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Brief Title: ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC

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)

INTRODUCTION

  • Org Study ID: ONC-392-001
  • Secondary ID: 4R44CA250824-02, 20193108
  • NTC ID: NCT04140526
  • Sponsor: OncoC4, Inc.

BRIEF 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.

DETAILED DESCRIPTION

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.

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.
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.
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.
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%).
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.
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.
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.
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.
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.
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.
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.

  • Overall Status
    Recruiting
  • Start Date
    September 16, 2020
  • Phase
    Phase 1, Phase 2
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Dose limiting toxicity (DLT) in monotherapy

Primary Outcome 1 - Timeframe: 21 days

Primary Outcome 2 - Measure: Maximal tolerable dose (MTD) in monotherapy

Primary Outcome 2 - Timeframe: 21 days

Primary Outcome 3 - Measure: Recommended Phase II Dose (RP2D)

Primary Outcome 3 - Timeframe: 21 days

Primary Outcome 4 - Measure: Rate of treatment related adverse events (TRAE) according to CTCAE v5.0

Primary Outcome 4 - Timeframe: One year

CONDITION

  • 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
  • Pancreas Cancer
  • Gastric Cancer
  • Esophageal Cancer
  • Gastroesophageal Junction Adenocarcinoma
  • Cervical Cancer
  • Adenoid Cystic Carcinoma
  • Salivary Gland Cancer
  • Urothelial Carcinoma

ELIGIBILITY

Inclusion Criteria:
. 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.
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.
In Part B 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.

- In Part C, patients with pancreatic cancer, triple negative breast cancer, non small cell lung cancer, melanoma, Head and Neck cancer, ovarian cancer, and other solid tumors are eligible.

- In Part D, patients with recurrent and/or metastatic adenoid cystic carcinoma with disease progression within 12 months are eligible.

- Patients must have RECIST V1.1 Measurable disease:

- Patient is male or female and >18 years of age on day of signing informed consent.

- Patient must have a performance status of 0 or 1 on the ECOG Performance Scale
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
Patient has voluntarily agreed to participate by giving written informed consent.

- Female patient of childbearing potential has a negative urine or serum pregnancy test.

- Female and Male patients must agree to use adequate methods of contraception starting with the first dose of study drug through 90 days after the last dose of study therapy.
Exclusion Criteria:
A patient meeting any of the following criteria is not eligible to participate in this study:
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.

- Patients who are currently enrolled in a clinical trial of an investigational agent or device.

- Patients who are on chronic systemic steroid therapy at doses >10 mg/day

- Patients who have active symptomatic brain metastasis or leptomeningeal metastasis.

- 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.

- 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.

- Patients with known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.

- Patients who are pregnant or breastfeeding.

- For the Part B and Part C Arm D to G, the patients that are deemed to be not suitable for Pembrolizumab.

Gender: All

Minimum Age: 18 Years

Maximum Age: N/A

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Tianhong Li, MD

Role: Principal Investigator

Affiliation: University of California, Davis

Overall Contact

Name: Tianhong Li, MD

Phone: 202 751 6823, 4102070582

Email: pzheng@oncoc4.com, mdevenport@oncoc4.com

LOCATION

Facility Status Contact
Facility: University of California at Davis
Davis, California 95817
United States
Status: Recruiting Contact: Principal Investigator
Tianhong Li, MD, PhD

Facility: The Oncology Institute of Hope and Innovation
Downey, California 90241
United States
Status: Recruiting Contact: Principal Investigator
Richy Agajanian, MD

Facility: City of Hope Cancer Center
Duarte, California 91010
United States
Status: Recruiting Contact: Principal Investigator
Lorna Rodriguez, MD

Facility: University of Colorado Hospital
Aurora, Colorado 80045
United States
Status: Recruiting Contact: Principal Investigator
Karl Lewis, MD

Facility: Nuvance Health
Norwalk, Connecticut 06856
United States
Status: Recruiting Contact: Principal Investigator
Richard Frank, MD

Facility: Florida Cancer Specialists
Atlantis, Florida 33462
United States
Status: Recruiting Contact: Principal Investigator
Shaachi Gupta, MD

Facility: University of Florida Health Cancer Center
Gainesville, Florida 32610
United States
Status: Recruiting Contact: Principal Investigator
Thomas George, MD

Facility: Ocala Oncology Florida Cancer Affiliates
Ocala, Florida 34474
United States
Status: Recruiting Contact: Principal Investigator
Rama Balaraman, MD

Facility: AdventHealth Cancer Institute
Orlando, Florida 32804
United States
Status: Recruiting Contact: Principal Investigator
George Simon, MD

Facility: Memorial Cancer Institute
Pembroke Pines, Florida 33028
United States
Status: Recruiting Contact: Principal Investigator
Mark Socinski, MD

Facility: Norton Health
Lexington, Kentucky 40202
United States
Status: Recruiting Contact: Principal Investigator
Nicole C Schmitt, MD

Facility: Greater Baltimore Medical Center
Baltimore, Maryland 21204
United States
Status: Recruiting Contact: Principal Investigator
Nabil F Saba, MD

Facility: The Center for Cancer and Blood Disorders
Bethesda, Maryland 20817
United States
Status: Recruiting Contact: Principal Investigator
John Hamm, MD

Facility: Massachusetts General Hospital
Boston, Massachusetts 02215
United States
Status: Recruiting Contact: Principal Investigator
Mark Goldstein, MD

Facility: University of Michigan Medical Center
Ann Arbor, Michigan 48109
United States
Status: Recruiting Contact: Principal Investigator
Glenn Hanna, MD

Facility: Atlantic Healthcare System
Morristown, New Jersey 07960
United States
Status: Recruiting Contact: Principal Investigator
Colin Weekes, MD

Facility: Memorial Sloan Kettering Cancer Center
New York, New York 10065
United States
Status: Recruiting Contact: Principal Investigator
Ulka Vaishampayan, MD

Facility: University of Cincinnati Medical Center
Cincinnati, Ohio 45219
United States
Status: Recruiting Contact: Principal Investigator
Eric Whitman, MD

Facility: The Ohio State University James Cancer Center
Columbus, Ohio 43210
United States
Status: Recruiting Contact: Principal Investigator
Kenneth Yu, MD

Facility: Zangmeister Cancer Center
Columbus, Ohio 43219
United States
Status: Recruiting Contact: Principal Investigator
Eileen O'Reilly, MD

Facility: Pennsylvania Cancer Specialists & Research Institute (Formerly Gettysburg Cancer Center)
Gettysburg, Pennsylvania 17325
United States
Status: Recruiting Contact: Principal Investigator
Amanda Jackson, MD

Facility: Tennessee Oncology Chattanooga Memorial Plaza
Chattanooga, Tennessee 37404
United States
Status: Recruiting Contact: Principal Investigator
Satish Shah, MD

Facility: Tennessee Oncology - Nashville
Nashville, Tennessee 37203
United States
Status: Recruiting Contact: Principal Investigator
Patrick Ma, MD

Facility: Oncology Consultants
Houston, Texas 77030
United States
Status: Recruiting Contact: Principal Investigator
Edward Arrowsmith, MD

Facility: University of Utah Huntsman Cancer Institute
Salt Lake City, Utah 84112
United States
Status: Recruiting Contact: Principal Investigator
Meredith McKean, MD

Facility: NEXT/Virginia Cancer Specialists
Fairfax, Virginia 22031
United States
Status: Recruiting Contact: Principal Investigator
Jenny Chang, MD

Facility: Newcastle Private Hospital
New Lambton Heights, New South Wales 2305
Australia
Status: Recruiting Contact: Principal Investigator
Julio Peguero, MD

Facility: Tasman Oncology Research
Southport, Queensland 4120
Australia
Status: Recruiting Contact: Principal Investigator
Siwen Hu-Lieskovan, MD, PhD

Facility: Cancer Research SA
Adelaide, South Australia 5000
Australia
Status: Recruiting Contact: Principal Investigator
Alexander Spira, MD

Facility: Southern Oncology Clinical Research Unit
Bedford Park, South Australia 5042
Australia
Status: Recruiting Contact: Principal Investigator
Hiren Mandaliya, MD