Clinical Trials /

Study of 2-hydroxyoleic Acid in Pediatric Patients With Malignant Glioma and Other Advanced Solid Tumors

NCT04299191

Description:

An open label, non-randomized study in pediatric patients with advanced high-grade gliomas and other solid tumors. The study will be performed in two phases: a dose escalation phase in up to 18 patients following a standard "3+3" design to establish dose-limiting toxicity (DLT) and a "safe" dose of 2-OHOA followed by an expanded safety cohort of up to 10 patients treated at the Maximum Tolerated Dose (MTD). If the MTD is well tolerated in the expanded safety cohort, that dose becomes the Recommended Phase 2 Dose (RP2D). Glioma patients and other solid tumor patients (including non-glial brain tumors) will be treated as a single cohort. Patients with either tumor type will be allowed to enroll on the study as positions are made available. No tumor type will be given priority over another and there is no minimum number of glioma patients or solid tumor patients that must be enrolled on the trial.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Study of 2-hydroxyoleic Acid in Pediatric Patients With Malignant Glioma and Other Advanced Solid Tumors
  • Official Title: Study of 2-hydroxyoleic Acid in Pediatric Patients With Malignant Glioma and Other Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: MIN-001P-1501
  • NCT ID: NCT04299191

Conditions

  • High-grade Glioma
  • Solid Tumor, Unspecified, Child

Interventions

DrugSynonymsArms
2-OHOADose Escalation

Purpose

An open label, non-randomized study in pediatric patients with advanced high-grade gliomas and other solid tumors. The study will be performed in two phases: a dose escalation phase in up to 18 patients following a standard "3+3" design to establish dose-limiting toxicity (DLT) and a "safe" dose of 2-OHOA followed by an expanded safety cohort of up to 10 patients treated at the Maximum Tolerated Dose (MTD). If the MTD is well tolerated in the expanded safety cohort, that dose becomes the Recommended Phase 2 Dose (RP2D). Glioma patients and other solid tumor patients (including non-glial brain tumors) will be treated as a single cohort. Patients with either tumor type will be allowed to enroll on the study as positions are made available. No tumor type will be given priority over another and there is no minimum number of glioma patients or solid tumor patients that must be enrolled on the trial.

Detailed Description

      The dose of 2-OHOA each patient will receive will depend on the dose cohort into which they
      are enrolled.

      Once a patient is allocated a dose of 2-OHOA (either in the dose escalation phase or the
      expanded safety cohort), it is planned that they will continue to receive the same dose on a
      daily basis in treatment cycles of 21 days (3 weeks), which may be repeated continuously
      without therapy interruption, until any criterion for discontinuation is met (clinical or
      radiological progression of disease, clinically unacceptable toxicity, or another "general"
      discontinuation criterion is met as defined in Section 5.5). In the event of significant
      gastrointestinal toxicity, the treatment schedule may be modified from continuous dosing to
      an intermittent regime (e.g. 1 week of dosing followed by 1 week not dosing), except during
      Cycle 1 of the dose escalation phase.

      In the case of toxicity, the dose of 2-OHOA may be reduced or delayed by no more than 14 days
      at the discretion of the Investigator. Treatment "holidays" of no more than 14 days are also
      permitted for reasons other than toxicity, except during Cycle 1 of the dose escalation
      phase.

      Intra-patient dose escalation may be permitted in certain specific circumstances (and only if
      ≤ Grade 2 toxicity was observed during previous treatment cycles), but toxicity will not be
      considered for definition of DLT.

      It is expected that most patients will receive between one and 6 cycles of 2-OHOA for a
      treatment period of 3 to 18 weeks. The treatment period may be extended provided that no DLT
      has been observed and if in the opinion of the Investigator the patient is showing benefit
      from treatment with 2-OHOA.

      Patients demonstrating clinical benefit from 2-OHOA will have the option of continuing
      treatment under compassionate use once the study has concluded.
    

Trial Arms

NameTypeDescriptionInterventions
Dose EscalationExperimentalThe dose level corresponds to 80% of the maximum tolerated dose of 2-OHOA in adult patients when adjusted for body surface area. The escalation will be to the 100%, and 120% of the maximum tolerated dose of 2-OHOA in adult patients when adjusted for body surface area. Dose escalation decisions will be made by all active Investigators in collaboration with the Medical Monitor when at least three patients have completed the DLT observation period (Cycle 1) at each dose level. When the third patient at any given dose level has received 14 days of therapy, an "escalation teleconference" will be scheduled after that patient has completed the DLT observation period (Cycle 1). The decision to progress to the next dose level will be made on the basis of review of all significant 2-OHOA-related toxicities.
  • 2-OHOA

Eligibility Criteria

        Inclusion Criteria:

          1. Age <18 years

          2. Diagnosis: Patients must have a histologically- or cytologically-confirmed advanced
             solid malignancy that is progressive, recurrent or refractory to standard-of-care
             treatment, or for which there is no standard therapy.

          3. Timing of therapy:

               -  Patients must be enrolled before treatment begins. Treatment must start within 14
                  days of study enrollment.

               -  All clinical and laboratory studies to determine eligibility must be performed
                  within 7 days prior to enrollment unless otherwise indicated in the eligibility
                  section.

          4. Patients must have a Lansky or Karnofsky performance status score of ≥ 50%,
             corresponding to ECOG categories of 0, 1 or 2. Use Karnofsky for patients > 16 years
             of age and Lansky for patients ≤ 16 years of age. Patients who are unable to walk
             because of paralysis, but who are up in a wheelchair will be considered ambulatory for
             the purpose of assessing the performance score.

          5. Able to swallow and ingest oral medication or have a NG or G-tube for drug
             administration

          6. Able to undergo adequate tumor imaging, via computerized tomography (CT) or magnetic
             resonance imaging (MRI) scans or any other standardized tumor assessment method based
             on tumor type (PET, MIBG, etc) to evaluate disease evolution

          7. Adequate hematologic, renal, liver function as demonstrated by laboratory values:

               -  ANC ≥ 1,000/ul

               -  Hemoglobin ≥8.0 gm/dl

               -  Platelet count ≥ 100,000/ul

               -  Adequate Liver Function Defined As

                    -  Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and

                    -  SGPT (ALT) < 2.5 x upper limit of normal (ULN) for age.

          8. Adequate Renal Function Defined As Either

               -  Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73m2

               -  or a serum creatinine less than or equal to the institutional normal for age

          9. No history of QTc prolongation, and a normal QTc interval at screening/baseline (QTc
             ≤450 msec)

         10. No evidence of a bleeding diathesis

         11. Negative pregnancy test in women of childbearing potential within 7 days of initiating
             investigational therapy

         12. Patient or legal guardian must give written, informed consent or assent (when
             applicable) -

         13. Recent mothers must agree not to breast feed while receiving medications on study.

        Exclusion Criteria:

          1. Age ≥ 18 years

          2. Known hypersensitivity to any component of the study drug (see Section 6.1)

          3. Use of any other investigational drug within five half-lives of that drug prior to the
             first dose of 2-OHOA

          4. Anti-cancer therapy within 4 weeks prior to the first dose of 2-OHOA (6 weeks for
             mitomycin and nitrosureas, 4 weeks for curative-intent radiotherapy, and 2 weeks for
             palliative radiotherapy)

          5. Any National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE
             version 4.0) >Grade 1 toxicities from prior chemotherapy or radiotherapy that could
             impact on safety outcome assessment

          6. Any surgery within 14 days prior to the first dose of 2-OHOA (excluding shunt or line
             insertion)

          7. Known >Grade 1 intracranial or intratumoral hemorrhage either by CT or MRI scan within
             the last 1 month. Patients with resolving hemorrhage changes, punctuate hemorrhage or
             hemosiderin may enter the study

          8. A history of significant or uncontrolled cardiovascular disease, including New York
             Heart Association Class III-IV heart failure, a left ventricular ejection fraction
             which is clinically significantly abnormal as measured by 2-dimensional (2-D)
             echocardiogram or Multi Gated Acquisition(MUGA) scan, unstable angina or myocardial
             infarction within the preceding 6 months

          9. Known impairment of gastrointestinal (GI) function that could alter the absorption of
             study drug (e.g. active Crohn's disease, malabsorption syndrome or states, unresolved
             diarrhea, small bowel resection or gastric by-pass surgery)

         10. Patients who are unable to take oral medications because of significant uncontrolled
             vomiting will be excluded.

         11. A history of uncontrolled hyperlipidemia and/or the need for concurrent lipid lowering
             therapy

         12. Concurrent severe and/or uncontrolled other medical disease (e.g. uncontrolled
             diabetes mellitus, active uncontrolled infection) that could compromise participation
             in the study

         13. Need for warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride,
             glipizide,glyburide or nateglanide)

         14. Any serious and/or unstable pre-existing medical, psychiatric or other condition which
             in the Investigator's opinion could interfere with subject safety, obtaining written
             informed consent, or compliance with the study protocol

         15. Pregnant female patients are not eligible for this study. Pregnancy tests with a
             negative result must be obtained in all post-menarchal females.

         16. Lactating females must agree they will not breastfeed a child while on this study.

         17. Males and females of reproductive potential may not participate unless they agree to
             use an effective contraceptive method and continue to do so for at least 6 months
             after the completion of therapy.
      
Maximum Eligible Age:18 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Safety and Tolerability of 2-OHOA
Time Frame:Between 1 to 6 cycles (each cycle is 3 weeks)
Safety Issue:
Description:To determine the safety and tolerability of 2-OHOA in pediatric patients (under 18 years) when administered orally using a continuous dosing schedule. It will be evaluated through the adverse events [AEs], physical examinations and vital signs, laboratory safety tests and 12-lead electrocardiograms [ECGs].

Secondary Outcome Measures

Measure:Characterize 2-OHOA PK profile
Time Frame:During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last 2-OHOA dose)
Safety Issue:
Description:The maximum plasma drug concentration observed
Measure:Characterize 2-OHOA PK profile
Time Frame:During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last 2-OHOA dose)
Safety Issue:
Description:The time at which the maximum plasma concentration is observed
Measure:Characterize 2-OHOA PK profile
Time Frame:During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last 2-OHOA dose)
Safety Issue:
Description:The area under the plasma concentration versus time curve from time zero to the last quantifiable sampling point, AUC0-t, calculated by using the linear trapezoidal method
Measure:Characterize 2-OHOA PK profile
Time Frame:During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last 2-OHOA dose)
Safety Issue:
Description:Accumulation ratio (R Cmax). Accumulation ratio calculated from Cmax after repeat dosing and Cmax after single dosing
Measure:Characterize 2-OHOA PK profile
Time Frame:During cycles 1 (Days 1, 8 and 15) and 2 (Day 1) (each cycle is 3 weeks) and at the end of study visit (30 days of the last 2-OHOA dose)
Safety Issue:
Description:Accumulation ratio (R AUC0-t) Accumulation ratio calculated from AUC(0-t) after repeat dosing and AUC(0-t) after single dosing
Measure:To assess the preliminary anti-tumor efficacy of 2-OHOA
Time Frame:Screening and every four cycles (12 weeks)
Safety Issue:
Description:Efficacy will be assessed by radiological response of the tumor to treatment

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Laminar Pharmaceuticals

Last Updated

March 5, 2020