Patients (pts) with relapsed/refractory (R/R) lymphomas have limited treatment options and poor mortality rates versus pts with non-R/R disease. CD30 is an established therapeutic target in R/R lymphoid malignancies. Brentuximab vedotin (BV), a CD30-directed antibody-drug conjugate (ADC), has demonstrated clinical benefit in cHL and PTCL. SGN-35T is an investigational ADC comprised of an anti-CD30 monoclonal antibody, conjugated to monomethyl auristatin E (MMAE) via a novel protease-cleavable tripeptide linker with a drug-to-antibody ratio of approximately 4. SGN-35T has the same antibody backbone as BV; however, the tripeptide linker is designed to preferentially release MMAE in target cells to improve tolerability. Preclinically, SGN-35T elicits antitumor activity through MMAE-mediated direct cytotoxicity, CD30+ regulatory T-cell depletion, bystander effect, and immunogenic cell death, providing rationale to clinically develop SGN-35T. SGN35T-001 (NCT06120504) is a first-in-human, open-label, global, multicenter, dose-escalation and dose-expansion study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SGN-35T in pts with R/R CD30-expressing lymphoid malignancies. Pts will be enrolled into dose-escalation (Part A), optional dose-optimization (Part B), dose-expansion (Part C), and optional biology cohorts. Pts in Part A will receive SGN-35T intravenously at various doses. Part B dosing may evaluate doses from Part A; Part C and biology cohort dosing will occur at the recommended dose from Parts A/B. For Parts A/B, pts must have histologically confirmed R/R lymphoid malignancy with no standard therapy available. CD30 expression must be ≥1% in tumor tissue from the most recent biopsy or obtained at or after relapse, as determined by local pathology except in diagnoses where CD30 is universally expressed. For Part C, pts are eligible irrespective of CD30 expression and must provide tumor tissue for evaluation; the number of prior therapies permitted is dependent on histologic subtype. Enrolled pts must be ≥18 years of age, have measurable disease, and ECOG PS ≤1. Primary endpoints include incidence and severity of adverse events and laboratory abnormalities, frequency of dose modifications, and incidence of dose-limiting toxicities. Secondary endpoints include PK parameters, objective response rate, duration of response, and complete response rate. Enrollment is ongoing in the US and planned globally.
Tatyana Feldman, Radhakrishnan Ramchandren, Hun Ju Lee, Gizelle Popradi, Graham P. Collins, Daniel Morillo, Mingjin Yan, Tara L. Chen, Youn H. Kim