FDA Grants Fast Track Designation to ADI-270 for Pretreated Advanced ccRCC

FDA Grants Fast Track Designation to ADI-270 for Pretreated Advanced ccRCC

A fast track designation has been granted by the FDA to ADI-270 as a potential therapy option for patients with metastatic or advanced clear cell renal cell carcinoma (ccRCC) previously treated with an immune checkpoint inhibitor and a VEGF inhibitor.¹

ADI-270 is an allogeneic, off-the-shelf, CD70-targeted gamma delta CAR T-cell therapy candidate. It is directed toward CD70 using the natural CD27 receptor and features a dominant negative form of the transforming growth factor-β receptor II intended to deliver functional resilience to the immunosuppressive tumor microenvironment. Furthermore, ADI-270 is intended to increase exposure and persistence by reducing susceptibility to graft-vs-host elimination.

“We are pleased that ADI-270, our first ever gamma delta 1 CAR T-cell therapy candidate to enter clinical trials for solid tumors, has been granted fast track designation by the FDA,” Chen Schor, president and chief executive officer of Adicet Bio, stated in a news release. “ccRCC is the most common type of kidney cancer, and this significant milestone underscores our commitment to advancing innovative treatments to these patients as quickly as possible.”

Findings from preclinical studies presented at the 2023 American Society of Gene + Cell Therapy Annual Meeting showed that ADI-270 successfully generated and expanded without indications of fratricide. The agent also displayed a less-differentiated T-cell memory phenotype with low expression of exhaustion markers; potent in vitro cytotoxicity; and favorable cytokine and chemokine profiles.²

Additionally, ADI-270 generated highly potent tumor growth inhibition via xenografts in immunodeficient mice. Furthermore, selective T-cell infiltration, proliferation, and activation were observed within the tumor.

A phase 1/2 trial (NCT06480565) will investigate ADI-270 in patients at least 18 years of age with histologically or cytologically confirmed ccRCC who have documented evidence of advanced or metastatic disease. Prior treatment with an immune checkpoint inhibitor and a VEGF inhibitor is required; notably, the VEGF inhibitor must have been given in the advanced/metastatic setting. Other key inclusion criteria include at least 1 measurable target lesion per RECIST v1.1 criteria and a Karnofsky performance status of at least 70. Patients will need to be at least 3 weeks or 5 half-lives removed from their last dose of prior therapy.³

The study will exclude patients with central nervous system (CNS) metastases or spinal cord compression, unless they have finished treatment and discontinued corticosteroids for at least 8 weeks and remain stable prior to enrollment. Other key exclusion criteria include clinically significant CNS dysfunction; prior radiation therapy within 21 days prior to start of study treatment, except for palliative radiotherapy to bone lesions completed at least 2 weeks prior to the first study treatment; prior gene therapy, genetically modified cell therapy, or adoptive T-cell therapy within 6 weeks of enrollment; and any prior treatment with a CD70-targeted therapy.

The trial will also exclude patients with an active malignancy within the past 24 months, other than RCC; definitively treated basal or squamous cell carcinoma of the skin; or carcinoma in-situ of the cervix or bladder. Patients with any primary immunodeficiency or active autoimmune disease requiring ongoing systemic immunosuppressive therapy will also be excluded.

Enrolled patients will undergo lymphodepletion with fludarabine plus cyclophosphamide prior to receiving a single dose of ADI-270. During dose escalation, ADI-270 will be given at ascending dose levels to determine the maximum tolerated dose (MTD) or maximum assessed dose (MAD). Dose expansion will further evaluate the CAR T-cell therapy at the MTD/MAD.

The primary end points of the study are the incidence of dose-limiting toxicities and the proportion of treatment-emergent and -related adverse effects.

References

1. Adicet Bio receives FDA fast track designation for ADI-270 in metastatic/advanced clear cell renal cell carcinoma. News release. Adicet Bio. July 8, 2024. Accessed July 8, 2024. https://investor.adicetbio.com/news-releases/news-release-details/adicet-bio-receives-fda-fast-track-designation-adi-270
2. Lamture G, Teague AG, Smith-Boeck M, et al. ADI-270: an armored allogeneic “off-the-shelf” CAR γδ T cell therapy targeting CD70+ cancers. Presented at: 2023 American Society of Gene + Cell Therapy; May 16-20, 2023; Los Angeles, CA.
3. A Phase 1/​2 trial of ADI-270 in ccRCC. ClinicalTrials.gov. Updated Jun 28, 2024. Accessed July 8, 2024. https://clinicaltrials.gov/study/NCT06480565