Safety, PK and Efficacy of ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC

Summary

Objectives

Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), also known as CD152 (cluster of
differentiation 152), is a cell surface protein receptor that interacts with B7-1 (CD80)
and B7-2 (CD86) to ensure proper function of regulatory T cells and protect host against
autoinflammatory diseases. Anti-CTLA-4 monoclonal antibodies (mAbs) have demonstrated
strong and broad cancer immunotherapeutic effects (CITE) in a variety of preclinical
models and are used clinically both as monotherapy and as part of combination therapy
with Nivolumab (anti-PD-1). However, CTLA-4 monotherapy has more immunotherapy-related
adverse effects (irAEs) than anti-PD-1/PD-L1 therapy. In addition, the rate of severe
irAE (Grades 3 and 4) reached 55% in melanoma patients receiving combination of
Ipilimumab and Nivolumab. The strong irAEs further limit the doses tolerated by cancer
patients. Nevertheless, combination with anti-PD-1 resulted in significantly improved
response rates and patient survival in multiple types of cancer. Furthermore, anti-CTLA-4
antibodies induce long-lasting immunity in cancer patients. Therefore, CTLA-4 remains an
important immunotherapy target, but major challenges remain in improving both safety and
efficacy of anti-CTLA-4 mAbs.

ONC-392 is a highly selective, humanized monoclonal IgG1-kappa isotype antibody against
CTLA-4. The parental clone was identified through in vivo screening in humanized CTLA-4
mouse model for high anti-tumor efficacy and low autoimmune toxicity. We have recently
demonstrated that ONC-392 is dissociation from CTLA-4 under low pH to allow its escape
from lysosomal degradation and recycle to cell surface. We have provided several lines of
evidence for the notion that a pH-sensitive antibody ONC-392 is not only safer but also
more effective in Treg depletion and tumor rejection than the Ipilimumab, which is
pH-insensitive. First, by preserving CTLA-4 on the cell surface, Onc-392 leaves higher
ligand density for better ADCC.

Second, Onc-392 is more efficient in Treg depletion in tumor microenvironment. Third,
Onc-392 is significantly more potent in inducing rejection of large tumors.

The study consists of four parts:

(1) The Part A study is a dose-finding rapid titration, Phase I trial of ONC-392 as a
single agent in patients with advanced or metastatic solid tumors with various histology.
The aim of this trial is to define the recommended Phase II dose for ONC-392 monotherapy
(RP2D-M). (2) The Part B study is a dose-finding phase with ONC-392 in combination with a
standard dose of 200 mg pembrolizumab in patients with advanced or metastatic solid
tumors.

(3) The Part C consists of different expansion arms.

1. Arm A: Pancreatic Cancer Cohort, ONC-392 monotherapy, will enroll
advanced/metastatic pancreatic cancer patients who have progressive disease after
first and second lines of systemic treatment.

2. Arm B: TNBC Cohort, ONC-392 monotherapy, will enroll advanced/metastatic TNBC
patients who have progressive disease after prior systemic treatments, including
checkpoint inhibitor immunotherapy.

3. Arm C: NSCLC Mono Cohort 1, ONC-392 monotherapy, will enroll advanced/metastatic
NSCLC patients with EGFR or ALK mutations who have progressive disease after prior
systemic treatments, including targeted therapy or checkpoint inhibitors.

4. Arm D: NSCLC IO Naïve Cohort, ONC-392/Pembrolizumab combination therapy, will enroll
advanced/metastatic NSCLC cancer patients who are treatment naïve, or anti PD (L)1
immunotherapy naïve and PD-L1-positive (PD L1 TPS = 1%).

5. Arm E: NSCLC IO R/R Cohort, ONC-392/Pembrolizumab combination therapy, will enroll
advanced/metastatic NSCLC cancer patients who are R/R to prior anti-PD-(L)1
immunotherapy regardless of PD-L1 status.

6. Arm F: Melanoma IO Naïve Cohort, ONC-392/Pembrolizumab combination therapy, will
enroll advanced/metastatic Melanoma patients who are treatment naïve, or checkpoint
inhibitor immunotherapy naive. Prior systemic chemotherapy or targeted therapy are
allowed.

7. Arm G: Melanoma IO R/R Cohort, ONC-392/Pembrolizumab combination therapy, will
enroll advanced/metastatic melanoma patients who are R/R to anti-PD-(L)1
immunotherapy.

8. Arm I: NSCLC Mono Cohort 2, ONC-392 monotherapy, will enroll advanced/metastatic
NSCLC patients without EGFR or ALK mutations who have progressive disease after
prior systemic treatments, including chemotherapy or checkpoint inhibitors. Patient
must have anti-PD-(L)1 treatment, either alone or in combination, as last treatment
before enrollment. Prior anti-CTLA-4 treatment is allowed.

9. Arm J: Melanoma Mono Cohort, ONC-392 monotherapy, will enroll advanced/metastatic
melanoma patients who are R/R to anti-PD-(L)1 immunotherapy.

10. Arm K: Head and Neck Squamous Cell Carcinoma (HNSCC), ONC-392 monotherapy, will
enroll advanced/metastatic HNSCC patients with or without positive HPV who have
progressive disease after prior systemic treatments, including chemotherapy or
checkpoint inhibitors. Patient must have anti-PD-(L)1 treatment, either alone or in
combination, as last treatment before enrollment.

11. Arm L: Ovarian Cancer, ONC-392 monotherapy, will enroll patients with
advanced/metastatic ovarian cancer who have progressive disease after prior systemic
treatments, including chemotherapy, targeted therapy or checkpoint inhibitors.

12. Arm M: Solid Tumors, ONC-392 monotherapy, will enroll patients with
advanced/metastatic solid tumors who are not eligible for Arm A-C or H-L, who have
progressive disease after prior systemic treatments, including chemotherapy,
targeted therapy or checkpoint inhibitors.

13. Arm N: Renal Cell Carcinoma, ONC-392 monotherapy, will enroll advanced/metastatic
RCC patients who are R/R to anti-PD-(L)1 immunotherapy.

(4) Part D is a Phase II study in recurrent and/or metastatic adenoid cystic carcinoma
with ONC-392 monotherapy.

(5) Part E Arm O will test ONC-392 in combination with docetaxel in PD-1 resistant NSCLC.