A Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (NDMM) (KarMMa-4)

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

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.

Study Overview

• Status: Completed
• Conditions: Multiple Myeloma
• Intervention / Treatment: Biological: bb2121; Drug: Fludarabine; Drug: Cyclophosphamide; Drug: Lenalidomide

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Local Institution - 119
  • California
    • Los Angeles, California, United States, 90095
      • Local Institution - 110
    • San Francisco, California, United States, 94143
      • Local Institution - 116
  • Colorado
    • Denver, Colorado, United States, 80218
      • Local Institution - 106
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Local Institution - 101
    • Tampa, Florida, United States, 33612
      • Local Institution - 113
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Local Institution - 108
    • Atlanta, Georgia, United States, 30342
      • Local Institution - 123
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Local Institution - 115
    • Boston, Massachusetts, United States, 02215
      • Local Institution - 122
  • New Jersey
    • Hackensack, New Jersey, United States, 07601
      • Local Institution - 117
  • New York
    • New York, New York, United States, 10016
      • Local Institution - 121
    • New York, New York, United States, 10029
      • Local Institution - 109
    • New York, New York, United States, 10065
      • Local Institution - 124
  • North Carolina
    • Charlotte, North Carolina, United States, 28207
      • Local Institution - 120
  • Oregon
    • Portland, Oregon, United States, 97239
      • Local Institution - 112
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Local Institution - 118
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Local Institution - 103
  • Texas
    • Dallas, Texas, United States, 75390
      • Local Institution - 102
    • Houston, Texas, United States, 77030
      • Local Institution - 114
  • Washington
    • Seattle, Washington, United States, 98109-1024
      • Local Institution - 104
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226-3522
      • Local Institution - 107

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Dose Escalation; bb2121 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

Biological: bb2121; CAR-T Cell Therapy; Other Names: ide-cel; Drug: Fludarabine; Lymphodepleting Chemotherapy; Drug: Cyclophosphamide; Lymphodepleting Chemotherapy; Drug: Lenalidomide; Maintenance Therapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-limiting toxicity (DLT) rates	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.	Up to completion of DLT period after last subject bb2121 infused
Adverse Events (AEs)	An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, a worsening concomitant illness, an injury, or any concomitant impairment of the subject's health, including laboratory test values, regardless of etiology. Any worsening (ie, any clinically significant adverse change in the frequency or intensity of a preexisting condition) should be considered an AE.	Approximately 2 years after last subject bb2121 infused

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of subjects who achieved Complete Response (CR) Rate	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.	Approximately 2 years after last subject bb2121 infused
Overall Response Rate (ORR)	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	Approximately 2 years after last subject bb2121 infused
Duration of Response (DoR)	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.	Approximately 2 years after last subject bb2121 infused
Time to Complete Response (TCR)	Is defined as time from bb2121 infusion date to first documentation of CR for responders (Complete Response (CR) or better).	Approximately 2 years after last subject bb2121 infused
Time to start maintenance	Is defined as time to start lenalidomide maintenance therapy post-bb2121 infusion	Approximately 2 years after last subject bb2121 infused
Feasibility of initiating maintenance	Number of subjects starting the maintenance or on maintenance between D90 and D110	Approximately 2 years after last subject bb2121 infused
Progression-free Survival (PFS)	Is defined as time from bb2121 infusion date to first documentation of PD, or death due to any cause, whichever occurs first.	Approximately 2 years after last subject bb2121 infused
Overall Survival (OS)	Is defined as time from bb2121 infusion date to time of death due to any cause	Approximately 2 years after last subject bb2121 infused
Pharmacokinetics - Cmax	Maximum transgene level	Approximately 2 years after last subject bb2121 infused
Pharmacokinetics - Tmax	Time to peak transgene level	Approximately 2 years after last subject bb2121 infused
Pharmacokinetics - AUC	Area under the curve of the transgene level	Approximately 2 years after last subject bb2121 infused

Collaborators and Investigators

• Sponsor: Celgene
• Investigators: Study Director: Bristol-Myers Squibb, Bristol-Myers Squibb

Publications and helpful links

General Publications

• Parmar H, Vesole DH, Biran N. From VAD to VRD: Is Transplant Still Needed in the Upfront Setting of Myeloma? Cancer J. 2021 May-Jun 01;27(3):190-195. doi: 10.1097/PPO.0000000000000522.

Helpful Links

• BMS Clinical Trial Information
• BMS Clinical Trial Patient Recruiting
• FDA Safety Alerts and Recalls

Study record dates

Study Major Dates

• Study Start (Actual): May 27, 2020
• Primary Completion (Actual): June 7, 2023
• Study Completion (Actual): June 7, 2023

Study Registration Dates

• First Submitted: December 10, 2019
• First Submitted That Met QC Criteria: December 10, 2019
• First Posted (Actual): December 12, 2019

Study Record Updates

• Last Update Posted (Actual): August 23, 2023
• Last Update Submitted That Met QC Criteria: August 21, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Multiple Myeloma; Phase I; BCMA; Newly diagnosed multiple myeloma; BB2121; KarMMa-4; NDMM; High Risk; R-ISS III; KRd; RVd; Dara-KRd; Dara-RVd; CyBorD
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Cyclophosphamide; Lenalidomide; Fludarabine
• Other Study ID Numbers: BB2121-MM-004; U1111-1243-5088 (Other Identifier: WHO)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES

IPD Plan Description

Information relating to our policy on data sharing and the process for requesting data can be found at the following link:

https://www.celgene.com/research-development/clinical-trials/clinical-trials-data-sharing/

• IPD Sharing Time Frame: See Plan Description
• IPD Sharing Access Criteria: See Plan Description
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No