Clinical trial NCT04196491: A Study to Evaluate the Safety of bb2121 in Subjects With High Risk, Newly Diagnosed Multiple Myeloma (NDMM)
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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Multiple Myeloma
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
Lead sponsor: Celgene
Sponsor class: INDUSTRY
First posted: 2019-12-12
Enrollment: 13
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.


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

Primary outcomes:
measure: Dose-limiting toxicity (DLT) rates
timeFrame: Up to completion of DLT period after last subject bb2121 infused
measure: Adverse Events (AEs)
timeFrame: Approximately 2 years after last subject bb2121 infused
Secondary outcomes:
measure: Proportion of subjects who achieved Complete Response (CR) Rate
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Overall Response Rate (ORR)
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Duration of Response (DoR)
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Time to Complete Response (TCR)
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Time to start maintenance
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Feasibility of initiating maintenance
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Progression-free Survival (PFS)
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Overall Survival (OS)
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Pharmacokinetics - Cmax
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Pharmacokinetics - Tmax
timeFrame: Approximately 2 years after last subject bb2121 infused
measure: Pharmacokinetics - AUC
timeFrame: Approximately 2 years after last subject bb2121 infused
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Local Institution - 119
state: Arizona
city: Los Angeles
country: United States
facility: Local Institution - 110
state: California
city: San Francisco
country: United States
facility: Local Institution - 116
state: California
city: Denver
country: United States
facility: Local Institution - 106
state: Colorado
city: Jacksonville
country: United States
facility: Local Institution - 101
state: Florida
city: Tampa
country: United States
facility: Local Institution - 113
state: Florida
city: Atlanta
country: United States
facility: Local Institution - 108
state: Georgia
city: Atlanta
country: United States
facility: Local Institution - 123
state: Georgia
city: Boston
country: United States
facility: Local Institution - 115
state: Massachusetts
city: Boston
country: United States
facility: Local Institution - 122
state: Massachusetts
city: Hackensack
country: United States
facility: Local Institution - 117
state: New Jersey
city: New York
country: United States
facility: Local Institution - 121
state: New York
city: New York
country: United States
facility: Local Institution - 109
state: New York
city: New York
country: United States
facility: Local Institution - 124
state: New York
city: Charlotte
country: United States
facility: Local Institution - 120
state: North Carolina
city: Portland
country: United States
facility: Local Institution - 112
state: Oregon
city: Philadelphia
country: United States
facility: Local Institution - 118
state: Pennsylvania
city: Nashville
country: United States
facility: Local Institution - 103
state: Tennessee
city: Dallas
country: United States
facility: Local Institution - 102
state: Texas
city: Houston
country: United States
facility: Local Institution - 114
state: Texas
city: Seattle
country: United States
facility: Local Institution - 104
state: Washington
city: Milwaukee
country: United States
facility: Local Institution - 107
state: Wisconsin
Study officials:
affiliation: Bristol-Myers Squibb
name: Bristol-Myers Squibb
role: STUDY_DIRECTOR
References:
citation: 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.