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

Study Overview
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Brief Summary
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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.

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

Conditions
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Multiple Myeloma

Intervention / Treatment
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* Biological: bb2121
* Drug: Fludarabine
* Drug: Cyclophosphamide
* Drug: Lenalidomide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must satisfy all of the following criteria to be enrolled in the study: Subject is newly diagnosed and has symptomatic Multiple Myeloma (MM) prior to initiating induction anti-myeloma therapy Subject is ≥ 18 years of age at the time of initial diagnosis of MM Subject has measurable disease at initial diagnosis by M-protein and/or Light chain MM without measurable disease in the serum or urine 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 Subject has Eastern Cooperative Oncology Group performance ≤ 1 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: Subject has non-secretory MM During Screening: Subject received any treatments for MM other than up to 3 cycles of induction therapy per protocol Subject has any of the following laboratory abnormalities: Absolute neutrophil count < 1,000/μL Platelet count < 50,000 mm3 Hemoglobin < 8 g/dL (< 4.9 mmol/L) Serum creatinine clearance < 45 mL/min Corrected serum calcium > 13.5 mg/dL (> 3.4 mmol/L) Serum aspartate aminotransferase or alanine aminotransferase > 2.5 × upper limit of normal Serum total bilirubin > 1.5 × ULN or > 3.0 mg/dL for subjects with documented Gilbert's syndrome INR or aPTT > 1.5 × ULN Subject has history or presence of clinically significant CNS pathology Subjects has high risk for developing deep vein thrombosis or pulmonary embolus and are unable or unwilling to undergo anti-thrombotic therapy Subject has peripheral neuropathy of > Grade 2 severity according to the NCI CTCAE Version 4.03 with bortezomib based induction regimen Subjects has moderate or severe pulmonary hypertension Subject has intolerance to components of induction regimen (KRd or RVd) or has any contraindication to one or the other drug Subject has not recovered from induction therapy-related toxicities (non-hematologic) to < grade 1 CTCAE at the time of screening Subject has prior history of deep vein thrombosis or pulmonary embolus (PE) within 6 months of starting study treatment Subject has cardiac conditions such as: Echocardiogram or multi gated acquisition assessment of left ventricular ejection fraction < 45% Subject has a history of clinically significant cardiovascular disease or clinically significant ECG abnormalities Subject has Pulmonary conditions such as: Subject has known chronic obstructive pulmonary with a forced expiratory vol in 1 sec 50% of predicted normal. Inadequate pulmonary function defined as oxygen saturation < 92 % on room air Subject needs ongoing treatment with chronic immunosuppressants Subject has history of primary immunodeficiency Subject is seropositive for human immunodeficiency virus, chronic or active hepatitis B or active hepatitis A or C

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dose Escalation<br>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<br>* CAR-T Cell Therapy<br>* Other names: ide-cel;Drug: Fludarabine<br>* Lymphodepleting Chemotherapy<br>Drug: Cyclophosphamide<br>* Lymphodepleting Chemotherapy<br>Drug: Lenalidomide<br>* Maintenance Therapy<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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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