Summary

Eligibility
for people ages 18 years and up (full criteria)
Location
at Davis, California and other locations
Dates
study started
estimated completion
Principal Investigator
by Tianhong Li, MD

Description

Summary

This is a First-in-Human Phase IA/IB 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.

Official Title

Safety, Pharmacokinetics (PK), and Efficacy of ONC-392 as a Single Agent and in Combination With Pembrolizumab in Advanced Solid Tumors and NSCLC: An Open Label Phase IA/IB Study. Preserve CTLA4 Checkpoint Function (PRESERVE-001)

Details

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 three 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 in combination therapies. Part B1 is ONC-392 in combination with a standard dose of 200 mg pembrolizumab in patients with advanced or metastatic solid tumors. Part B2 is ONC-392 in combination with a standard dose of oral TKI Osimertinib in patients with non small cell lung cancer with EGFR mutations. (3) The Part C consists of 8 different expansion arms. Arms A, B, and C monotherapy expansion cohorts can be initiated after the RP2D-M is determined. Arms D through H expansion cohorts can be initiated after the RP2D-C is determined. 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, 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 Mel 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 Mel 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 or other forms of combination immunotherapy. Prior treatment with Ipilimumab is allowed. Patients who have melanoma recurrence under adjuvant immunotherapy are considered to be immunotherapy refractory. 8. Arm H MCC IO R/R Cohort, ONC-392/Pembrolizumab combination therapy will enroll advanced/metastatic MCC patients who are R/R to prior immunotherapy or experience cancer recurrence within 1 year of IO adjuvant treatment.

Keywords

Non Small Cell Lung Cancer Advanced Solid Tumor Metastatic Melanoma Metastatic Head and Neck Carcinoma Metastatic Renal Cell Carcinoma Metastatic Colorectal Cancer Sarcomas Metastatic Prostate Cancer Ovarian Cancer Small Cell Lung Cancer Metastatic Breast Cancer Merkel Cell Carcinoma Pancreas Cancer Gastric Cancer Esophageal Cancer Gastroesophageal Junction Adenocarcinoma Cervical Cancer Carcinoma, Merkel Cell Carcinoma Lung Neoplasms Small Cell Lung Carcinoma Pancreatic Neoplasms Pembrolizumab Osimertinib ONC-392

Eligibility

You can join if…

Open to people ages 18 years and up

  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.
  2. In the Part A Phase I dose escalation study of ONC-392 monotherapy, patients with advanced/metastatic solid tumors of any histology are eligible for participation.

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.

  1. In Part B1 dose finding of the ONC-392 plus pembrolizumab combination, patients with advanced/metastatic solid tumors of any histology that Pembrolizumab has been approval as standard of care are eligible for participation. Part B2 is for patients with non small cell lung cancer with EGFR mutations.
  2. In Part C, patients with pancreatic cancer, triple negative breast cancer, non small cell lung cancer, melanoma and Merkel cell carcinoma are eligible.
  3. Measurable disease:
  4. In Phase IA dose-finding studies (trial A and B), patients may have non-measurable disease.

ii. In Phase IB 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).

  1. Patient is male or female and >18 years of age on day of signing informed consent.
  2. Patient must have a performance status of ≤ 2 on the ECOG Performance Scale
  3. Patient must have adequate organ function as indicated by the following laboratory values:

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

  1. Patient has voluntarily agreed to participate by giving written informed consent.
  2. 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 eligible.
  3. 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.
  4. 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.

You CAN'T join if...

A patient meeting any of the following criteria is not eligible to participate in this study:

  1. Patients who have not recovered to CTCAE ≤ 1 from the AE due to cancer therapeutics. The washout period for cancer therapeutic drugs (such as chemotherapy, radioactive, or targeted therapy) is 21 days, and for antibody drug 28 days.
  2. Patients who are currently enrolled in a clinical trial of an investigational agent or device.
  3. Patients who are on chronic systemic steroid therapy at doses >10 mg/day
  4. Patients who previously had a severe hypersensitivity reaction to another mAb.
  5. Patients who have an active infection requiring systemic IV therapy within 14 days of prior to administration of ONC-392 or combined ONC-392 and Pembrolizumab.
  6. Patients who have 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.
  7. Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
  8. Patients who are pregnant or breastfeeding.
  9. For the Part B1 and Part C Arm D to H, the patients that are deemed to be not suitable for Pembrolizumab.

Locations

  • University of California at Davis accepting new patients
    Davis California 95817 United States
  • University of Utah Huntsman Cancer Institute accepting new patients
    Salt Lake City Utah 84112 United States

Lead Scientist at UC Davis

  • Tianhong Li, MD
    Associate Professor, Hematology and Oncology. Authored (or co-authored) 65 research publications.

Details

Status
accepting new patients
Start Date
Completion Date
(estimated)
Sponsor
OncoC4, Inc.
Links
Sign up for this study
ID
NCT04140526
Phase
Phase 1
Study Type
Interventional
Last Updated