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.

The field of immunotherapy in cHL is now moving toward combinations of PD-1 inhibitors with other immunological agents such as cytotoxic T- lymphocyte associated protein-4 (CTLA-4) inhibitors, newer PD-1 inhibitors such as sintilimab, tislelizumab, avelumab and camrelizumab, bispecific antibodies such as AFM-13, cellular therapies using CD30 chimeric antigen T-cells (CD30.CART) and anti-CD25 antibody-drug conjugates such as camidanlumab tesirine (cami-T). Here we review early phase studies evaluating these approaches in the treatment of cHL.

There are limited treatment options for relapsed/refractory classical Hodgkin lymphoma (cHL) patients who progress on brentuximab vedotin and programmed death-1 inhibitors. The toxicity profile was similar to that seen in the phase 1 study, with no new safety signals.. As the phase 2 study with Cami is continuing to accrue patients and we await the final results, the preliminary results with Cami are encouraging and provide an additional therapeutic option especially for patients with multiply relapsed/refractory cHL and perhaps other hematological malignancies expression CD25.

The trial was terminated during dose escalation due to programmatic reasons other than safety. Hence, recommended dose was not determined.

While Treg modulation was seen with all populations, these data support further study, particularly of the Cami 45 µg/kg dose for pts with HL. Given that CD25 is the cognate target of Cami, these data suggest pts with HL achieving CR have higher drug exposure, resulting from lower baseline sCD25, and potential association with lower tumor burden. Although exposure at the 45 µg/kg dose showed moderate inter-patient variability, it was associated with noteworthy, cycle-related modulation in circulating Treg and clear increases in Teff:Treg ratios, thought to favor clinical response.

Synergistic anti-tumor activity was also demonstrated in a colorectal cancer model using CD25-ADC, a mouse-cross-reactive version of camidanlumab tesirine, in combination with gemcitabine. Altogether, these novel pre-clinical data warrant translation of the combination between camidanlumab tesirine and gemcitabine into the clinic.

This study shows that a PBD dimer-based, CD25-targeted ADC is able to deplete T and eradicate established tumors via antitumor immunity. This represents a novel approach to efficiently deplete T via a very potent DNA damaging toxin known to induce immunogenic cell death. Moreover, this study provides proof of concept for a completely new application of ADCs as immunotherapeutic agents, as the main mode of action relies on the ADC directly targeting immune cells, rather than tumor cells. These strong preclinical data warrant the clinical evaluation of camidanlumab tesirine (ADCT-301), a PBD-based ADC targeting human CD25, either alone or in combination with checkpoint inhibitors in solid tumors with known T infiltration. A phase I trial (NCT03621982) of camidanlumab tesirine in patients with selected advanced solid tumors is ongoing.

Funding: ADC Therapeutics SA. Clinical trial identification: NCT03621982.

These include ADCT-301 (camidanlumab tesirine) and ADCT-402 (loncastuximab tesirine) in pivotal Phase 2 trials that contain the payload tesirine which releases the PBD dimer warhead SG3199...The level of resistance achieved was ~3000-fold for ADCT-301 and 3-fold for SG3199 in Karpas-299, and 8-fold for ADCT-502 and 4-fold for SG3199 in NCI-N87...These data show that acquired resistance to PBD-ADCs and SG3199 can involve specific ATP-binding cassette (ABC) drug transporters. This has clinical implications as potential biomarkers of resistance and for the rational design of drug combinations.

In patient-derived xenograft models of drug-resistant B-cell malignancies, treatment with a CD25-specific antibody drug-conjugate (ADCT-301) extended survival of transplant recipients or eradicated disease. These findings identified CD25 as previously unrecognized feedback regulator of oncogenic BCR-signaling and provide a rationale for therapeutic targeting of CD25 in refractory B-cell malignancies.

P1b, N=50, Not yet recruiting, ADC Therapeutics S.A.

22 pts with HL have been treated with doses ≥30 µg/kg, with an ORR of 63.6% (14/22) and a complete response rate of 27.3% (6/22); ORRs by prior treatment were: 13/21 (61.9%) pts who previously received brentuximab vedotin (BV), 10/16 (62.5%) pts who previously received a checkpoint inhibitor and BV and 5/11 (45.5%) pts who had prior stem cell transplant. In pts with R/R HL, active doses of Cami-T with acceptable safety profiles have been preliminarily identified during dose escalation and expansion of this study. The ORR in this heavily pretreated population is very promising and HL expansion cohorts are underway to better define the efficacy and safety of Cami-T. Dose escalation will continue to identify the MTD in NHL, with planned subtype-specific expansion cohorts at the MTD.