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

NCT04140526 | Active Not Recruiting Phase 1 FDA Drug

• 3 other identifiers: ONC-392-0014R44CA250824-0220193108
• Study Type: interventional
• Target: 733
• Locations: 2 countries
• Sites: 37

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.

Conditions

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

Outcome Measures

Primary Outcomes (4)

• Dose limiting toxicity (DLT) in monotherapy

  The number of subjects who have dose limiting toxicity during the first cycle of study drug, ONC-392, administration.

  21 days

• Maximal tolerable dose (MTD) in monotherapy

  The study drug, ONC-392, dose level that has two out of six subjects who have dose limiting toxicity.

  21 days

• Recommended Phase II Dose (RP2D)

  The study drug, ONC-392, dose level that is one level below MTD, or an intermediate dose level that below MTD and pre-specified in protocol. This dose level will be the RP2D for monotherapy.

  21 days

• Rate of treatment related adverse events (TRAE) according to CTCAE v5.0

  The safety profile will be presented as tabulated TRAE.

  One year

Secondary Outcomes (5)

• The serum half life of the study drug, ONC-392, in monotherapy.

  12 weeks

• The serum half life of the study drug, ONC-392, in combination therapy with Pembrolizumab.

  12 weeks

• Objective Response Rate (ORR)

  1 year

• Progression Free Survival (PFS)

  1 year

• Overall Survival (OS)

  1 year

Study Arms (3)

ONC-392 Treatment as single agent

EXPERIMENTAL

The Part A study will test ONC-392 intravenous (IV) infusion up to five predefined dose levels from 0.1 mg/kg to 10 mg/kg ONC-392 as monotherapy every 21 days (Q3W). The Part A study will determine the maximal tolerable dose (MTD) and the recommended Phase 2 dose in monotherapy (RP2D-M). In Part C, Arms A-C, I-N monotherapy expansion cohorts will further assess the safety and efficacy of ONC-392 in different dose levels as monotherapy in pancreatic cancer, triple negative breast cancer, non small cell lung cancer with driver mutations, PD-1 resistant non small cell lung cancer, PD-1 resistant melanoma, head and neck cancer, ovarian cancer, renal cell carcinoma and other solid tumors. Part D is a Phase II study on recurrent and/or metastatic adenoid cystic carcinoma.

Drug: ONC-392

ONC-392 in combination with pembrolizumab

EXPERIMENTAL

The Part B1 study will test ONC-392 intravenous (IV) infusion, Q3W, in combination with fixed dose of pembrolizumab. The dose for pembrolizumab will be fixed at 200mg/cycle dosed every 21 days (Q3W). The Part B1 will start at one level below RP2D-M dose for ONC-392 and 200mg of pembrolizumab. When 2 DLTs occur before 6 patients are enrolled, the ONC-392 dose will be decreased to the next dose level until ≤ 1/6 patients treated at that dose develops a DLT. This dose level will be designated RP2D-C. In Part C, the expansion cohorts Arm D to G will assess the safety and efficacy of ONC-392 in different dose levels and Pembrolizumab combination therapy in non small cell lung cancer, and metastatic melanoma.

Drug: ONC-392; Drug: Pembrolizumab

ONC-392 and docetaxel

EXPERIMENTAL

Part E Arm O will test ONC-392 in combination with docetaxel, IV infusion, Q3W, in PD-1 resistant NSCLC patients.

Drug: ONC-392; Drug: Docetaxel

Interventions

ONC-392 DRUG

ONC-392 will be given by intravenous infusion, once every 21 days (Q3W). In Part C Arm M and in Part D, ONC-392 will be given Q4W.

Also known as: A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoC4, Inc.

ONC-392 Treatment as single agent; ONC-392 and docetaxel; ONC-392 in combination with pembrolizumab

Pembrolizumab DRUG

Pembrolizumab will be given intravenous (IV) infusion at 200 mg/cycle, once every 21 days (Q3W).

Also known as: Keytruda, MK3475

ONC-392 in combination with pembrolizumab

Docetaxel DRUG

Docetaxel will be given intravenous (IV) infusion at 75 mg/m2, once every 21 days (Q3W).

Also known as: Taxotere, Docefrez

ONC-392 and docetaxel

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• OncoC4, Inc.: lead
• National Cancer Institute (NCI): collaborator

Study Sites (37)

Highlands Oncology Group

Springdale, Arkansas, 72762, United States

Location

University of California at Davis

Davis, California, 95817, United States

Location

The Oncology Institute of Hope and Innovation

Downey, California, 90241, United States

Location

City of Hope Cancer Center

Duarte, California, 91010, United States

Location

University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Nuvance Health

Norwalk, Connecticut, 06856, United States

Location

MedStar Georgetown University Hospital

Washington D.C., District of Columbia, 20007, United States

Location

Florida Cancer Specialists

Atlantis, Florida, 33462, United States

Location

University of Florida Health Cancer Center

Gainesville, Florida, 32610, United States

Location

Ocala Oncology Florida Cancer Affiliates

Ocala, Florida, 34474, United States

Location

AdventHealth Cancer Institute

Orlando, Florida, 32804, United States

Location

Memorial Cancer Institute

Pembroke Pines, Florida, 33028, United States

Location

Emory University Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

Norton Health

Lexington, Kentucky, 40202, United States

Location

Greater Baltimore Medical Center

Baltimore, Maryland, 21204, United States

Location

The Center for Cancer and Blood Disorders

Bethesda, Maryland, 20817, United States

Location

Dana Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Massachusetts General Hospital

Boston, Massachusetts, 02215, United States

Location

University of Michigan Medical Center

Ann Arbor, Michigan, 48109, United States

Location

Atlantic Healthcare System

Morristown, New Jersey, 07960, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Cincinnati Medical Center

Cincinnati, Ohio, 45219, United States

Location

The Ohio State University James Cancer Center

Columbus, Ohio, 43210, United States

Location

Zangmeister Cancer Center

Columbus, Ohio, 43219, United States

Location

Pennsylvania Cancer Specialists & Research Institute (Formerly Gettysburg Cancer Center)

Gettysburg, Pennsylvania, 17325, United States

Location

Prisma Health

Greenville, South Carolina, 29605, United States

Location

Tennessee Oncology Chattanooga Memorial Plaza

Chattanooga, Tennessee, 37404, United States

Location

Tennessee Oncology - Nashville

Nashville, Tennessee, 37203, United States

Location

Houston Methodist Cancer Center

Houston, Texas, 77030, United States

Location

Oncology Consultants

Houston, Texas, 77030, United States

Location

University of Utah Huntsman Cancer Institute

Salt Lake City, Utah, 84112, United States

Location

NEXT/Virginia Cancer Specialists

Fairfax, Virginia, 22031, United States

Location

University of Washington / Fred Hutchinson Cancer Center

Seattle, Washington, 98109, United States

Location

Newcastle Private Hospital

New Lambton Heights, New South Wales, 2305, Australia

Location

Tasman Oncology Research

Southport, Queensland, 4120, Australia

Location

Cancer Research SA

Adelaide, South Australia, 5000, Australia

Location

Southern Oncology Clinical Research Unit

Bedford Park, South Australia, 5042, Australia

Location

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• Zhang Y, Du X, Liu M, Tang F, Zhang P, Ai C, Fields JK, Sundberg EJ, Latinovic OS, Devenport M, Zheng P, Liu Y. Hijacking antibody-induced CTLA-4 lysosomal degradation for safer and more effective cancer immunotherapy. Cell Res. 2019 Aug;29(8):609-627. doi: 10.1038/s41422-019-0184-1. Epub 2019 Jul 2.

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• Du X, Tang F, Liu M, Su J, Zhang Y, Wu W, Devenport M, Lazarski CA, Zhang P, Wang X, Ye P, Wang C, Hwang E, Zhu T, Xu T, Zheng P, Liu Y. A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy. Cell Res. 2018 Apr;28(4):416-432. doi: 10.1038/s41422-018-0011-0. Epub 2018 Feb 22.

  PMID: 29472691 BACKGROUND

• Du X, Liu M, Su J, Zhang P, Tang F, Ye P, Devenport M, Wang X, Zhang Y, Liu Y, Zheng P. Uncoupling therapeutic from immunotherapy-related adverse effects for safer and effective anti-CTLA-4 antibodies in CTLA4 humanized mice. Cell Res. 2018 Apr;28(4):433-447. doi: 10.1038/s41422-018-0012-z. Epub 2018 Feb 20.

  PMID: 29463898 BACKGROUND

• May KF Jr, Roychowdhury S, Bhatt D, Kocak E, Bai XF, Liu JQ, Ferketich AK, Martin EW Jr, Caligiuri MA, Zheng P, Liu Y. Anti-human CTLA-4 monoclonal antibody promotes T-cell expansion and immunity in a hu-PBL-SCID model: a new method for preclinical screening of costimulatory monoclonal antibodies. Blood. 2005 Feb 1;105(3):1114-20. doi: 10.1182/blood-2004-07-2561. Epub 2004 Oct 14.

  PMID: 15486062 BACKGROUND

• Lute KD, May KF Jr, Lu P, Zhang H, Kocak E, Mosinger B, Wolford C, Phillips G, Caligiuri MA, Zheng P, Liu Y. Human CTLA4 knock-in mice unravel the quantitative link between tumor immunity and autoimmunity induced by anti-CTLA-4 antibodies. Blood. 2005 Nov 1;106(9):3127-33. doi: 10.1182/blood-2005-06-2298. Epub 2005 Jul 21.

  PMID: 16037385 BACKGROUND

• Liu Y, Zheng P. Preserving the CTLA-4 Checkpoint for Safer and More Effective Cancer Immunotherapy. Trends Pharmacol Sci. 2020 Jan;41(1):4-12. doi: 10.1016/j.tips.2019.11.003. Epub 2019 Dec 10.

  PMID: 31836191 BACKGROUND

• Li T, Tang M, Kelly, K, Chen HA, Joo S, Khan I, Do N, Touomou R, Chen D, Liu Y, Zheng P. 949 First-in-human study of the first acid pH-sensitive and recycling CTLA-4 antibody that preserves the immune tolerance checkpoint to avoid immunotherapy-related adverse events in cancer patients. Journal for ImmunoTherapy of Cancer, 2021. 9(Suppl 2): p. A998-A998. doi: 10.1136/jitc-2021-SITC2021.949

  BACKGROUND

• Hu-Lieskovan S, He K, Tang M, Chen D, Liu Y, Zheng P, Li T. 594 Dose escalation of next generation anti-CTLA-4 antibody ONC-392 in combination with fixed dose of pembrolizumab in patients with advanced solid tumors. Journal for ImmunoTherapy of Cancer, 2022. 10(Suppl 2): p. A622-A622. doi: 10.1136/jitc-2022-SITC2022.0594

  BACKGROUND

• He K, Carbone DP, McKean M, Balaraman R, Shah S, Arrowsmith E, Peguero JA, Joshi R, He AR, Milillo A, Hamm JT, Goldstein MG, Li Z, Liu Y, Zheng P, Li T. Safety and clinical activity of target-preserving anti-CTLA-4 antibody ONC-392 as monotherapy in NSCLC patients who progressed on PD(L)1-targeted immunotherapy. Journal of Clinical Oncology, 2023. 41(16_suppl): p. 9024-9024. doi: 10.1200/JCO.2023.41.16_suppl.9024

  BACKGROUND

• He K, McKean M, Balaraman R, Shah S, Arrowsmith E, Peguero JA, Hamm JT, He AR, Spira AI, Milillo-Naraine A, Joshi R, Goldstein MG, Carbone DP, Tang M, Hu-Lieskovan S, Li Z, Chen D, Chou HY, Yang J, Liu Y, Zheng P, Li T. 599 Single-agent safety and activities of target-preserving anti-CTLA-4 antibody gotistobart (ONC-392/BNT316) in PD-(L)1 resistant metastatic NSCLC and population PK analysis in patients with solid tumors. Journal for ImmunoTherapy of Cancer, 2023. 11(Suppl 1): p. A682-A682. doi: 10.1136/jitc-2023-SITC2023.0599

  BACKGROUND

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung; Melanoma; Carcinoma, Renal Cell; Colorectal Neoplasms; Sarcoma; Prostatic Neoplasms; Ovarian Neoplasms; Small Cell Lung Carcinoma; Breast Neoplasms; Pancreatic Neoplasms; Stomach Neoplasms; Esophageal Neoplasms; Uterine Cervical Neoplasms; Carcinoma, Adenoid Cystic; Salivary Gland Neoplasms; Carcinoma, Transitional Cell

Interventions

pembrolizumab; Docetaxel

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Nerve Tissue; Nevi and Melanomas; Skin Neoplasms; Skin Diseases; Skin and Connective Tissue Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplasms, Connective and Soft Tissue; Genital Neoplasms, Male; Genital Diseases, Male; Genital Diseases; Prostatic Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Genital Neoplasms, Female; Endocrine System Diseases; Gonadal Disorders; Breast Diseases; Pancreatic Diseases; Stomach Diseases; Head and Neck Neoplasms; Esophageal Diseases; Uterine Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Mouth Neoplasms; Mouth Diseases; Stomatognathic Diseases; Salivary Gland Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes

Study Officials

• Tianhong Li, MD

  University of California, Davis

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Open label

Study Record Dates

• First Submitted: October 24, 2019
• First Posted: October 28, 2019
• Study Start: September 16, 2020
• Primary Completion (Estimated): June 30, 2026
• Study Completion (Estimated): December 31, 2027
• Last Updated: May 23, 2025

Record last verified: 2025-05

Data Sharing

• IPD Sharing: Will not share

Locations

AU (4); US (33)