Open-Label Phase 1 Study to Evaluate the Safety of SGN-35T in Patients with Relapsed/Refractory CD30-Expressing Lymphoid Malignancies (SGN35T-001; trial in progress)

Background & Significance: Patients with relapsed/refractory (R/R) lymphomas have limited treatment options and poor mortality rates versus patients 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 classic Hodgkin lymphoma and peripheral T-cell lymphomas. 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 four. 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 phase 1 study to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and antitumor activity of SGN-35T in patients with R/R CD30-expressing lymphoid malignancies. Methods: Patients will be enrolled into dose-escalation (Part A), optional dose-optimization (Part B), dose-expansion (Part C), and optional biology cohorts. Patients 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. The biology cohort may enroll patients from Parts A, B and C, who consent to protocol-specified research biopsies. For Parts A/B, patients must have histologically confirmed R/R lymphoid malignancy according to 2016 World Health Organization (WHO) classification 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 pathologist except in diagnoses where CD30 is universally expressed. Eligible lymphoma subtypes include classical Hodgkin lymphoma, peripheral T cell lymphoma, mature B cell lymphoma, and primary cutaneous lymphoma. For Part C, patients 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 patients must be ≥18 years of age, have measurable disease per Lugano (as applicable), and ECOG PS ≤1. Key exclusion criteria include prior exposure to CD30 targeted therapy, history of another malignancy within 3 years of first dose, active cerebral/meningeal disease, autologous stem cell transplant (SCT) within 12 weeks of first dose, allogenic SCT in <100 days, active acute or chronic graft vs host disease and having received immunosuppressive therapy for graft vs host disease, significant cytomegalovirus infection, grade ≥2 pulmonary or interstitial lung disease, or clinically significant lung disease requiring treatment with systemic corticosteroids 6 months prior to enrollment. 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 Spain but planned globally.

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