This is a First-in-Human Phase I/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.
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 two 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
2. The Part B study is a seamless Phase I/II trial of ONC-392 in combination with a
standard dose of 200 mg pembrolizumab in patients with NSCLC. The trial consists of a
dose-finding, dose de-escalation, Phase I component aiming at defining the recommended
phase II dose for ONC-392 in combination with a standard dose of pembrolizumab (RP2D-C),
then progressing into two parallel, single arm, single stage Phase II trials to test for
efficacy in two cohorts of patients with NSCLC:
1. Stage IV NSCLC anti-PD(L)-1 immunotherapy naïve;
2. Stage IV NSCLC anti-PD(L)-1 refractory or resistant to immunotherapy. In the Par B
Phase I component both immunotherapy naïve and refractory/resistant disease will be
1. . Patients must have a histological or cytological diagnosis of NSCLC or any other
type of carcinoma or sarcomas, progressive metastatic disease, or progressive locally
advanced disease not amenable to local therapy.
1. In the Part A Phase I dose escalation study of ONC-392 monotherapy (trial A),
patients with advanced/metastatic solid tumors of any histology are eligible for
Please note: tumor types of primary interest in this study are malignant
melanoma, renal cell carcinoma, hepatocellular carcinoma, non-small cell lung
cancer, head and neck carcinoma, gastric carcinoma, ovarian carcinoma, colorectal
cancer, any type of sarcoma.
2. In Part B Phase I dose de-escalation of the ONC-392 plus pembrolizumab
combination and in the Phase II expansion cohorts (trial B), only patients with a
histological diagnosis of advanced/metastatic NSCLC are eligible for
3. Two Phase II expansion cohorts are planned:
i. Immunotherapy naïve NSCLC patients ii. Refractory and resistant NSCLC patients d.
Measurable disease: i. In Phase I dose-finding studies (trial A and B), patients may
have non-measurable disease.
ii. In Phase II expansion cohorts, patients must have measurable disease as defined
per RECIST version 1.1: iii. Tumor mass: Must be accurately measurable in at least 1
dimension (longest diameter to be recorded) with a minimum size of:
1. 10 mm by computed tomography (CT) scan (CT scan slide thickness must be <5 mm),
2. 20 mm by chest X-ray (if clearly defined and surrounded by aerated lung). iv.
Malignant lymph nodes: >15 mm in short axis when assessed by CT scan (CT scan
slice thickness must be <5 mm).
2. Patient is male or female and >18 years of age on day of signing informed consent.
3. Patient must have a performance status of ≤ 2 on the ECOG Performance Scale
4. Patient must have adequate organ function as indicated by the following laboratory
Hematological: Absolute neutrophil count (ANC) ≥1,500 /mcL; Plateletsa ≥100,000 / mcL;
Hemoglobin ≥9 g/dL or ≥5.6 mmol/L- without qualifications; Renal: Serum creatinine
≤1.5 X upper limit of normal (ULN); Hepatic: Serum total bilirubin ≤1.5 X ULN; OR
Direct bilirubin ≤ ULN for patients with total bilirubin levels >1.5 ULN; AST (SGOT)
and ALT (SGPT) ≤2.5 X ULN, OR ≤5 X ULN for patients with active liver metastases
Coagulation: International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 X ULN
Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN
5. Patient has voluntarily agreed to participate by giving written informed consent.
6. Female patient of childbearing potential has a negative urine or serum pregnancy test.
If the urine test is positive or cannot be confirmed as negative, a serum pregnancy
test will be required. The serum pregnancy test must be negative for the patient to be
7. Female patients enrolled in the study, who are not free from menses for >2 years, post
hysterectomy / oophorectomy, or surgically sterilized, must be willing to use 2
adequate barrier methods of contraception to prevent pregnancy or to abstain from
heterosexual activity throughout the study, starting with Visit 1 through 30 days
after the last dose of study therapy. Approved contraceptive methods include for
example; intra uterine device, diaphragm with spermicide, cervical cap with
spermicide, male condoms, or female condom with spermicide. Spermicides alone are not
an acceptable method of contraception.
8. Male patients must agree to use an adequate method of contraception starting with the
first dose of study drug through 90 days after the last dose of study therapy.
A patient meeting any of the following criteria is not eligible to participate in this
1. Patient who has had chemotherapy, radioactive, or biological cancer therapy within 4
weeks prior to the first dose of study therapy, or who has not recovered to CTCAE
grade 1 or better from the adverse events due to cancer therapeutics administered more
than 4 weeks earlier.
2. Patient is currently participating or has participated in a study of an
investigational agent or using an investigational device within 30 days of
administration of ONC-392.
3. Patient is expected to require any other form of antineoplastic therapy while on
study. Exempted are patients with prostate cancer who are on luteinizing
hormone-releasing hormone (LHRH) agonists and continue on the same dose and type of
4. Patient is on chronic systemic steroid therapy at doses >10 mg/day, or on any other
form of immunosuppressive medication.
5. Patient is on chronic anti-coagulation treatment with warfarin (Low molecular weight
heparin or low dose aspirin are permitted).
6. Patient has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Patients with previously treated brain metastases may participate provided
they are clinically stable for at least 1 month prior to study entry, defined as: (1)
no evidence of new or enlarging brain metastases and (2) off steroids, or on a stable
dose of steroids for at least 1 month.
7. Patient had previously a severe hypersensitivity reaction to another mAb.
8. Patient has any active autoimmune disease or a documented history of autoimmune
disease, except vitiligo or resolved childhood asthma/atopy.
9. Patient had prior therapy with anti-CTLA-4 antibody.
10. Patient has an active infection requiring therapy. Patient has systemic antibiotics
treatment 30 days prior to enrollment will not be allowed.
11. Patient is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B or
Hepatitis C virus.
12. Patient has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the patient's
participation for the full duration of the study, or is not in the best interest of
the patient to participate, in the opinion of the treating Investigator.
13. Patient has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
14. Patient is, at the time of signing informed consent, a regular user of any illicit
drugs or had a recent history (within the last year) of substance abuse (including
15. Patients with symptomatic ascites or pleural effusion. A patient who is clinically
stable following treatment for these conditions (including therapeutic thoraco- or
paracentesis) is eligible.
16. Patient is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study.