On December 13, 2022 Cellectis S.A. (the "Company") (Euronext Growth: ALCLS – NASDAQ: CLLS), a clinical-stage biotechnology company using its pioneering gene-editing platform to develop life-saving cell and gene therapies, reported that it will host a live webcast reviewing updated clinical data on its Phase 1/2a BALLI-01 clinical trial (evaluating UCART22) and on its Phase 1 AMELI-01 clinical trial (evaluating UCART123) that were presented in an oral session on December 12, 2022 at the 64th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) (Press release, Cellectis, DEC 13, 2022, View Source [SID1234625188]).
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Preliminary Data from the BALLI-01 Clinical Study
BALLI-01 is a Phase 1/2a open-label dose-escalation trial evaluating the safety and clinical activity of UCART22 given at escalating dose levels after lymphodepletion (LD) with either fludarabine and cyclophosphamide (FC) or FC with alemtuzumab (FCA) in patients with relapsed or refractory acute lymphoblastic leukemia (r/r ALL). Alemtuzumab was added to the LD regimen to sustain host T-cell and Natural Killer (NK) cell depletion and to promote UCART22 cell expansion and persistence.
Compared to the last clinical update on BALLI-01 at ASH (Free ASH Whitepaper) 2021, the webcast presented data from five additional patients who received UCART22 at dose level 3 (DL3) 5×106 cells/kg after lymphodepletion with FCA. No dose limiting toxicities (DLTs), Grade 2 or higher cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS) or adverse events of special interest (AESI) were observed.
Evidence of UCART22 anti-tumor activity was observed in 60% (n=3) of the five patients at DL3 after lymphodepletion with FCA:
A patient experienced a durable minimal residual disease (MRD) negative complete response with incomplete count recovery (CRi) that continues beyond 6 months.
A patient experienced an MRD negative complete response (CR) that continues beyond Day 56.
A patient experienced a morphologic leukemia-free state (MLFS) that continues beyond Day 84 (MRD-negative until Day 84; MRD-positive at Day 117).
All three of the responders failed multiple lines of prior therapy including chemotherapy, CD19-directed autologous CAR T cell therapy, and allogeneic stem cell transplant. Additionally, the patient with the MRD negative CR also failed both prior blinatumomab (a CD19-directed bi-specific antibody) and inotuzumab (a CD22-directed antibody-drug conjugate).
"These treatment responses in combination with the safety data are very encouraging for patients with r/r B-cell ALL who have limited, if any, treatment options, especially for those who have failed prior CD19 directed CAR T-cell therapy and allogeneic stem cell transplant’, said Nitin Jain, M.D., The University of Texas MD Anderson Cancer Center, Department of Leukemia, and coordinating investigator for the BALLI-01 study.
Next Steps
Overall, these preliminary data support the continued administration of UCART22 after FCA lymphodepletion in patients with r/r ALL. The Company is now enrolling patients in BALLI-01 with product candidate manufactured fully in-house at DL2 after FCA lymphodepletion. The first patient has been dosed at dose level 2 (DL2) 1×106 cells/kg. The next data set is expected to be released in 2023.
Preliminary Clinical Data from the AMELI-01 Study Presented at ASH (Free ASH Whitepaper) 2022
AMELI-01 is a Phase 1 open-label dose-escalation trial evaluating the safety, tolerability, expansion and preliminary activity of UCART123 given at escalating dose levels after lymphodepletion (LD) with either fludarabine and cyclophosphamide (FC) or FC with alemtuzumab (FCA) in patients with relapsed or refractory acute myeloid leukemia (r/r AML).
The oral presentation reviewed preliminary data from patients who received UCART123 at one of the following dose levels: dose level 1 (DL1) 2.5×105 cells/kg; dose level 2 (DL2) 6.25×105 cells/kg; intermediate dose level 2 (DL2i) 1.5×106 cells/kg; or dose level 3 (DL3) 3.30×106 cells/kg after lymphodepletion with FC ([n=8], DL1 – DL3) or FCA ([n=9], DL2 & DL2i).
Preliminary Safety Data
The FCA LD regimen resulted in robust lymphodepletion for greater than 28 days in all patients. Seven out of nine patients demonstrated UCART123 expansion, with maximum concentration (C max) ranging from 13,177 to 330,530 copies/µg DNA, an almost nine-fold increase compared with FC LD, and a significant increase in area under the curve (AUC)(0-28 days) (p=0.04; FC 10.2±15.7 vs. FCA 34.9±28.4).
Cytokine release syndrome (CRS) occurred in eight patients in the FC arm and nine patients in the FCA arm. In the FC arm, one patient experienced Grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS) and two patients experienced Grade 4 protocol-defined dose limiting toxicities (DLTs) secondary to CRS. In the FCA arm, two patients experienced Grade 5 DLTs secondary to CRS. Grade 4 toxicities are potentially life threatening and Grade 5 toxicities result in death.
Preliminary Efficacy Data
Evidence of UCART123 anti-tumor activity was observed in four patients out of fifteen at DL2 or above with best overall responses in the FCA arm. Two out of eight patients (25%) at DL2 with FCA arm achieved meaningful response:
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A patient who failed five prior lines of therapy experienced a durable minimal residual disease (MRD) negative complete response (CR) with full count recovery at Day 56 that continues beyond one year.
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A patient with stable disease achieved greater than 90% bone marrow blast reduction (60% to 5%) at Day 28.
"Exemplary activity was seen in a 64-year-old female with AML who had relapsed after allogeneic stem cell transplantation (allo-SCT) and has maintained a durable MRD-negative complete response for over one year without salvage donor lymphocyte infusion or second allo-SCT," said David A. Sallman, M.D., Moffit Cancer Center, Department of Malignant Hematology, Tampa, FL. "Overall, these encouraging clinical data are a meaningful step forward for patients and support further enrollment into the study. This trial addresses a patient population with severe unmet medical need, where a successful CAR T-cell product candidate could be a major breakthrough."
The preliminary data show that adding alemtuzumab to the FC LD regimen was associated with sustained lymphodepletion and significantly higher UCART123 cell expansion, which correlated with improved anti-tumor activity.
Next Steps: 2-Dose Regimen
Overall, these preliminary data support the continued administration of UCART123 after FCA lymphodepletion in patients with r/r AML. Based on observed UCART123 expansion patterns and cytokine profiles, pursuant to an amended protocol (as described below), a second dose of UCART123 will be given after 10-14 days to allow for additional UCART123 expansion and clinical activity without the use of additional lymphodepletion. The second expansion phase in the setting of reduced disease burden is expected to be safe and allow for clearance of residual disease.
After a protocol-based pause in patient recruitment following a Grade 5 event related to CRS, the protocol treatment strategy has been modified and AMELI-01 has now commenced enrolling patients in the FCA 2-dose regimen arm at DL2, a dose that has already been administered and cleared for safety as a single dose. The arm incorporates the use of prophylactic tocilizumab, which is associated with reduced incidence of CRS.
A copy of the ASH (Free ASH Whitepaper) oral presentation is available on Cellectis’ website.
"These clinically meaningful preliminary data from both the BALLI-01 and AMELI-01 studies are very encouraging for patients and for the future of allogeneic CART-cell therapy. Both ALL and AML are diseases with an urgent need for alternative treatment options for patients, and we are excited to be moving each of these studies forward," said Dr. Mark Frattini, M.D., Ph.D., Chief Medical Officer at Cellectis. "We are now implementing a two-dose regimen arm for our AMELI-01 trial, as well as enrolling patients with in-house manufactured product for our BALLI-01 trial. We look forward to sharing future updates as they become available for both of these clinical studies."
Pipeline Overview
The following chart highlights our and our licensee’s key product candidates:
(1)
ALLO-501 and ALLO-501A are exclusively licensed to Servier and under a joint clinical development program between Servier and Allogene. The ALPHA and ALPHA2 studies targets Diffuse Large B-Cell Lymphoma (DLBCL) and Follicular Lymphoma (FL) indications, which are subtypes of NHL.
(2)
Phase 3 may not be required if Phase 2 is registrational.
(3)
ALLO-715 and ALLO-605 target BCMA which is a licensed target from Cellectis. Allogene has an exclusive license to the Cellectis technology for allogeneic products directed at the BCMA target. Allogene holds global development and commercial rights for this Investigational candidate.
(4)
Allogene is promoting this clinical trial in combination with SpringWorks Therapeutics.
(5)
ALLO-316 targets CD70 which is a licensed target from Cellectis.. Allogene has an exclusive license to the Cellectis technology for allogeneic products directed at the CD70 target. Allogene holds global development and commercial rights for this investigational candidate.
As of September 21, 2022, Servier has notified Allogene that Servier was discontinuing involvement in the development of CD-19-targeting allogeneic CAR T-cell products.
NATHALI-01 Study (evaluating UCART20x22):
Cellectis is enrolling patients at dose level 1 (50×106 cells) with a fludarabine, cyclophosphamide, and alemtuzumab lymphodepletion regimen in the NATHALI-01 Phase 1 dose-escalation clinical study of UCART20x22. UCART20x22 is Cellectis’ first allogeneic dual CAR T-cell product candidate being developed for patients with relapsed or refractory non-Hodgkin lymphoma and fully designed, developed and manufactured in-house.
MELANI-01 Study (evaluating UCARTCS1):
Cellectis is enrolling patients at dose level 1 (1.0×106 cells/kg) with a fludarabine and cyclophosphamide (FC) lymphodepletion regimen in the MELANI-01 Phase 1 dose-escalation clinical study of UCARTCS1 for patients with relapsed or refractory multiple myeloma (MM).
ASH 2022 Poster Presentation on UCARTCS1, in Collaboration with Amsterdam UMC
On December 10, 2022, the Amsterdam University Medical Center (VUmc location), in collaboration with Cellectis, presented preclinical data in a poster session showcasing Cellectis’ UCARTCS1 product candidate. These initial preclinical data demonstrated anti-tumor activity in vitro and in vivo, supporting the potential benefit of Cellectis’ UCARTCS1 first in-human study MELANI-01.
Collectively, the preclinical data demonstrated that UCARTCS1 has potent anti-MM activity against MM cell lines and primary MM cells, as well as in a MM xenograft model. These preclinical data support the ongoing Phase 1 clinical trial with UCARTCS1 in heavily pretreated multiple myeloma patients.
A copy of the poster presentation is available here on Cellectis’ website.
Webcast Information
The event will feature presentations by the management team and will be followed by a live Q&A. A replay of the webcast will be made available under the "Events and Webcasts" section on the Investor page of the Company’s website: View Source
In this context, the listing of the Company’s ordinary shares on Euronext Growth will be suspended on December 13, 2022 until the opening of trading of Cellectis’ ADSs on the Nasdaq Global Market at 3:30 pm (Paris time)/ 9:30 a.m. (New York time).