

        2. High-risk disease: i. Del(1p) ii. Gain of 1q21 [greater than or equal to 3 copies] iii.
        Monosomy 13 or del(13q) by conventional karyotype iv. High risk IgH translocation [t(4;14),
        t(14;16) or t(14;20)] v. del(17p) 3. Measurable disease by 1 or more of the following:

          1. Serum monoclonal protein level greater than or equal to 0.5 g/dL

          2. 24-hour urinary M-protein greater than or equal to 200 mg

          3. Involved free light chain level greater than or equal to 10 mg/dL (100 mg/L), along
             with an abnormal free light chain ratio.

          4. Note: for subjects who have received a prior cycle of non-protocol therapy, measurable
             disease will be based on the serum and urine monoclonal protein and serum free light
             chain levels prior to the cycle of non-protocol therapy 4. No more than one prior
             cycle of non-protocol therapy will be allowed, recognizing that high-risk multiple
             myeloma subjects frequently require immediate therapy at initial diagnosis even before
             risk assessment is complete. For those subjects who receive a cycle of non-protocol
             induction therapy:

        a. There should be a washout period of ≥7 days from the last dose of pre-study therapy AND
        b. The subject must have adequate recovery from toxicity of pre-study therapy as defined by
        the following: i. Hematologic lab results within parameters ii. Non-hematologic toxicity
        resolved to grade 1 or baseline with the following exceptions:

          1. Subjects who have started a course of antibiotic therapy for infection and symptoms
             have improved to baseline or grade 1, but remain on antibiotic therapy are eligible

          2. Subjects with less than or equal to grade 2 fatigue are eligible

          3. Subjects with less than or equal to grade 2 hyperglycemia are eligible, even if
             pharmacologic treatment was required

          4. Subjects with less than or equal to grade 2 electrolyte abnormalities are eligible,
             even if pharmacologic treatment was required

          5. Subjects with less than or equal to grade 2 nausea, constipation or diarrhea are
             eligible, even if pharmacologic treatment was required

        EXCLUSION CRITERIA for all subjects:

          1. Active infection requiring systemic therapy. NOTE: at the discretion of the treating
             investigator, subjects who have started antibiotic therapy for subjects who had
             symptoms present, symptoms must have improved to baseline or grade 1 in severity may
             start treatment prior to completion of their course of antibiotic therapy.

          2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
             mother is being treated on study.)

          3. Subjects cannot have other prior or concomitant malignancies except for:

               1. Curatively treated non-melanoma skin cancer

               2. Other cancer for which the subject has been medically stable for at least 2 years
                  and/or, in the opinion of the Site Principal Investigators, will not affect the
                  evaluation of the effects of clinical trial treatments on the currently targeted
                  malignancy

          4. Active central nervous system (CNS) involvement

          5. Concomitant AL amyloidosis or POEMS syndrome

          6. Plasma cell leukemia

          7. Treatment with any investigational drug within 14 days or five half-lives, whichever
             is shorter, prior to first dose of study treatment.

          8. Medical, psychiatric, or other condition/disorder (including lab abnormalities) which,
             in the opinion of the treating physician, would make this protocol treatment
             unreasonably hazardous for the subject, or could interfere with obtaining informed
             consent or compliance to the study procedures

          9. Significant cardiac disease, including any of the following:

               1. Greater than or equal to Class 3 New York Heart Association (NYHA) congestive
                  heart failure (see Appendix B)

               2. ECG evidence of acute ischemia

               3. Unstable angina

               4. Myocardial infarction, Coronary angioplasty, stenting, or bypass grafting within
                  three months prior to day 1 of treatment

               5. Clinically significant uncontrolled and/or untreated arrhythmias or conduction
                  block, including clinically significant ECG abnormalities such as 2nd degree
                  Mobitz Type ll or 3rd degree atrioventricular (AV)block. However, PACs, PVCs,
                  rate controlled atrial fibrillation, sinus arrhythmia, asymptomatic sinus
                  bradycardia or sinus tachycardia and 1st degree heart block are not considered
                  clinically significant.

               6. Greater than or equal to Grade 2 QTcF prolongation (i.e. >480 msec)

         10. Uncontrolled hypertension, defined as a systolic blood pressure of greater than or
             equal to 160 mmHg or a diastolic blood pressure of greater than or equal to 90 mmHg

         11. Grade greater than or equal to 2 peripheral neuropathy

         12. Psychiatric illness/social situation that would limit compliance with study
             requirements as determined by the investigator

         13. Known immediate or delayed hypersensitivity or allergic reaction to any components of,
             or related to, protocol therapy (e.g. during exposure to carfilzomib, lenalidomide or
             dexamethasone as part of a pre-study cycle of therapy).

         14. History of erythema multiforme to lenalidomide or other IMID

         15. Discontinuation of prior carfilzomib, lenalidomide or dexamethasone due to treatment
             toxicity

         16. Major surgery within 4 weeks prior to day 1 of treatment

         17. Radiation within 14 days prior to day 1 of treatment. Note: palliative XRT to less
             than 5% of the total marrow volume as assessed by the treating investigator is allowed
             within 14 days prior to day 1 of treatment

         18. Current corneal epithelial disease except mild changes in corneal epithelium

         19. Positive hepatitis C antibody test result (this test preferable) or positive hepatitis
             C RNA test result at screening or within 3 months prior to first dose of study
             treatment

             a. NOTE: Subjects with positive Hepatitis C antibody due to prior eradicated disease
             can be enrolled if a confirmatory negative Hepatitis C RNA test is obtained

         20. A known diagnosis of HIV

         21. Is seropositive for hepatitis B (defined by a positive test for hepatitis B surface
             antigen [HBsAg]). Subjects with resolved infection (i.e. subjects who are HBsAg
             negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or
             antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time
             polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels.
             Subjects who are PCR positive will be excluded. Subjects with Hepatitis B surface
             antibodies and previous Hepatitis B vaccination will be eligible.

         22. 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 non-cirrhotic chronic liver disease
             (including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement
             of malignancy is acceptable if otherwise meets entry criteria

         23. Participant must not have presence of active renal condition (infection, requirement
             for dialysis or any other condition that could affect participant's safety).
             Participants with isolated proteinuria resulting from MM are eligible, provided they
             fulfill inclusion criteria

         24. Participant must not have had plasmapheresis within 7 days prior to first dose of
             study treatment

         25. Any evidence of active mucosal or internal bleeding

         26. Participant must not be simultaneously enrolled in any interventional clinical trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Establish Maximum Tolerated Dose (MTD)
Time Frame:time to complete Cycle 1 (28 days)
Safety Issue:
Description:DLTs will be determined for each subject enrolled in Phase I as a binary variable indicating whether the subject experienced a DLT during Cycle 1 of belantamab mafodotin-containing protocol directed induction therapy.

Secondary Outcome Measures

Measure:Complete Response (CR)
Time Frame:Up to 5 years
Safety Issue:
Description:CR will be determined for each subject as a binary variable indicating whether the achieved a best overall response to induction therapy of CR or better
Measure:Best Response
Time Frame:Up to 5 years
Safety Issue:
Description:The best overall response will be determined as an ordered categorial variable indicating the subject's best response at any point along the treatment continuum.
Measure:Very Good Partial Response (VGPR)
Time Frame:up to 5 year
Safety Issue:
Description:will be determined for each subject as a binary variable indicating whether the achieved a best overall response to induction therapy of VGPR or better.
Measure:Overall Response
Time Frame:up to 5 years post treatment discontinuation
Safety Issue:
Description:The best overall response will be determined as an ordered categorial variable indicating the subject's best response at any point along the treatment continuum
Measure:MRD Negative
Time Frame:Up to 5 years
Safety Issue:
Description:. Minimal residual disease (MRD) (via NGF 10-5 and 10-6) will be determined for each subject after suspected CR for Phase I subjects and at the following timepoints for Phase II subjects: after induction therapy, after ASCT, and after 12 cycles of maintenance therapy (post Cycle 18visit) and every 12 months post Cycle 18 sample.
Measure:Time to First Response (TTFR)
Time Frame:up to 30 days post treatment discontinuation
Safety Issue:
Description:TTFR will be calculated for all subjects achieving an sCR, CR, VGPR, or PR. This will be defined as the time from initiation of belantamab mafodotin-containing protocol directed induction therapy to the time of first disease assessment indicating either sCR, CR, VGPR or PR
Measure:Time to Best Response (TTBR)
Time Frame:up to 30 days post treatment discontinuation
Safety Issue:
Description:Time to best response will be calculated for all subjects achieving an sCR, CR, VGPR or PR. This will be defined as the time from initiation of belantamab mafodotin-containing protocol directed induction therapy to the time of best disease assessment indicating either sCR, CR, VGPR or PR.
Measure:Time to Progression (TTP)
Time Frame:Up to 5 years
Safety Issue:
Description:TTP is defined as the duration of time from enrollment to the study (treatment start date) to first occurrence of progressive disease
Measure:Duration of Response (DoR)
Time Frame:Up to 5 years post treatment response
Safety Issue:
Description:DoR will be calculated for each subject achieving a PR or better and will be calculated from the time of the first assessment that identified response until disease progression or death.
Measure:Overall Survival (OS)
Time Frame:Up to 8 years
Safety Issue:
Description:OS is defined as the duration from enrollment to the study (treatment start date) to the date of death from any cause.
Measure:Progression Free Survival (PFS)
Time Frame:Up to 8 years
Safety Issue:
Description:PFS is defined as the duration of time from enrollment to the study (treatment start date) to first occurrence of either progressive disease or death (from any cause), whichever comes first.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Shebli Atrash

Last Updated

May 28, 2021