Clinical Trials /

A Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (NDMM)

NCT04196491

Description:

This is a multicenter, open-label, phase 1, single arm study intended to determine the optimal target dose and safety of bb2121 in subjects with HR (R-ISS Stage III per IMWG criteria) NDMM. Subjects should have received 3 Cycles of standard induction therapy prior to undergoing leukapheresis procedure to collect autologous mononuclear cells for manufacture of the drug product (bb2121). Following manufacture of the drug product, subjects will receive fourth cycle of induction therapy followed by lymphodepleting therapy with fludarabine and cyclophosphamide prior to bb2121 infusion. Maintenance therapy is recommended for all subjects who have received bb2121 infusion and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later.

Related Conditions:
  • Multiple Myeloma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: A Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (NDMM) (KarMMa-4)
  • Official Title: A Phase 1, Open-label, Multicenter Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (KarMMa-4)

Clinical Trial IDs

  • ORG STUDY ID: BB2121-MM-004
  • SECONDARY ID: U1111-1243-5088
  • NCT ID: NCT04196491

Conditions

  • Multiple Myeloma

Interventions

DrugSynonymsArms
bb2121 carfilzomibide-celDose Escalation
FludarabineDose Escalation
CyclophosphamideDose Escalation
LenalidomideDose Escalation

Purpose

This is a multicenter, open-label, phase 1, single arm study intended to determine the optimal target dose and safety of bb2121 in subjects with HR (R-ISS Stage III per IMWG criteria) NDMM. Subjects should have received 3 Cycles of standard induction therapy prior to undergoing leukapheresis procedure to collect autologous mononuclear cells for manufacture of the drug product (bb2121). Following manufacture of the drug product, subjects will receive fourth cycle of induction therapy followed by lymphodepleting therapy with fludarabine and cyclophosphamide prior to bb2121 infusion. Maintenance therapy is recommended for all subjects who have received bb2121 infusion and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later.

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalbb2121 autologous CAR T cells will be infused at a dose ranging from 150 - 800 x 10^6 CAR+ T cells after receiving lymphodepleting chemotherapy with a planned starting dose of 450 x 10^6 CAR+ T cells. Lenalidomide maintenance therapy is recommended for all patients and should be initiated upon adequate bone marrow recovery or from 90-day post-bb2121 infusion, whichever is later
  • bb2121 carfilzomib
  • Fludarabine
  • Cyclophosphamide
  • Lenalidomide

Eligibility Criteria

        Inclusion Criteria:

        Subjects must satisfy all of the following criteria to be enrolled in the study:

          1. Subject is newly diagnosed and has symptomatic Multiple Myeloma (MM) prior to
             initiating induction anti-myeloma therapy

          2. Subject is ≥ 18 years of age at the time of initial diagnosis of MM

          3. Subject has measurable disease at initial diagnosis by

               -  M-protein and/or

               -  Light chain MM without measurable disease in the serum or urine

          4. Subject has high-risk MM at the time of initial diagnosis of MM per R-ISS Stage III as
             defined by IMWG:

               -  ISS Stage III and cytogenetic abnormalities with t(4; 14) and/or del(17p); and/or
                  t(14:16) by iFISH; or;

               -  ISS Stage III and serum LDH > ULN

          5. Subject has Eastern Cooperative Oncology Group performance ≤ 1

          6. Subjects has received ≤ to 3 cycles of the following induction anti-myeloma therapy
             prior to enrollment:

               -  Cycle 1: one of the following regimens (RVd, KRd, CyBorD, D-RVd and D-KRd)

               -  Cycle 2 to Cycle 3: either KRd or RVd (Cycle 3 must be without dexamethasone)

        Exclusion Criteria:

        The presence of any of the following will exclude a subject from enrollment: The presence
        of any of the following will exclude a subject from enrollment:

        At initial diagnosis, screening and prior to initiation of induction therapy for MM:

          1. Subject has non-secretory MM

             During Screening:

          2. Subject received any treatments for MM other than up to 3 cycles of induction therapy
             per protocol

          3. Subject has any of the following laboratory abnormalities:

               1. Absolute neutrophil count < 1,000/μL

               2. Platelet count < 50,000 mm3

               3. Hemoglobin < 8 g/dL (< 4.9 mmol/L)

               4. Serum creatinine clearance < 45 mL/min

               5. Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L)

               6. Serum aspartate aminotransferase or alanine aminotransferase > 2.5 × upper limit
                  of normal

               7. Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented
                  Gilbert's syndrome

               8. INR or aPTT > 1.5 × ULN

          4. Subject has history or presence of clinically significant CNS pathology

          5. Subjects has high risk for developing deep vein thrombosis or pulmonary embolus and
             are unable or unwilling to undergo anti-thrombotic therapy

          6. Subject has peripheral neuropathy of > Grade 2 severity according to the NCI CTCAE
             Version 4.03 with bortezomib based induction regimen

          7. Subjects has moderate or severe pulmonary hypertension

          8. Subject has intolerance to components of induction regimen (KRd or RVd) or has any
             contraindication to one or the other drug

          9. Subject has not recovered from induction therapy-related toxicities (non-hematologic)
             to < grade 1 CTCAE at the time of screening

         10. Subject has prior history of deep vein thrombosis or pulmonary embolus (PE) within 6
             months of starting study treatment

         11. Subject has cardiac conditions such as:

               1. Echocardiogram or multi gated acquisition assessment of left ventricular ejection
                  fraction < 45%

               2. Subject has a history of clinically significant cardiovascular disease or
                  clinically significant ECG abnormalities

         12. Subject has Pulmonary conditions such as:

               1. Subject has known chronic obstructive pulmonary with a forced expiratory vol in 1
                  sec 50% of predicted normal.

               2. Inadequate pulmonary function defined as oxygen saturation < 92 % on room air

         13. Subject needs ongoing treatment with chronic immunosuppressants

         14. Subject has history of primary immunodeficiency

         15. Subject is seropositive for human immunodeficiency virus, chronic or active hepatitis
             B or active hepatitis A or C
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-limiting toxicity (DLT) rates
Time Frame:Up to approximately 2 years after first subject bb2121 infused
Safety Issue:
Description:DLTs will be assessed during the DLT interval (ie, within 21 days immediately after bb2121 infusion). DLTs are defined as any bb2121 related Grade 3 to 5 toxicity.

Secondary Outcome Measures

Measure:Proportion of subjects who achieved Complete Response (CR) Rate
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Is defined as proportion of subjects who achieved CR or better according to IMWG Uniform Response Criteria for Multiple Myeloma for multiple myeloma will be determined by an Investigator assessment.
Measure:Overall Response Rate (ORR)
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Is defined as proportion of subjects who achieved PR or better according to IMWG Uniform Response Criteria for Multiple Myeloma as determined by an Investigator assessment
Measure:Duration of Response (DoR)
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Is defined as time from first documentation of response (PR or better) to first documentation of progressive disease (PD) or death from any cause, whichever occurs first, for responders.
Measure:Time to Complete Response (TCR)
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Is defined as time from bb2121 infusion date to first documentation of CR for responders (Complete Response (CR) or better).
Measure:Time to start maintenance
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Is defined as time to start lenalidomide maintenance therapy post-bb2121 infusion
Measure:Feasibility of initiating maintenance
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Number of subjects starting the maintenance or on maintenance between D90 and D110
Measure:Progression-free Survival (PFS)
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Is defined as time from bb2121 infusion date to first documentation of PD, or death due to any cause, whichever occurs first.
Measure:Overall Survival (OS)
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Is defined as time from bb2121 infusion date to time of death due to any cause
Measure:Pharmacokinetics - Cmax
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Maximum transgene level
Measure:Pharmacokinetics - Tmax
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Time to peak transgene level
Measure:Pharmacokinetics - AUC
Time Frame:Approximately 2.5 years after first subject bb2121 infused
Safety Issue:
Description:Area under the curve of the transgene level

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Celgene

Trial Keywords

  • Multiple Myeloma
  • Newly diagnosed multiple myeloma
  • BB2121
  • KarMMa-4
  • Phase I
  • NDMM
  • High Risk
  • R-ISS III
  • KRd
  • RVd
  • Dara-KRd
  • Dara-RVd
  • CyBorD
  • BCMA

Last Updated

February 14, 2020