bb21217, an anti-BCMA CAR T-cell therapy, in patients with R/R MM - updated results from phase I study

Chimeric antigen receptor (CAR) T-cell therapy is rapidly evolving and changing the treatment landscape of multiple myeloma (MM). Therefore the MM Hub is featuring January’s educational theme based on the topic. One of the targets of CAR T therapies is plasma cell surface molecule BCMA (B-cell maturation antigen). You can read more about the anti-BCMA T-cell therapies here. bb21217, an investigational anti-BCMA CAR T cell therapy, uses the idecabtagene vicleucel (ide-cel; bb2121) CAR molecule and is cultured with the PI3 kinase inhibitor (bb007).

CRB-402 (NCT03274219) is a first-in-human, phase I clinical trial investigating safety, pharmacokinetics, and efficacy of bb21217 in patients with R/R MM. The MM Hub has previously covered the initial results of the ongoing trial. During the 61^st American Society of Hematology (ASH) Annual Meeting & Exposition in Orlando, US, Jesus G. Berdeja, Sarah Cannon Center for Blood Cancers, Nashville, US, presented updated results from the trial.¹ Here we provide a summary of this oral presentation.*

Study design

• A phase I study with 3 + 3 dose-escalation, followed by an expansion phase
• The study enrolled patients with R/R MM, having a minimum of three prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or double refractory to both agents
• Dose escalation, at three dose levels 150 x 10⁶ (n= 12 patients), 300 x 10⁶ (n= 6 patients), and 450 x 10⁶ (n= 6 patients), was restricted to patients with ≥ 50% BCMA expression
• Dose expansion was done at 300 x 10⁶ (n= 8 patients) and 450 x 10⁶ (n= 6 patients and ongoing)
• After enrolment, patients underwent leukapheresis before lymphodepletion with fludarabine (30mg/m²) and cyclophosphamide (300mg/m²) for 3 days, followed by bb21217 infusion 5 days later
• The CAR T product was manufactured using viral transduction of patients T-cells with the bb21217 construct, expansion, and testing prior to infusion

 

Key results

• bb21217 manufacturing success rate was 100%; however, three patients required re-manufacturing run
• Samples collected before the data cut-off (n=41)
  • Withdrew (n=1)
  • Infused after cut-off (n=1)
  • Infused by cut-off (n=38)
• Baseline patient characteristics and prior therapies are presented in Table 1
• Median follow-up was 6 months (< 1–23)

Table 1. Baseline patient characteristics

ECOG PS, The Eastern Cooperative Oncology Group performance status; IMiD, immunomodulatory imide drug; ISS, International Staging System; SCT, stem cell transplantation
Characteristics	Patients (N= 38)
Median (min, max) age, years	62 (33, 74)
Male, n (%)	21 (55)
Median (min, max) time since initial diagnosis, years	5.5 (1.0, 13.5)
ECOG PS, n (%) 0 1 2	12 (32) 24 (63) 2 (5)
ISS stage, n (%) I II III Unavailable	11 (29) 7 (18) 10 (26) 10 (26)
High-risk cytogenetics, n (%) Del(17p), t(4;14), t(14;16) Unknown	13 (34) 1 (3)
Median (min, max) number prior regimens	6 (3, 7)
Prior autologous SCT, n (%) 0 1 >1	7 (18) 22 (58) 9 (24)
Prior therapies, n (%), exposed/refractory IMiD agent Proteosome inhibitor Anti-CD38 antibody Cumulative PI/IMiD/Anti-CD38	38 (100)/ 30 (79) 38 (100)/ 33 (89) 36 (95)/ 29 (76) 36 (95)/ 24 (63)

Safety and tolerability

• There were no new safety concerns when compared to the previous report
• All patients infused with bb21217 experienced at least one treatment-emergent adverse event (TEAE),
  • 50% experienced ≥ 1 serious TEAE (n= 19)
  • 95% experienced ≥ 1 Grade 3/4 TEAE (n= 36) (Table 2)

Table 2. Grade 3/4 treatment-emergent AEs (TEAEs) in >2 patients

TEAE, treatment-emergent adverse event
TEAE, n (%)	Grade 3/4 (N=38)
Neutropenia	31 (82)
Leukopenia	21 (55)
Thrombocytopenia	21 (55)
Anemia	19 (50)
Lymphopenia	13 (34)
Hypophosphatemia	8 (21)
Infections	7 (18)
Hyponatremia	5 (13)
Febrile neutropenia	4 (11)

• Cytokine release syndrome (CRS)
  • There were 25 cases (66%) of CRS of any grade (Table 3)
  • The median time to CRS onset was 3 days (1–20), with the median duration of 4 days (1–28)
  • Fourteen (out of 25) patients had CRS adequately managed with tocilizumab (n= 10) or tocilizumab plus corticosteroids (n= 4)
  • There was one case fatal CRS associated with grade 3 neurotoxicity, at the highest dose
• Neurotoxicity
  • There were nine cases (24%) of any grade (Table 3)
  • The median time to onset of neurotoxicity was 7 days (3–24)

Table 3. Summary of cytokine release syndrome (CRS) and neurotoxicity events

	N	Grade, n (%)			Total
		3	4	5
CRS
Total 150 x 106 300 x 106 450 x 106	38 12 14 12	1 (3) 1 (8) 0 0	0 0 0 0	1 (3) 0 0 1 (8)	25 (66) 8 (67) 7 (50) 10 (83)
Neurotoxicity
Total 150 x 106 300 x 106 450 x 106	38 12 14 12	2 (5) 0 1 (7) 1 (8)	1 (3) 1 (8) 0 0	0 0 0 0	9 (24) 3 (25) 4 (29)  2 (17)
CRS,  cytokine release syndrome

Efficacy

• Responses were seen at all dose levels (Table 4)
• Responses improve with time and therefore the data for 300 x 10⁶ and 450 x 10⁶ doses are still maturing
• The median duration of response for dose 150 x 10⁶ was 11.1 months (3.3–not estimable) and for the higher doses was not yet reached

Table 4. Responses to bb21217 and measurable residual disease (MRD) status

aMRD negativity defined as < 10-5 tumor plasma cells; CR, complete response; PD, progressive disease; PR, partial response; sCR, stringent complete response; VGPR, very good partial response
Response	CAR+ T cells
	150 x 106	300 x 106	450 x 106
Median follow-up (range), months	17.6 (12–23)	4.0 (2 –10)	3.3 (< 1–6)
Confirmed response, n (%) sCR/CR VGPR PR Total	4 (33) 6 (50) 0 10 (83)	0 4 (29) 2 (14) 6 (43)	1 (14) 2 (29) 1 (14) 4 (57)
Median time to 1st response (range), months	1.0 (1.0–1.9)	1.0 (1.0–1.0)	1.0 (1.0–1.8)
MRD status in bone marrow Evaluable responders, n MRD negativea, n	7 7	6 5	4 4

Pharmacokinetics

• CAR T-cells expanded and persisted, with higher expansion seen in patients who responded to bb21217 vs non-responding patients (p= 0.0007)
• A total of 13/15 patients assessed for vector copy number had detectable levels at 3 months, 8/10 after 6 months, and 2/2 after 18 months
• LEF1⁺ and CCR7⁺ memory-like T cells were enriched upon treatment
• Higher enrichment was associated with better peak expansion and lower risk of progression by 6 months

Conclusion

The presented data demonstrate the safety profile of bb21217 as consistent with known CAR T-cell products and show promising efficacy in patients with R/R MM. The expansion part of the study is ongoing to confirm the dose recommended for phase II study.

*The article is based on the data presented at the ASH meeting and may supersede the data in the published abstract.