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.
Title
- Brief Title: 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)
Clinical Trial IDs
- ORG STUDY ID:
BB2121-MM-004
- SECONDARY ID:
U1111-1243-5088
- NCT ID:
NCT04196491
Conditions
Interventions
Drug | Synonyms | Arms |
---|
bb2121 carfilzomib | ide-cel | Dose Escalation |
Fludarabine | | Dose Escalation |
Cyclophosphamide | | Dose Escalation |
Lenalidomide | | Dose 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
Name | Type | Description | Interventions |
---|
Dose Escalation | Experimental | 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 | - 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
May 18, 2021