Background CTLA-4 is the first immune checkpoint target for cancer immunotherapy. However, the clinical benefit of targeting CTLA-4 has been limited by suboptimal doses and early discontinuation due to immunotherapy-related adverse events (irAE). Our preclinical studies suggest that acid pH-sensitive anti-CTLA-4 antibodies that preserve CTLA-4 recycling and avoid lysosomal degradation are more effective for immunotherapy but largely devoid of immunotherapy-related adverse events (irAE) [1-6]. To test this new hypothesis in human, we initiated first-in-human study evaluating the safety and tolerability of ONC-392 in patients with advanced solid tumors.

Methods ONC-392-001 Part A is a dose finding study of ONC 392, IV infusion, Q3W. Patients (pt) with advanced solid tumors who had progressed to standard of care cancer therapies with ≥1 measurable tumor were enrolled. Intra-patient dose-escalation were performed for 4 doses (0.1, 0.3, 1.0 and 3.0 mg/kg) and 6 pts for the final dose of 10.0 mg/kg. The primary endpoints are the safety and tolerability of ONC-392 for identifying recommended Phase II dose (RP2D).

Results Ten pts have received 2-11 cycles of ONC-392 treatment at dose levels ranging from 0.1 to 10 mg/kg. Pt characteristics: median age 62 (range 43-81), female/male: 7/3, White/Asian/Black: 6/3/1. Tumor types: 4 ovarian, 4 NSCLC, 1 cervical and 1 GE junction cancer. Prior line of treatment: 2-7. Six pts were in 10 mg/kg dose level and received 2-4 doses of the drug as of this writing. None of the 10 pts experienced dose limiting toxicity (DLT) or Gr 3-4 adverse events (AEs) in DLT period. The RP2D for ONC-392 monotherapy is 10 mg/kg. After the DLT period, 1 patient developed Gr 3-4 elevated amylase/lipase at 10 weeks after 4 cycle of 10 mg/kg. No other treatment-related severe AE was observed. Among eight evaluable pts, 7/8 (87.5%) had stable disease (SD) after three cycle of treatment, and beneficial clinical efficacy activities was observed in 3/8 (37.5%) pts. Among them, a stage 4B ovarian cancer patient had stayed in treatment for 30 weeks till disease progression, and 2/2 evaluable PD(L)-1 antibody-refractory NSCLC patients were either eligible for surgery or had significant tumor shrinkage.

Conclusions ONC-392 monotherapy is well tolerated with very low irAE rate. The RP2D for ONC-392 monotherapy is 10 mg/kg. The acid pH-sensitive anti-CTLA-4 mAb that preserves CTLA-4 recycling and avoids lysosomal degradation was safe and well tolerated. Our work paves the way for significant increase of drug exposure to reach full immunotherapeutic potential of CTLA-4 targeting.

Acknowledgements The study is sponsored by OncoC4, Inc with the support of NCI SBIR grant R44CA250824.

Trial Registration NCT04140526

References

1. Du X, et al. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res 2018;28(4):433–447.

2. Du X, et al. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res 2018;28(4):416–432.

3. Liu Y, Zheng P. How does an anti-CTLA-4 antibody promote cancer immunity? Trends Immunol 2018;39(12):953–956.

4. Zhang Y, et al. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Research 2019;29(8):609–627.

5. Liu Y, Zheng P. Preserving the CTLA-4 checkpoint for safer and more effective cancer immunotherapy. Trends Pharmacol Sci 2020;41(1):4–12.

6. Zhang P, et al. Mechanism- and immune landscape-based ranking of therapeutic responsiveness of 22 major human cancers to next generation anti-CTLA-4 antibodies. Cancers (Basel), 2020;12(2):284.

Ethics Approval This study obtained ethic approval from WIRB with Study #20193108. All participants gave informed consent before taking part of the study.

Consent N/A.