On December 5, 2020 Allogene Therapeutics, Inc. (Nasdaq: ALLO), a clinical-stage biotechnology company pioneering the development of allogeneic CAR T (AlloCAR T) therapies for cancer, reported positive initial results from the Phase 1 UNIVERSAL study of ALLO-715 in relapsed/refractory multiple myeloma (MM) (Press release, Allogene, DEC 5, 2020, View Source [SID1234572472]). Data were presented at an oral session of the American Society of Hematology (ASH) (Free ASH Whitepaper) annual meeting. This study utilizes ALLO-647, Allogene’s anti-CD52 monoclonal antibody (mAb), as a part of its differentiated lymphodepletion regimen.

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"We are excited to demonstrate for the first time that an allogeneic CAR T therapy directed at BCMA can achieve deep clinical responses. We believe these initial results support that we are on the right track to bring the benefits of an off-the-shelf therapy to patients with refractory multiple myeloma," said David Chang, M.D., Ph.D., President, Chief Executive Officer and Co-Founder of Allogene. "We look forward to optimizing multiple aspects of this therapy in the ongoing UNIVERSAL trial."

"These data highlight the potential for an off-the-shelf CAR T therapy to treat patients within a matter of days, which eliminates the need for bridging therapy, a significant benefit in this refractory myeloma population," said Sham Mailankody, MBBS, Assistant Attending Physician, Memorial Sloan Kettering Cancer Center in New York, New York. "I am encouraged by the initial data from this trial, including the feasibility, safety and the ability of ALLO-715 to produce MRD negative responses."

As of the October 30, 2020 data cutoff, 35 patients were enrolled with 31 patients evaluable for safety and 26 patients evaluable for efficacy. Patients were refractory to their last line of myeloma therapy, had a median of five prior lines of therapy, and 94% were penta-exposed. Four patients became ineligible for treatment due to rapidly progressing disease. The median time from enrollment to the start of therapy was five days.

In the initial dose escalation phase of the UNIVERSAL trial, patients received lymphodepletion (LD) followed by ALLO-715 at one of three dose levels (DL1 = 40M cells, DL2 = 160M cells, DL3 = 320M cells) in a 3+3 dose escalation design. DL4 (480M cells) was added in a subsequent cohort. Two LD regimens were evaluated, with the trial enrollment primarily focused on the FCA lymphodepletion regimen:

FCA: Fludarabine 90 mg/m2, Cyclophosphamide 900 mg/m2, and ALLO-647 from 39 to 90mg divided over three days; and
CA: Cyclophosphamide 900 mg/m2 and ALLO-647 39mg divided over three days.
Higher CAR T cell doses were associated with an increased response rate and greater AlloCAR T cell expansion. In the DL3 cohort (320M CAR T+ cells), the overall response rate (ORR) was 60% with 40% of patients achieving a very good partial response (VGPR) or better (VGPR+). VGPR+ is defined as a stringent complete response (sCR), complete response (CR) or VGPR. Across all cohorts and lymphodepletion regimens, six patients achieved VGPR+, five of whom were in the FCA lymphodepletion regimen. Minimal residual disease (MRD) assessment was completed in five of the six patients with a VGPR+ response and all achieved an MRD negative status.

As of the data cutoff, the overall median follow-up for efficacy was 3.2 months and six out of the nine patients treated with DL3 or DL4 with a response remain in response. The longest response was ongoing at six months from the DL3 cohort with FCA lymphodepletion.

Cell Dose
and LD
regimen
FCA CA
DL1
40 x 106
CAR+ cells DL2
160 x 106
CAR+ cells DL3
320 x 106
CAR+ cells DL4
480 x 106
CAR+ cells DL2
160 x 106
CAR+ cells DL3
320 x 106
CAR+ cells
Low
ALLO-647
(N=3) Low
ALLO-647
(N=4) Low
ALLO-647
(N=6) High
ALLO-647
(N=4) ALL
ALLO-647
(N=10) Low
ALLO-647
(N=3) Low
ALLO-647
(N=3) Low
ALLO-647
(N=3)
ORR,
n (%) - 2 (50%) 3 (50%) 3 (75%) 6 (60%) 1 (33%) - 2 (67%)
VGPR+ Rate,
n (%) - 1 (25%) 3 (50%) 1 (25%) 4 (40%) - - 1 (33%)
Of the 31 patients evaluable for safety, there was no graft-vs-host disease (GvHD) or Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) observed. Grade 1 and Grade 2 cytokine release syndrome (CRS) was reported in 14 patients (45%) and was manageable with standard therapies. Infection events ≥ Grade 3 in the trial was similar to what has been reported in other advanced MM studies. Adverse events ≥ Grade 3 reported as serious adverse events occurred in 19% of patients. As previously reported, a single Grade 5 event related to progressive myeloma and conditioning regimen occurred in the CA cohort.

Adverse Events of Interest Grade 1
N (%) Grade 2
N (%) Grade 3
N (%) Grade 4
N (%) Grade 5
N (%) All Grades
N (%)
Cytokine Release Syndrome 5 (16%) 9 (29%) - - - 14 (45%)
ICANS - - - - - -
Graft-versus-Host Disease - - - - - -
Infection 2 (7%) 6 (19%) 4 (13%) - 1 (3%) 13 (42%)
Infusion Reaction to ALLO-647 4 (13%) 3 (10%) - - - 7 (23%)
As part of the Company’s three-pronged anti-BCMA strategy, the Phase 1 UNIVERSAL study continues to enroll patients at higher doses of ALLO-715 and ALLO-647 in an effort to optimize the therapy. The UNIVERSAL study is expected to begin enrolling patients in the first half of 2021 to evaluate ALLO-715 in combination with SpringWorks Therapeutics’ investigational gamma secretase inhibitor, nirogacestat. An investigational new drug application (IND) is expected to be submitted in the first half of 2021 for the Company’s first TurboCAR candidate, ALLO-605, an investigational BCMA-directed AlloCAR T therapy for MM. TurboCAR technology allows cytokine activation signaling to be engineered selectively into CAR T cells and has shown the ability to improve the potency and persistence of allogeneic cells in preclinical models.

Webinar
Allogene will be hosting a webinar to discuss the data from UNIVERSAL on December 5 at 11:00 a.m. PT/2:00 p.m. ET. Please register for the webinar on the Company’s website at www.allogene.com under the Investors tab in the News and Events section (View Source) or by clicking the following link directly.

The webinar will also be available in replay and the materials presented will be posted on the Allogene website prior to the start of the event.