A Phase I, Multi Center, Open Label Study of CC-98633, BCMA Targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in Subjects With Relapsed and/or Refractory Multiple Myeloma

This is a Phase 1, multicenter, open-label study of CC-98633, BCMA-Targeted NEX-T Chimeric Antigen Receptor (CAR) T Cells, in participants with relapsed and/or refractory multiple myeloma.
The study will consist of 2 parts: dose-escalation (Part A) and dose-expansion (Part B). The dose-escalation part (Part A) of the study is to evaluate the safety and tolerability of increasing dose levels of CC-98633 to establish a recommended Phase 2 dose RP2D(s); and the dose-expansion part (Part B) of the study is to further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of CC-98633 at the RP2D(s).

Start Date18 Aug 2020

Sponsor / Collaborator

Juno Therapeutics, Inc.

100 Clinical Results associated with CC-98633

100 Translational Medicine associated with CC-98633

100 Patents (Medical) associated with CC-98633

Literatures (Medical) associated with CC-98633

01 Apr 2025·LEUKEMIA

Phase 1 clinical trial of B-Cell Maturation Antigen (BCMA) NEX-T® Chimeric Antigen Receptor (CAR) T cell therapy CC-98633/BMS-986354 in participants with triple-class exposed multiple myeloma

Article

Author: Varun, Divya ; Burgess, Michael R ; Ly, Thomas ; Thorpe, Jerill ; Navarro, Garnet ; Costa, Luciano J ; Ravi, Gayathri ; Atrash, Shebli ; Mailankody, Sham ; Hege, Kristen ; Kaur, Gurbakhash ; Maier, Alison ; McCarthy, Philip ; Derman, Benjamin ; Kumar, Shaji ; Koegel, Ashley K ; Richard, Shambavi ; Shrestha, Alok ; Liedtke, Michaela ; Kelly, Lisa M ; Das, Sharmila ; Bergsagel, P Leif

Abstract:

BCMA-targeted CAR T-cells transformed the treatment of relapsed and refractory multiple myeloma (RRMM), yet improvements are needed in manufacturing, toxicity and efficacy. We conducted a phase 1 clinical trial of BMS-986354, an autologous BCMA CAR T manufactured using an optimized NEX-T® process, in participants with triple-class exposed, RRMM. The 65 participants had a median of 5 (range 3–13) prior regimens, 39% had cytogenetic high-risk, 91% triple-class refractory, and 43% extra-medullar disease. Part A (dose-escalation) of the study enrolled participants in cohorts receiving 20 (N = 7), 40 (N = 24), or 80 (N = 11)x 106 CAR + T-cells. In part B (expansion), an additional 23 participants were treated at the recommended phase 2 dose, 40 ×106 CAR + T cells. Across dose levels, cytokine release syndrome (CRS) occurred in 82% (2% grade ≥3), neurotoxicity in 8% (2% grade ≥3), and infections in 32% of participants (5% grade ≥ 3). The response rate was 95%, with 46% achieving complete responses. Median progression-free survival was 12.3 months (95% CI 11.3–16). Compared to orvacabtagene autoleucel (same CAR construct, conventional manufacturing), BMS-986354 had higher proportion of T central memory cells, were less differentiated and had enhanced potency and proliferative capacity, supporting the use of NEX-T® in future CAR T development.

13 Sep 2024·CLINICAL CANCER RESEARCH

Reconstitution of the Multiple Myeloma Microenvironment Following Lymphodepletion with BCMA CAR-T Therapy

Article

Author: Zhang, Chunli ; Wang, Yue ; Ning, Shangyong ; Zhou, Xuehong ; Shang, Yongfeng ; Wang, Ting ; He, Lin ; Zuo, Xin ; Sun, Luyang ; Liu, Hui ; Qin, Sen ; Yun, Xiaoya ; Li, Qinghua ; Zhang, Shuai ; Zheng, Enrun ; Xu, Xiaodong ; Xiang, Pengyu ; Yang, Yazi ; Feng, Ru ; Yang, Mengyu

Abstract:

Purpose::

The purpose of this study was to investigate the remodeling of the multiple myeloma microenvironment after B-cell maturation antigen (BCMA)–targeted chimeric antigen receptor T (CAR-T) cell therapy.

Experimental Design::

We performed single-cell RNA sequencing on paired bone marrow specimens (n = 14) from seven patients with multiple myeloma before (i.e., baseline, “day −4”) and after (i.e., “day 28”) lymphodepleted BCMA CAR-T cell therapy.

Results::

Our analysis revealed heterogeneity in gene expression profiles among multiple myeloma cells, even those harboring the same cytogenetic abnormalities. The best overall responses of patients over the 15-month follow-up are positively correlated with the abundance and targeted cytotoxic activity of CD8+ effector CAR-T cells on day 28 after CAR-T cell infusion. Additionally, favorable responses are associated with attenuated immunosuppression mediated by regulatory T cells, enhanced CD8+ effector T-cell cytotoxic activity, and elevated type 1 conventional dendritic cell (DC) antigen presentation ability. DC re-clustering inferred intramedullary-originated type 3 conventional DCs with extramedullary migration. Cell–cell communication network analysis indicated that BCMA CAR-T therapy mitigates BAFF/GALECTIN/MK pathway–mediated immunosuppression and activates MIF pathway–mediated anti–multiple myeloma immunity.

Conclusions::

Our study sheds light on multiple myeloma microenvironment dynamics after BCMA CAR-T therapy, offering clues for predicting treatment responsivity.

01 Mar 2024·Transplantation and cellular therapy

Impact of Frailty on Outcomes after Chimeric Antigen Receptor T Cell Therapy for Patients with Relapsed/Refractory Multiple Myeloma

Article

Author: Jia, Xuefei ; Hashmi, Hamza ; Raza, Shahzad ; Khouri, Jack ; DeJarnette, Shaun ; Abdallah, Al-Ola ; Anwer, Faiz ; Davis, James A ; Dima, Danai ; Ahmed, Nausheen ; McGuirk, Joseph ; Valent, Jason

The literature is limited regarding outcomes in older adults and frail patients receiving BCMA-directed chimeric antigen receptor T cell therapy (CAR-T) for relapsed or refractory multiple myeloma. Here we describe the safety and efficacy of CAR-T in these clinically important subgroups treated in a real-world setting. Frailty was defined as a frail score ≥2 using the simplified frailty index (score based on age + Eastern Cooperative Oncology Group [ECOG] Performance Status + Hematopoietic Cell Transplantation Comorbidity Index [HCT-CI]). Of the 136 patients analyzed (age range, 41 to 81 years), 83 (61%) were considered frail at the time of CAR-T infusion. Compared to the nonfrail group, the frail group had higher proportions of patients with renal insufficiency (18% versus 6%), high-risk cytogenetics (45% versus 35%), extramedullary disease (51% versus 43%), and ECOG Performance Status ≥2 (18% versus 2%), and worse HCT-CI (3 versus 1). Although patients in the frail group had a higher incidence of immune effector cell-associated neurotoxicity syndrome (ICANS) (39% versus 17%), the incidences of all- grade cytokine release syndrome (CRS), as well as high-grade CRS and ICANS, were similar in the 2 groups. With a median follow-up of 7 months, the median progression-free survival was 6.9 months in the frail group versus 11.1 months in the nonfrail group (P = .028). The median overall survival was 14 months in the frail group and was not reached in the nonfrail group (P = .025). This study highlights the tolerable safety and reasonable efficacy of CAR-T for frail myeloma patients in a real-world practice. Although the frail patients did not experience any excessive high-grade toxicities, they did have inferior efficacy outcomes.

News (Medical) associated with CC-98633

27 Feb 2024

·www.pharmaceutical-technology.com

Bristol Myers Squibb acquires RayzeBio for $4.1bn

Through the RayzeBio acquisition, BMS will gain access to an RPT manufacturing facility. Credit: JHVEPhoto / Shutterstock.com. Bristol Myers Squibb (BMS) has announced the conclusion of its acquisition of RayzeBio, a clinical-stage radiopharmaceutical company, for $4.1bn. RayzeBio is now a wholly owned BMS subsidiary. The companies signed an agreement for the acquisition in December 2023 in which BMS would acquire all outstanding shares of RayzeBio. The acquisition introduces a radiopharmaceutical therapeutics (RPTs) pipeline to BMS, including the lead programme, RYZ101 (²²⁵Ac-DOTATATE). This therapy is designed to target somatostatin receptor (SSTR)2, which is overexpressed in gastroenteropancreatic neuroendocrine tumours (GEP-NETs) and extensive stage small cell lung cancer (ES-SCLC). A Phase III clinical trial is currently enrolling subjects to assess RYZ101 in individuals with SSTR-positive GEP-NETs who have previously received treatment with lutetium-177-based somatostatin therapies. See Also: CC-98633 by Bristol-Myers Squibb for Refractory Multiple Myeloma: Likelihood of Approval CC-98633 by Bristol-Myers Squibb for Relapsed Multiple Myeloma: Likelihood of Approval Interim data from the Phase Ib portion of the ACTION-1 clinical trial for RYZ101 have shown encouraging tolerability and efficacy. A Phase Ib trial is also progressing to assess RYZ101 as a first-line treatment for ES-SCLC in combination with standard-of-care therapy. The acquisition also includes an RPT manufacturing facility which will commence operations in the first half of 2024. BMS CEO Chris Boerner stated: “We are excited to complete this transaction, which adds RPTs, one of the fastest-growing new modalities for treating patients with solid tumours. “By strengthening and further diversifying our oncology pipeline beyond I-O, we will unlock exciting opportunities that support BMS’s growth in the back half of the decade and beyond. RayzeBio is a pioneer in the application of this novel modality, and we look forward to working with their talented team to accelerate their preclinical and clinical programmes for the benefit of patients around the world.” The latest deal comes after BMS entered a $674m collaboration with US deep tech company VantAI. The partnership will focus on using VantAI’s generative AI platform to design and develop molecular glues – a small molecule that induces or stabilises interactions between two proteins that would not normally go together.

Phase 1Phase 3Acquisition

100 Deals associated with CC-98633

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Indication	Highest Phase	Country/Location	Organization	Date
Relapse multiple myeloma	Phase 1	United States	Juno Therapeutics, Inc.	18 Aug 2020

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04394650 (ASH 12022 \| ASH 22022) Manual	Phase 1	Relapse multiple myeloma	54	CC 98633	zzwueqdpmu(dzhzprflzy) = nybegrrjfu momspggyxt (sqxmyrrfyw ) View more	Positive	15 Nov 2022

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