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


Active: Yes
Cancer Type: Breast Cancer
Colon/Rectal Cancer
Head and Neck Cancer
Liver Cancer / Hepatoblastoma
Lung Cancer
Melanoma
Ovarian Cancer
Pancreatic Cancer
Sarcoma
Stomach/ Gastric Cancer
NCT ID: NCT04140526
Trial Phases: Phase I
Phase II
Protocol IDs: ONC-392-001 (primary)
R44CA250824-01
NCI-2020-06149
20193108
4R44CA250824-02
Eligibility: 18 Years and older, Male and Female Study Type: Treatment
Study Sponsor: OncoC4, Inc.
NCI Full Details: http://clinicaltrials.gov/show/NCT04140526

Summary

This is a First-in-Human Phase IA/IB/II open label dose escalation study of intravenous (IV)
administration of ONC-392, a humanized anti-CTLA4 IgG1 monoclonal antibody, as single agent
and in combination with pembrolizumab in participants with advanced or metastatic solid
tumors and non-small cell lung cancers.

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 and with disease progression with ONC-392
monotherapy from Arm C or Arm I.

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 and
progressed with ONC-392 monotherapy from Arm J.

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 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.

10. 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.

11. 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.

(4) Part D is a Phase II study in recurrent and/or metastatic adenoid cystic carcinoma with
ONC-392 monotherapy.
**Clinical trials are research studies that involve people. These studies test new ways to prevent, detect, diagnose, or treat diseases. People who take part in cancer clinical trials have an opportunity to contribute to scientists’ knowledge about cancer and to help in the development of improved cancer treatments. They also receive state-of-the-art care from cancer experts... Click here to learn more about clinical trials.