Study of Safety and Pharmacokinetic Properties of Oral OKN-007 in Patients With Recurrent High-Grade Glioma
Study Details
Study Description
Brief Summary
This is a phase 1 open-label, multicenter study to investigate tolerability, safety and PK properties of oral OKN-007 in patients with recurrent high-grade glioma.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 1 |
Detailed Description
This phase 1 open-label study is based on the traditional 3+3 design following the initial single-participant cohort to determine the maximum tolerated dose (MTD). Eligible participants will be enrolled each of the cohorts with escalated dose levels and administered the study drug OKN-007 orally daily in 28-day cycles: Cohort 1, Cohort 2, Cohort 3, Cohort 4. Participants may receive study treatment up to 2 years or until tumor progression, unacceptable toxicity, death, or patient withdrawal. The safety and pharmacokinetic properties of oral OKN-007 will be investigated.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Low-dose OKN-007, two times a day (BID) Dose Escalation Cohort 1 |
Drug: Low-dose OKN-007, BID
Participants will be administered low doses of oral OKN-007 two times a day daily in 28-day cycles.
|
| Experimental: Low-dose OKN-007, three times a day (TID) Dose Escalation Cohort 2 |
Drug: Low-dose OKN-007, TID
Participants will be administered low doses of oral OKN-007 three times a day daily in 28-day cycles.
|
| Experimental: Mid-dose OKN-007, three times a day (TID) Dose Escalation Cohort 3 |
Drug: Mid-dose OKN-007, TID
Participants will be administered mid doses of oral OKN-007 three times a day daily in 28-day cycles.
|
| Experimental: High-dose OKN-007, three times a day (TID) Dose Escalation Cohort 4 |
Drug: High-dose OKN-007, TID
Participants will be administered high doses of oral OKN-007 three times a day daily in 28-day cycles.
|
Outcome Measures
Primary Outcome Measures
- Dose-limiting toxicities (DLTs) [28 days]
For dose escalation, DLTs will be assessed throughout the first 28-day cycle according to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
- Maximum tolerated dose (MTD) [28 days]
MTD will be defined as one (or more) dose level(s) below the dose at which DLT was observed in 2 or more participants in the cohort during the first 28 days of cycle.
- Safety and tolerability: Eastern Cooperative Oncology Group (ECOG) performance status assessment [From Day 1 to 30 days after the last treatment]
A physical functional status of participant will be evaluated based on Eastern Cooperative Oncology Group (ECOG) with 6 point performance status scale, where 0= fully active and 5 = dead.
- Safety and tolerability: Neurologic Assessment in Neuro-Oncology (NANO) assessment [From Day 1 to 30 days after the last treatment]
A neurological functional status of participant will be evaluated based on NANO criteria.
- Safety and tolerability: Adverse events [From Day 1 to 30 days after the last treatment]
Safety and tolerability will be evaluated from adverse events as reported according to CTCAE version 5.0.
- Pharmacokinetic profile: Maximum plasma concentration (Cmax) [Pre-dose, 2 hours, 4 hours, 5 hours, 6 hours, and 8 hours post-dose on Days 1 and 2; 5 hours post-dose on Days 5; Pre-dose, 5 hours post-dose on Days 8 in Cycle 1 (each cycle is 28 days)]
Maximum plasma concentration (Cmax) will be calculated using the actual sample collection times.
- Pharmacokinetic profile: Time to Cmax (Tmax) [Pre-dose, 2 hours, 4 hours, 5 hours, 6 hours, and 8 hours post-dose on Days 1 and 2; 5 hours post-dose on Days 5; Pre-dose, 5 hours post-dose on Days 8 in Cycle 1 (each cycle is 28 days)]
Time to Cmax (Tmax) will be calculated using the actual sample collection times.
- Pharmacokinetic profile: Area under the curve (AUC) [Pre-dose, 2 hours, 4 hours, 5 hours, 6 hours, and 8 hours post-dose on Days 1 and 2; 5 hours post-dose on Days 5; Pre-dose, 5 hours post-dose on Days 8 in Cycle 1 (each cycle is 28 days)]
Area under the curve (AUC) will be calculated using the actual sample collection times.
- Pharmacokinetic profile: Clearance (CL) [Pre-dose, 2 hours, 4 hours, 5 hours, 6 hours, and 8 hours post-dose on Days 1 and 2; 5 hours post-dose on Days 5; Pre-dose, 5 hours post-dose on Days 8 in Cycle 1 (each cycle is 28 days)]
Clearance (CL) will be calculated using the actual sample collection times.
- Pharmacokinetic profile: Half-life time (t1/2) [Pre-dose, 2 hours, 4 hours, 5 hours, 6 hours, and 8 hours post-dose on Days 1 and 2; 5 hours post-dose on Days 5; Pre-dose, 5 hours post-dose on Days 8 in Cycle 1 (each cycle is 28 days)]
Half-life time (t1/2) will be calculated using the actual sample collection times.
Secondary Outcome Measures
- Median Progression-Free Survival (PFS) assessed by Radiographic Assessment in Neuro-Oncology (RANO) criteria [Up to 24 months]
Median PFS is defined as the period from the date of the first treatment dose until the earliest date of progression, or death from any cause, or the date of last contact.
- Median Overall Survival (OS) by RANO criteria [Up to 24 months]
Median OS is defined as the period from the date of the first treatment dose until the date of death due to any cause.
Eligibility Criteria
Criteria
Inclusion Criteria:
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Confirmed recurrent gliomas that were originally diagnosed as high-grade glioma (World Health Organization [WHO] Grade 3 or 4; astrocytoma, oligodendroglioma, or glioblastoma) by histopathology or molecular studies.
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Progressive or recurrent gliomas documented by magnetic resonance imaging (MRI) no earlier than 180 days after first surgery for gliomas and no earlier than 90 days after completion of radiotherapy (applies to patients with first progression/recurrence only).
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Patients must have medical records available documenting known histology or molecular and genetic information resulting from prior analyses, or tumor tissue samples available from prior glioma surgery or open biopsy for correlative research.
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For patients with unresected recurrent tumor, unequivocal radiographic evidence of tumor progression by MRI as per the RANO1 criteria within 21 days prior to the first dose. These patients must have at least one measurable lesion per RANO.
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No more than two prior lines of therapy for high-grade glioma (WHO Grade 3 or 4). The first-line therapy must include radiotherapy (minimum of 50 Gy; 34 Gy in elderly patients) with concomitant or adjuvant standard chemotherapy (temozolomide (TMZ), or procarbazine, lomustine and vincristine in patients with anaplastic oligodendroglioma).
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Eastern Cooperative Oncology Group (ECOG) performance status <2.
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Full recovery (grade ≤1) from the toxic effects of any earlier intervention and a minimum of 28 days from the last administration of any investigational agent that has not received regulatory approval for any indication at the time of registration.
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Adequate renal, liver and bone marrow function without packed red blood cell/platelet transfusions within 4 weeks of the date of lab test during screening:
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Leukocytes ≥3.0 × 10^9/L
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Absolute neutrophil count (ANC) ≥1.5 × 10^9/L
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Platelets ≥100 × 10^9/L
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Hemoglobin ≥ 9.0 g/dL
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Total bilirubin ≤1.5 × upper limit of normal (ULN), unless documented Gilbert's syndrome.
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Aspartate transaminase/alanine transaminase ≤2.5 × ULN
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Creatinine clearance ≥60 mL/min calculated as per Cockcroft-Gault equation.
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Patients must be ≥18 years of age.
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Life expectancy (as assessed by the Investigator) at least three months.
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Patients must not have significantly diseased or obstructed gastrointestinal tract, malabsorption, uncontrolled vomiting or diarrhea, or inability to swallow oral medications.
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Have provided written informed consent.
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Patients must be willing to have multiple blood draws for PK analysis.
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Female patients, of childbearing potential, must have a negative serum pregnancy test within 7 days prior to study treatment initiation and agree to abstain from activities that could result in pregnancy from enrollment through 120 days (4 months) after the last dose of study treatment.
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Male patients must agree to use an adequate method of contraception.
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Human immunodeficiency virus infected patients on effective antiretroviral therapy with undetectable viral load within 6 months prior to study registration are eligible for this trial.
Exclusion Criteria:
- Prior malignancy (other than glioma) expected to require treatment within a 6-month period (except adequately treated basal cell carcinoma of the skin).
Patients who had another malignancy in the past but have been free of active disease for more than 2 years, are eligible.
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Have received treatment within the last 28 days with a drug that has not received regulatory approval for any indication at the time of study registration.
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Have received chemotherapeutic agents (including TMZ) within 28 days or within 5 half-lives for non-cytotoxic agents (whichever is shorter) of study registration.
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Serious concomitant systemic disorders, for example, abnormal electrocardiogram (ECG) indicative of cardiac disease (patients with Fridericia-corrected QT interval [QTcF]
450 msec if male and QTcF >470 msec if female.
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Patients with abnormal sodium, potassium, or creatinine levels grade ≥2.
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Inability to comply with protocol or study procedures.
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Women who are pregnant or breastfeeding.
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Patients who have received bevacizumab for recurrent glioblastoma or are planning to initiate treatment with bevacizumab for tumor necrosis.
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Patients completing radiotherapy treatment less than 2 weeks prior to planned study treatment initiation.
Contacts and Locations
Locations
No locations specified.Sponsors and Collaborators
- Oblato, Inc.
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- OKN-007-OL-RMG-101