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

Multiple Myeloma Clinical Trial

— 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 Details — Status: Completed

Administrative data

• NCT number: NCT04196491
• Other study ID #: BB2121-MM-004
• Secondary ID: U1111-1243-5088
• Status: Completed
• Phase: Phase 1
• Start date: May 27, 2020
• Est. completion date: June 7, 2023

Study information

• Verified date: August 2023
• Source: Celgene
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 13
• Est. completion date: June 7, 2023
• Est. primary completion date: June 7, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Multiple Myeloma
• Neoplasms, Plasma Cell

Intervention

Biological:
• bb2121
CAR-T Cell Therapy

Drug:
• Fludarabine
Lymphodepleting Chemotherapy
• Cyclophosphamide
Lymphodepleting Chemotherapy
• Lenalidomide
Maintenance Therapy

Locations

Country	Name	City	State
United States	Local Institution - 108	Atlanta	Georgia
United States	Local Institution - 123	Atlanta	Georgia
United States	Local Institution - 115	Boston	Massachusetts
United States	Local Institution - 122	Boston	Massachusetts
United States	Local Institution - 120	Charlotte	North Carolina
United States	Local Institution - 102	Dallas	Texas
United States	Local Institution - 106	Denver	Colorado
United States	Local Institution - 117	Hackensack	New Jersey
United States	Local Institution - 114	Houston	Texas
United States	Local Institution - 101	Jacksonville	Florida
United States	Local Institution - 110	Los Angeles	California
United States	Local Institution - 107	Milwaukee	Wisconsin
United States	Local Institution - 103	Nashville	Tennessee
United States	Local Institution - 109	New York	New York
United States	Local Institution - 121	New York	New York
United States	Local Institution - 124	New York	New York
United States	Local Institution - 118	Philadelphia	Pennsylvania
United States	Local Institution - 119	Phoenix	Arizona
United States	Local Institution - 112	Portland	Oregon
United States	Local Institution - 116	San Francisco	California
United States	Local Institution - 104	Seattle	Washington
United States	Local Institution - 113	Tampa	Florida

Sponsors (1)

Lead Sponsor	Collaborator
Celgene

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	Time to start maintenance	Is defined as time to start lenalidomide maintenance therapy post-bb2121 infusion	Approximately 2 years after last subject bb2121 infused
Secondary	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
Secondary	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
Secondary	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
Secondary	Pharmacokinetics - Cmax	Maximum transgene level	Approximately 2 years after last subject bb2121 infused
Secondary	Pharmacokinetics - Tmax	Time to peak transgene level	Approximately 2 years after last subject bb2121 infused
Secondary	Pharmacokinetics - AUC	Area under the curve of the transgene level	Approximately 2 years after last subject bb2121 infused

External Links

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