Safety, PK and Efficacy of ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC
Head and Neck Cancer
Liver Cancer / Hepatoblastoma
Stomach/ Gastric Cancer
18 Years and older, Male and Female
|NCI Full Details:
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
2. Arm B: TNBC Cohort, ONC-392 monotherapy, will enroll advanced/metastatic TNBC patients
who have progressive disease after prior systemic treatments, including checkpoint
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
(4) Part D is a Phase II study in recurrent and/or metastatic adenoid cystic carcinoma with
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