Clinical Trials

Date: 2017-11-06

Type of information: update on patient enrollment

phase: 1

Announcement: update on patient enrollment - lift of clinical hold

Company: Cellectis (France)

Product: UCART123

Action mechanism:

• cell therapy/immunotherapy product/gene therapy/CAR-T cell therapy. UCART123 is a gene-edited T-cell investigational drug that targets CD123, an antigen expressed at the surface of leukemic cells in acute myeloid leukemia, and tumoral cells in blastic plasmacytoid dendritic cell neoplasm.
• This first allogeneic, “off-the-shelf” gene edited CAR T-cell product candidate targeting CD123 is to be investigated in U.S. clinical trials.

Disease: acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN)

Therapeutic area: Cancer - Oncology

Country: USA

Trial details:

Latest news:

• • On November 6, 2017, Cellectis announced that the FDA has lifted the clinical hold, previously announced on September 4, 2017, on Phase 1 trials of Cellectis’ UCART123 product candidate in acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Cellectis agreed with the FDA to the following main revisions to be implemented in Phase 1 UCART123 protocols to lift the hold:
• – Decrease of the cohort dose level to 6.25x10⁴UCART123 cells/kg;
• – Decrease of the cyclophosphamide dose of the lympho-depleting regimen to 750 mg/m²/day over three days with a maximum daily dose of 1.33 grams of cyclophosphamide;
• – Inclusion of specific criteria at Day 0, the day of UCART123 infusion, such as no new uncontrolled infection after receipt of lymphodepletion, afebrile, off all but replacement dose of corticosteroids, no organ dysfunction since eligibility screening;
• – Provision to ensure that the next three patients to be treated in each protocol will be under the age of 65;
• – Provision to ensure that the enrollment will be staggered across the UCART123 protocols AML123 and ABC123: at least 28 days should elapse between the enrollments of two patients across the two studies.
• Cellectis is currently working with the investigators and clinical sites to obtain IRB’s approval on the revised protocols and resume patient enrollment.
• • On September 4, 2017, Cellectis announced having received notice from the FDA that a clinical hold was placed on both UCART123 ongoing Phase 1 studies, respectively in acute myeloid leukemia and in blastic plasmacytoid dendritic cell neoplasm. Cellectis is working closely with the investigators and the FDA in order to resume the trials with an amended protocol including a lowered dosing of UCART123. The clinical hold was initiated after Cellectis reported one fatality in the BPDCN clinical trial (ABC study). This was the first patient treated in the BPDCN study, a 78-year-old male treated with one prior therapy, who presented with relapsed/refractory BPDCN with 30% blasts in his bone marrow and cutaneous lesions (biopsy-proven BPDCN) at baseline prior to conditioning regimen. He received 30mg/m2/day fludarabine for 4 days and 1g/m2/day cyclophosphamide for 3 days, as a preconditioning regimen. On August 16, 2017 (Day 0), he received 6.25x105 UCART123 cells per kilogram, the first dose level explored in the protocol, without complication. At Day 5, the patient experienced a grade 2 Cytokine Release Syndrome (CRS) and a grade 3 lung infection, which quickly improved after a first dose of tocilizumab and institution of anti-infective therapy (broad spectrum intravenous antibiotics). He then experienced at Day 8 a grade 5 CRS, together with a grade 4 Capillary Leak Syndrome. Despite a treatment in keeping with CRS management including administration of corticosteroids and tociluzumab x 2 as well as intensive care unit support, the patient died on Day 9.
• The first patient treated in the AML study was a 58-year-old woman, with 84% blasts in her bone marrow at baseline prior to conditioning regimen. On June 27, 2017 (Day 0), the patient received the same preconditioning regimen and the same dose of UCART123 as the BPDCN patient, without complication. She experienced an initial grade 2 CRS at Day 8, worsening to a grade 3 at Day 9 and resolving at Day 11 with treatment management in intensive care unit. She also experienced a grade 4 Capillary Leak Syndrome at Day 9, resolved at Day 12. No GvHD3 was reported for any of these patients. The DSMB (Data Safety Monitoring Board) met on August 28 and recommended lowering the dose to 6.25x 10⁴ UCART123 cells per kilogram in both studies and capping cyclophosphamide to a total dose of 4g over 3 days.
• • On August 17, 2017, Cellectis announced that the first patient with blastic plasmacytoid dendritic cell neoplasm has been dosed in Cellectis’ Phase I clinical study using the UCART123, one of the Company’s wholly-controlled TALEN® gene-edited product candidates. at the MD Anderson Cancer Center.
• The UCART123 clinical program for BPDCN is led by Dr. Naveen Pemmaraju, Professor Marina Konopleva MD, PhD, and Professor Hagop Kantarjian, MD, Department Chair, Department of Leukemia, Division of Cancer Medicine, at the MD Anderson Cancer Center. The clinical trial will investigate the safety and efficacy of UCART123 in patients with BPDCN in the relapsed, refractory and front-line setting.
• • On June 27, 2017,  Cellectis announced the first administration in the Phase I clinical study in acute myeloid leukemia for UCART123. This marks the first allogeneic, “off-the-shelf” gene-edited CAR T-cell product candidate targeting CD123 to be investigated in clinical trials. This clinical research in acute myeloid leukemia is led by Principal Investigator Dr. Gail J. Roboz, Professor of Medicine at Weill Cornell Medicine and Director of the Clinical and Translational Leukemia Programs at Weill Cornell Medicine and NewYork-Presbyterian Hospital. The clinical trial will investigate the safety and efficacy of UCART123 in patients with acute myeloid leukemia The clinical trial is part of a strategic translational research alliance that was formed between Cellectis and Weill Cornell Medicine in 2015.
• • On February 6, 2017, Cellectis announced that the company has received an Investigational New Drug (IND) approval from the FDA to conduct Phase 1 clinical trials with UCART123 in patients with acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). This marks the first allogeneic, “off-the-shelf” gene-edited CAR T-cell product candidate that the FDA has approved for clinical trials. Cellectis intends to initiate Phase 1 trials in the first half of 2017.
• • On January 3, 2017, Cellectis announced the submission of an Investigational New Drug (IND) application to the FDA requesting approval to initiate Phase 1 clinical trials of UCART123 in patients with acute myeloid leukemia (AML) and blastic plasmacytoid dendritic cell neoplasm (BPDCN). Pending regulatory clearance, Cellectis plans to initiate Phase 1 clinical trials in the first half of 2017. This is the first IND filing for human clinical applications of a gene edited allogeneic “off-the-shelf” product candidate in the U.S.
• The UCART123 program was subject to a public hearing by the National Institutes of Health's Recombinant DNA Advisory Committee (RAC) in December 2016, where it received the unanimous approval of the RAC committee members.
• The clinical research at Weill Cornell will be led by principal investigator Dr. Gail J. Roboz, Director of the Clinical and Translational Leukemia Programs and Professor of Medicine. The UCART123 clinical program at MD Anderson will be led by Dr Naveen Pemmaraju, MD, Assistant Professor, and Professor Hagop Kantarjian, MD, Department Chair, Department of Leukemia, Division of Cancer Medicine.

 

Is general: Yes