Clinical Trials /

A First-in-man Phase I/II Study of Oral ONC201 in Patients With Advanced Cancer

NCT02038699

Description:

ONC201 is a new potential drug that kills cancer cells but not normal cells in laboratory studies. This clinical trial will be the first evaluation of ONC201 in humans and will enroll patients with advanced cancer. This trial includes a phase I portion that will evaluate the safety of ONC201 and the recommended dose for the phase II portion. The phase II portion will evaluate the initial efficacy profile of ONC201 in select types of cancer.

Related Conditions:
  • Breast Carcinoma
  • Colorectal Carcinoma
  • Glioblastoma
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Withdrawn

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A First-in-man Phase I/II Study of Oral ONC201 in Patients With Advanced Cancer
  • Official Title: A First-in-man Phase I/II Single-agent Open-label Dose-escalation Study of Every Three-week Dosing of Oral ONC201 in Patients With Advanced Cancer and Limited Treatment Options

Clinical Trial IDs

  • ORG STUDY ID: 00001
  • NCT ID: NCT02038699

Conditions

  • Advanced Glioblastoma
  • Advanced Colorectal Cancer
  • Advanced Triple-negative Breast Cancer
  • Advanced Non-small Cell Lung Cancer

Interventions

DrugSynonymsArms
ONC201TIC10ONC201

Purpose

ONC201 is a new potential drug that kills cancer cells but not normal cells in laboratory studies. This clinical trial will be the first evaluation of ONC201 in humans and will enroll patients with advanced cancer. This trial includes a phase I portion that will evaluate the safety of ONC201 and the recommended dose for the phase II portion. The phase II portion will evaluate the initial efficacy profile of ONC201 in select types of cancer.

Detailed Description

      ONC201 (TIC10) is a first-in-class small molecule that inactivates the Ras effector target
      kinases, Akt and ERK, selectively in tumor, but not normal, cells to safely trigger cancer
      cell death. The dual inactivation of Akt and ERK by ONC201 results in broad-spectrum
      cytotoxic activity that includes activation of TRAIL-mediated apoptotic and other downstream
      antitumor effects to produce a potent antitumor response. The safety margin (ratio of
      therapeutic dose to lowest dose with a mild adverse event) of ONC201 is at least 10-fold in
      rats and dogs in GLP toxicology. The efficacy of ONC201 has been consistently demonstrated in
      multiple in vitro, ex vivo, and in vivo preclinical cancer models. Favorable attributes of
      ONC201 observed in preclinical models include antitumor efficacy with infrequent
      administration, broad-spectrum activity independent of mutations or tumor type, orally
      active, high safety margins, synergistic activity with many approved therapies, highly
      stable, highly water soluble, and ability to penetrate the blood-brain barrier. In the phase
      I portion of the trial, the hypothesis is that ONC201 will exhibit an acceptable safety
      profile in patients with advanced cancer. In the phase II portion of the trial, the
      hypothesis is that ONC201 will show preliminary signs of efficacy in patients with advanced
      cancer as defined by endpoints that include progression-free survival, response rate,
      biomarkers, and overall survival.
    

Trial Arms

NameTypeDescriptionInterventions
ONC201ExperimentalOral ONC201 will be administered once every three weeks at various doses.
  • ONC201

Eligibility Criteria

        Inclusion Criteria:

          1. Patients must have histologically confirmed glioblastoma multiforme, triple-negative
             breast cancer, colorectal cancer, or non-small cell lung cancer patients with advanced
             disease and limited therapeutic options.

          2. Patients must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional
             techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam. For
             lymph nodes to be considered measurable, the short axis must be ≥15 mm when assessed
             by CT scan. All other lesions (or sites of disease), including small lesions (longest
             diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), are
             considered non-measurable disease. Bone lesions, leptomeningeal disease, ascites,
             pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast
             disease, and abdominal masses (not followed by CT or MRI), are considered
             non-measurable. See Section 11 for the evaluation of measurable disease.

          3. Patients are eligible for enrollment if they have not had prior chemotherapy,
             radiotherapy, anticancer therapy, or investigational agent within 28 days prior to the
             first dose (Week 1, Day 1); 42 days weeks in the case of alkylating agents. Patients
             are eligible for enrollment if they have had no surgery within 6 weeks prior to the
             first dose. Any number of prior therapies is allowable.

          4. All adverse events Grade > 1 related to prior therapies (chemotherapy, radiotherapy,
             and/or surgery) must be resolved, except for alopecia.

          5. Age ≥18 years.

          6. ECOG performance status ≤ 2 (Karnofsky ≥ 60%, see Appendix A).

          7. Life expectancy of greater than 10 weeks.

          8. Patients must have normal organ and marrow function as defined below:

               -  leukocytes ≥ 3,000/mcL

               -  absolute neutrophil count ≥ 1,500/mcL

               -  platelets ≥ 100,000/mcL

               -  hemoglobin > 8.0 mg/dL

               -  total bilirubin < 2.0 x upper limit of normal

               -  AST (SGOT)/ALT (SGPT) ≤2.5 × upper limit of normal creatinine OR creatinine
                  clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above normal.

          9. The effects of ONC201 on the developing human fetus are unknown. For this reason,
             women of childbearing potential and men must agree to use adequate contraception
             (hormonal or barrier method of birth control; abstinence) prior to study entry and for
             the duration of study participation. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately.

         10. Tumor specimen (paraffin-embedded block or frozen tissue) from prior resection or
             biopsy available that is sufficient to perform pharmacodynamic assays (>3 slides for
             IHC)

         11. Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          1. Patients who have received bevacizumab therapy.

          2. Patients with known brain metastases will be excluded from the phase I portion of the
             study. In the phase II portion, patients with known CNS metastases will be limited to
             20% of the patient population to accrue proportionately. Patients with CNS metastases
             must be stable after therapy for CNS metastases (such as surgery, radiotherapy or
             stereotactic radiosurgery) for > 3 month and must be off steroid treatment prior to
             study enrollment and must have a life expectancy of 3 months or greater to be
             eligible.

          3. History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to ONC201 or its excipients.

          4. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection or psychiatric illness/social situations that would limit compliance with
             study requirements

          5. Pregnant women are excluded from this study because ONC201 is novel agent with unknown
             potential for teratogenic or abortifacient effects. Because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with ONC201, breastfeeding should be discontinued if the mother is treated with
             ONC201.

          6. Patients with a known HIV-positive test on combination antiretroviral therapy are
             ineligible for the initial first-in-man trial because of the potential for
             pharmacokinetic interactions with ONC201. In addition, these patients are at increased
             risk of lethal infections when treated with marrow-suppressive therapy. Appropriate
             studies will be undertaken in patients receiving combination antiretroviral therapy
             when indicated.

          7. Patients with known history of cardiac arrhythmias including atrial fibrillation,
             tachyarrhythmias or bradycardia will be excluded. Patients receiving therapeutic
             agents known to prolong QT interval will be excluded. Patients with history of CHF, or
             MI or stroke in the last 3 months will be excluded. Patients with a history of
             seizures will be excluded form the initial trial because ONC201 crosses the
             blood-brain barrier and this may affect their anti-seizure therapy.

          8. Active drug use or alcoholism.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:In Phase I, to determine the recommended phase II doses of ONC201.
Time Frame:Participants will be followed for the duration of the study, an expected average of 6 months.
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Withdrawn
Lead Sponsor:Oncoceutics, Inc.

Last Updated

December 18, 2015