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

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ClinicalTrials.gov Identifier: NCT04140526
Recruitment Status : Not yet recruiting
First Posted : October 28, 2019
Last Update Posted : October 28, 2019
Sponsor:
Information provided by (Responsible Party):
OncoImmune, Inc.

Brief Summary:
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.

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 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 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 (RP2D-M).
  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 enrolled.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 91 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description: Open 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 I/II Study
Estimated Study Start Date : February 2020
Estimated Primary Completion Date : February 2022
Estimated Study Completion Date : February 2023

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ONC-392 Treatment as single agent
The Part A study will test ONC-392 intravenous (IV) infusion up to four predefined dose levels: 0.3 mg/kg (cohort 1), 1 mg/kg (cohort 2), 3 mg/kg (cohort 3) and 10 mg/kg (cohort 4) of ONC-392 as monotherapy every 21 days (Q3W). The treatment will continue for up to 1 year, or discontinued upon disease progression, or unacceptable toxicity, or voluntary withdraw. The Part A study will determine the maximal tolerable dose (MTD) and the recommended Phase 2 dose in monotherapy (RP2D-M).
Drug: ONC-392
ONC-392 will be given by intravenous infusion, once every 21 days (Q3W).
Other Name: A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoImmune, Inc.

Experimental: ONC-392 in combination with pembrolizumab

The Part B 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 phase I trial 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.

The Part B study will progress to 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. The treatment will continue for up to 1 year, or discontinued upon disease progression, or unacceptable toxicity, or voluntary withdraw.
Drug: ONC-392
ONC-392 will be given by intravenous infusion, once every 21 days (Q3W).
Other Name: A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoImmune, Inc.

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




Primary Outcome Measures :
  1. Dose limiting toxicity (DLT) in monotherapy [ Time Frame: 21 days ]
    The number of subjects who have dose limiting toxicity during the first cycle of study drug, ONC-392, administration.

  2. Maximal tolerable dose (MTD) in monotherapy [ Time Frame: 21 days ]
    The study drug, ONC-392, dose level that has two out of six subjects who have dose limiting toxicity.

  3. Recommended Phase II Dose (RP2D) [ Time Frame: 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.

  4. Rate of treatment related adverse events (TRAE) according to CTCAE v5.0 [ Time Frame: One year ]
    The safety profile will be presented as tabulated TRAE.


Secondary Outcome Measures :
  1. The serum half life of the study drug, ONC-392, in monotherapy. [ Time Frame: 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.

  2. The serum half life of the study drug, ONC-392, in combination therapy with Pembrolizumab. [ Time Frame: 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.

  3. Objective Response Rate (ORR) [ Time Frame: 1 year ]
    To determine the objective response rate based on RECIST v1.1.

  4. Progression Free Survival (PFS) [ Time Frame: 1 year ]
    To determine the progression free survival based on RECIST 1.1 and iRECIST.

  5. Overall Survival (OS) [ Time Frame: 1 year ]
    To determine the overall survival.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  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 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.

    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 participation.
    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 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

  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 eligible.
  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.

Exclusion Criteria:

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

  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 LHRH agonists.
  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 alcohol).
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04140526


Contacts
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Contact: Pan Zheng, MD, PhD 202 751 6823 pzheng@oncoimmune.com

Locations
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United States, Maryland
University of Maryland Greenebaum Cancer Center Not yet recruiting
Baltimore, Maryland, United States, 21201
Principal Investigator: Christian Rolfo, MD         
Sponsors and Collaborators
OncoImmune, Inc.
Investigators
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Principal Investigator: Christian Rolfo, MD University of Maryland, Baltimore

Publications:

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Responsible Party: OncoImmune, Inc.
ClinicalTrials.gov Identifier: NCT04140526     History of Changes
Other Study ID Numbers: ONC-392-001
First Posted: October 28, 2019    Key Record Dates
Last Update Posted: October 28, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Adenocarcinoma
Kidney Neoplasms
Urologic Neoplasms
Kidney Diseases
Urologic Diseases
Pembrolizumab
Antineoplastic Agents, Immunological
Antineoplastic Agents