PRESERVE-001: Safety, PK and Efficacy of ONC-392 in Monotherapy and in Combination of Anti-PD-1 in Advanced Solid Tumors and NSCLC

Sponsor

OncoC4, Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04140526

Collaborator

National Cancer Institute (NCI) (NIH)

468

Enrollment

Locations

Arms

51.5

Anticipated Duration (Months)

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
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	Drug: ONC-392 Drug: Pembrolizumab	Phase 1/Phase 2

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

468 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Intervention Model Description:

Open labelOpen label

Masking:

None (Open Label)

Primary Purpose:

Treatment

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)

Actual Study Start Date :

Sep 16, 2020

Anticipated Primary Completion Date :

Dec 31, 2023

Anticipated Study Completion Date :

Dec 31, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ONC-392 Treatment as single agent 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, K, L and M monotherapy expansion cohorts will further assess the safety and efficacy of ONC-392 in dose level of RP2D-M 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, head and neck cancer, ovarian cancer, and other solid tumors. Part D is a Phase II study on recurrent and/or metastatic adenoid cystic carcinoma.	Drug: ONC-392 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. Other Names: A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoC4, Inc.
Experimental: ONC-392 in combination with pembrolizumab 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 RP2D-C dose level and Pembrolizumab combination therapy in non small cell lung cancer, and metastatic melanoma.	Drug: ONC-392 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. Other Names: A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoC4, Inc. Drug: Pembrolizumab Pembrolizumab will be given intravenous (IV) infusion at 200 mg/cycle, once every 21 days (Q3W). Other Names: Keytruda MK3475

Arm

Intervention/Treatment

Experimental: ONC-392 Treatment as single agent

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, K, L and M monotherapy expansion cohorts will further assess the safety and efficacy of ONC-392 in dose level of RP2D-M 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, head and neck cancer, ovarian cancer, and other solid tumors. Part D is a Phase II study on recurrent and/or metastatic adenoid cystic carcinoma.

Drug: ONC-392

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.

Other Names:

A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoC4, Inc.

Experimental: ONC-392 in combination with pembrolizumab

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 RP2D-C dose level and Pembrolizumab combination therapy in non small cell lung cancer, and metastatic melanoma.

Drug: ONC-392

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.

Other Names:

A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoC4, Inc.

Drug: Pembrolizumab

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

Other Names:

Keytruda

MK3475

Outcome Measures

Primary Outcome Measures

Dose limiting toxicity (DLT) in monotherapy [21 days]
The number of subjects who have dose limiting toxicity during the first cycle of study drug, ONC-392, administration.
Maximal tolerable dose (MTD) in monotherapy [21 days]
The study drug, ONC-392, dose level that has two out of six subjects who have dose limiting toxicity.
Recommended Phase II Dose (RP2D) [21 days]
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.
Rate of treatment related adverse events (TRAE) according to CTCAE v5.0 [One year]
The safety profile will be presented as tabulated TRAE.

Secondary Outcome Measures

The serum half life of the study drug, ONC-392, in monotherapy. [12 weeks]
To determine the drug concentration in serum samples that are taken in various timepoints during the treatment in order to calculate drug half life.
The serum half life of the study drug, ONC-392, in combination therapy with Pembrolizumab. [12 weeks]
To determine the drug concentration in serum samples that are taken in various timepoints during the treatment in order to calculate drug half life.
Objective Response Rate (ORR) [1 year]
To determine the objective response rate based on RECIST v1.1.
Progression Free Survival (PFS) [1 year]
To determine the progression free survival based on RECIST 1.1 and iRECIST.
Overall Survival (OS) [1 year]
To determine the overall survival.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Virginia G. Piper Cancer Center	Scottsdale	Arizona	United States	85258
2	Highlands Oncology Group	Springdale	Arkansas	United States	72762
3	University of California at Davis	Davis	California	United States	95817
4	The Oncology Institute of Hope and Innovation	Downey	California	United States	90241
5	City of Hope Cancer Center	Duarte	California	United States	91010
6	University of Colorado Hospital	Aurora	Colorado	United States	80045
7	University of Connecticut Medical Center	Farmington	Connecticut	United States	06030
8	Nuvance Health	Norwalk	Connecticut	United States	06856
9	MedStar Georgetown University Hospital	Washington	District of Columbia	United States	20007
10	Florida Cancer Specialists	Atlantis	Florida	United States	33462
11	University of Florida Health Cancer Center	Gainesville	Florida	United States	32610
12	Ocala Oncology Florida Cancer Affiliates	Ocala	Florida	United States	34474
13	AdventHealth Cancer Institute	Orlando	Florida	United States	32804
14	Memorial Cancer Institute	Pembroke Pines	Florida	United States	33028
15	Emory University Winship Cancer Institute	Atlanta	Georgia	United States	30322
16	Norton Health	Lexington	Kentucky	United States	40202
17	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
18	The Center for Cancer and Blood Disorders	Bethesda	Maryland	United States	20817
19	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
20	Massachusetts General Hospital	Boston	Massachusetts	United States	02215
21	University of Michigan Medical Center	Ann Arbor	Michigan	United States	48109
22	Atlantic Healthcare System	Morristown	New Jersey	United States	07960
23	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
24	University of Cincinnati Medical Center	Cincinnati	Ohio	United States	45219
25	The Ohio State University James Cancer Center	Columbus	Ohio	United States	43210
26	Zangmeister Cancer Center	Columbus	Ohio	United States	43219
27	Pennsylvania Cancer Specialists & Research Institute (Formerly Gettysburg Cancer Center)	Gettysburg	Pennsylvania	United States	17325
28	Penn State Cancer Institute	Hershey	Pennsylvania	United States	17033
29	Prisma Health	Greenville	South Carolina	United States	29605
30	Tennessee Oncology Chattanooga Memorial Plaza	Chattanooga	Tennessee	United States	37404
31	Tennessee Oncology - Nashville	Nashville	Tennessee	United States	37203
32	Houston Methodist Cancer Center	Houston	Texas	United States	77030
33	Oncology Consultants	Houston	Texas	United States	77030
34	University of Utah Huntsman Cancer Institute	Salt Lake City	Utah	United States	84112
35	NEXT/Virginia Cancer Specialists	Fairfax	Virginia	United States	22031
36	Newcastle Private Hospital	New Lambton Heights	New South Wales	Australia	2305
37	Tasman Oncology Research	Southport	Queensland	Australia	4120
38	Cancer Research SA	Adelaide	South Australia	Australia	5000
39	Southern Oncology Clinical Research Unit	Bedford Park	South Australia	Australia	5042