Clinical Trials /

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

NCT04140526

Description:

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.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: ONC-392-001
  • NCT ID: NCT04140526

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

Interventions

DrugSynonymsArms
ONC-392A humanized anti-CTLA4 IgG1 monoclonal antibody made by OncoImmune, Inc.ONC-392 Treatment as single agent
PembrolizumabKeytrudaONC-392 in combination with pembrolizumab

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
ONC-392 Treatment as single agentExperimentalThe 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).
  • ONC-392
ONC-392 in combination with pembrolizumabExperimentalThe 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: Stage IV NSCLC anti-PD(L)-1 immunotherapy naïve; 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.
  • ONC-392
  • Pembrolizumab

Eligibility 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose limiting toxicity (DLT) in monotherapy
Time Frame:21 days
Safety Issue:
Description:The number of subjects who have dose limiting toxicity during the first cycle of study drug, ONC-392, administration.

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:OncoImmune, Inc.

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