camidanlumab tesirine (ADCT-301)

When camidanlumab tesirine-containing combinations were evaluated in four T-cell lymphoma models, the most active partners were everolimus, copanlisib, venetoclax, vorinostat, and pralatrexate, followed by bortezomib, romidepsin, bendamustine, and 5-azacytidine. The strong camidanlumab tesirine single-agent anti-lymphoma activity and the in vitro synergisms with targeted agents identify potential combination partners for future clinical studies.

P1, N=78, Terminated, ADC Therapeutics S.A. | Phase classification: P1b --> P1

Targeted therapies, including the antibody drug conjugate, camidanlumab tesirine, and transcriptional agents such mammalian target of rapamycin and histone deacetylase inhibitors have shown some potential in patients with refractory disease. Clinical trials with cellular therapies, including chimeric antigen receptor T cells targeting CD30 and allogeneic natural killer cells combined with AFM13, a CD30/CD16a-bispecific antibody, have shown promising results. The availability of more therapeutic options for this patient population is eagerly awaited.

P2, N=3, Terminated, Gwynn Long, M.D. | N=10 --> 3 | Trial completion date: Dec 2024 --> Nov 2022 | Recruiting --> Terminated | Trial primary completion date: Dec 2024 --> Nov 2022; ADCT is reallocating all resources to the phase III program.

Clinical studies on novel agents, including brentuximab vedotin (BV) and PD-1 inhibitors, have successfully demonstrated their effectiveness in relapsed disease after ASCT. Additionally, studies examining combination strategies with the goal of reducing the risk of relapse and chemotherapy-related toxicity have showed encouraging results, mainly in untreated early unfavorable or advanced stage classical HL (cHL). Other non-approved immunotherapies such as camidanlumab tesirine, bispecific CD30/CD16A antibody, and CD30 chimeric antigen receptor (CAR) T-cell therapy are promising approaches that may reinforce the therapeutic arsenal available to patients.

P1b, N=78, Terminated, ADC Therapeutics S.A. | Trial completion date: Nov 2023 --> Nov 2022 | Recruiting --> Terminated; Cami in combination with pembrolizumab in solid tumors showed signals of immunomodulatory activity. However, the signals were insufficiently compelling at the tested dose/schedule to justify continuation of the study.

The pivotal phase 2 trial showed significant antitumor activity of camidanlumab tesirine in heavily pretreated R/R cHL patients who failed brentuximab vedotin and programmed death-1 blockade: ORR was 70.1% and CRR was 33.3%, and the median duration of response was 13.7 months. Adverse events such as fatigue, maculopapular rash, and anemia were frequently observed following administration of camidanlumab tesirine. Moreover, camidanlumab tesirine may cause Guillain-Barré syndrome or polyradiculopathy.

The final model described the observed data well, estimates of PK parameters were obtained, and covariates with significant effects on Cami exposure were identified. Altogether, this final PPK model provides a robust basis for analysis of Cami exposure-response relationships and further supports identification of the optimal Cami dosing schedule for patients with relapsed/refractory lymphoma.

Higher median tumor cell CD25 H-score was seen in responders vs nonresponders in all and recent biopsies but the differences did not reach significance. These data warrant further investigations as phase 1 data showed significantly higher tumor CD25 expression in responders (Hamadani, et al. 2021).

PK exposure of Cami was dose-related with varying degrees of interpatient variability. Circulating Tregs were significantly decreased and Teff:Treg was significantly increased by Cami exposure, demonstrating the intended immunomodulatory effect of Cami in circulation and suggesting that a combination approach with Cami could address an immune-resistance mechanism. Future analyses will consider discrete PEM effect, correlates to tumor biopsy expression and response, and combined Cami+PEM effect in tumor biopsies.

In the past decade, novel therapies including, brentuximab vedotin, PD-1 inhibitors, and the incorporation of PET-imaging into management have changed the paradigm of relapsed/refractory disease care. There is promising early work into the utility of CD30.CAR-T cell therapy, AFM13, camidanlumab tesirine, novel PD-1 inhibitors, and JAK1/JAK2 inhibition in management. Herein, we will review current salvage therapies in Hodgkin lymphoma and future directions in relapsed/refractory disease management.