CB-012 Earns FDA Fast Track Status in R/R Acute Myeloid Leukemia

The FDA previously cleared an investigational new drug application for CB-012 as a treatment for patients with relapsed/refractory AML in October 2023.

The FDA has granted fast track designation to the investigational anti–CLL-1 CAR T-cell therapy CB-012 as a treatment for patients with relapsed/refractory acute myeloid leukemia (AML), according to a press release from the developer, Caribou Biosciences, Inc.¹

Developers designed CB-012 to exhibit 5 genome edits through a next-generation CRISPR platform employing Cas12a chRDNA genome editing. According to the press release, CB-012 may be the first allogeneic CAR T-cell therapy candidate to make use of both checkpoint disruption and immune cloaking; these features are intended to enhance the agent’s potential anti-cancer activity.

Investigators are currently evaluating treatment with CB-012 for patients with relapsed/refractory AML as part of the phase 1 AMpLify trial (NCT06128044).

“Most patients with acute AML [quickly become] refractory or relapse after [receiving] currently available therapeutic options, and allogeneic hematopoietic stem cell transplant is the only potentially curative option after salvage chemotherapy regimens,” Tina Albertson, MD, PhD, chief medical officer at Caribou Biosciences, said in the press release.¹ “As we advance CB-012 and enroll patients at dose level 2 [in the AMpLify trial], we are focused on our goal to deliver an effective, off-the-shelf treatment option for patients living with this disease.”

Preclinical data on the use of CB-012 in AML with xenograft models were previously presented at the 2024 American Association for Cancer Research Annual Meeting (AACR).² Findings showed that the agent exhibited potent antigen-dependent expansion and cytotoxic activity in human CLL-1–positive cell lines. Additionally, CB-012 yielded robust tumor control and prolonged survival among AML xenograft models. Investigators concluded that treatment with CB-012 was associated with specific and potent in vitro and in vivo CLL-1–targeted cytolytic activity.

In the open-label AMpLify trial, patients will receive treatment with CB-012 as part of the dose-escalation portion in part A and as part of the dose-expansion portion in part B.³ Study treatment will also include lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine.

The trial’s primary end point is dose-limiting toxicities in part A of the trial. In part B, the primary end point is overall response rate based on European Leukemia Net criteria.

Patients 18 years and older with documented relapsed/refractory AML, non-proliferative disease, and a maximum of 3 prior lines of therapy are eligible for enrollment on the trial. Other criteria for study entry include having an ECOG performance status of 0 or 1 and eligibility to undergo an allogeneic stem cell transplant. Having adequate renal, hepatic, pulmonary, and cardiac function is another requirement for enrollment.

Those with acute promyelocytic leukemia, metabolically inactive extramedullary disease per 18-FDG PET-CT, or prior receipt of CAR T-cell therapy are ineligible for enrollment on the trial. Patients are also unsuitable for study entry if they have had an allogeneic stem cell transplant within 100 days prior to lymphodepleting chemotherapy, acute graft-versus-host disease requiring treatment, active or prior central nervous system involvement, or primary immunodeficiency or autoimmune disease.

The FDA previously cleared an investigational new drug application for CB-012 as a treatment for patients with relapsed/refractory AML in October 2023.⁴

“There is an urgent need to develop new treatments for patients with relapsed/refractory AML, for which the treatment options are predominantly limited to salvage chemotherapy regimens. An allogeneic CAR T-cell therapy that could safely and effectively target AML blasts while preserving healthy hematopoietic stem cells could provide a much-needed off-the-shelf option for these patients,” Naval Daver, MD, a professor and director of the Leukemia Research Alliance Program in the Department of Leukemia at The University of Texas MD Anderson Cancer Center, said in a press release at the time the FDA cleared the investigational new drug application.⁴

References

1. Caribou Biosciences announces the FDA has granted fast track designations to CB-010 in refractory SLE and to CB-012 in relapsed or refractory AML. News release. Caribou Biosciences, Inc. September 3, 2024. Accessed September 4, 2024. https://tinyurl.com/yc7d9c4y
2. Francica B, Garner E, Namburi S, et al. Abstract 6323: Preclinical evaluation of CB-012, an allogeneic anti-CLL-1 CAR-T cell therapy, that exhibits specific and potent toxicity in acute myeloid leukemia (AML) xenograft models. Cancer Res. 2024;84(suppl 6):6323. doi:10.1158/1538-7445.AM2024-6323
3. CRISPR-edited allogeneic anti-CLL-1 CAR-T cell therapy in patients with relapsed/​refractory acute myeloid leukemia (AMpLify). ClinicalTrials.gov. Updated April 26, 2024. Accessed September 4, 2024. https://tinyurl.com/5h7xkhj7
4. Caribou Biosciences announces FDA clearance of IND application for CB-012, an allogeneic anti-CLL-1 CAR-T cell therapy for the treatment of relapsed or refractory acute myeloid leukemia. News release. Caribou Biosciences, Inc. October 18, 2023. Accessed September 4, 2024. https://tinyurl.com/av6d4bsx