A Study to Evaluate the Safety of 2-OHOA Added to Standard of Care in Newly-diagnosed Glioblastoma Patients

• ClinicalTrials.gov Identifier: NCT03867123
• Recruitment Status: Recruiting
• First Posted: March 7, 2019
• Last Update Posted: August 29, 2019
• Sponsor: Laminar Pharmaceuticals
• Information provided by (Responsible Party): Laminar Pharmaceuticals

Tracking Information

• First Submitted Date: January 3, 2019
• First Posted Date: March 7, 2019
• Last Update Posted Date: August 29, 2019
• Actual Study Start Date: December 4, 2018
• Estimated Primary Completion Date: June 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 6, 2019)

• Safety and Tolerability of 2-OHOA in association with Standard of Care (Stupp Protocol) [ Time Frame: 10 to 12 weeks ]
  Incidence of Treatment-Emergent Adverse Events.
• Maximum Tolerated dose (MTD) [ Time Frame: 10 to 12 months ]
  MTD of 2-OHOA administered with Standard of Care

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: March 6, 2019)

Plasma concentration of temozolomide (TMZ). [ Time Frame: First five days of cycle 2 of maintenance phase (each cycle is 4 weeks) ]

To verify that the administration of 2-OHOA is not modifying the exposition of patients to TMZ.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study to Evaluate the Safety of 2-OHOA Added to Standard of Care in Newly-diagnosed Glioblastoma Patients
• Official Title: A Phase 1B Study of the Safety of 2-Hydroxyoleic Acid Sodium Salt (2-OHOA) Administered Orally in Combination With Temozolomide (TMZ) and Radiation Therapy or With TMZ Alone in the First Line Treatment of Subjects With Glioblastoma
• Brief Summary: The purpose of this study is to determine the safety and tolerability of 2-OHOA added to first-line treatment for subjects with newly diagnosed glioblastoma (GBM), and to determine the highest safe dose of 2-OHOA administered orally when added to the concurrent phase of treatment with temozolomide (TMZ) and radiation therapy (RT) or when added to the maintenance phase of treatment with TMZ (once TMZ 200 g/m2/day is started).

Detailed Description

This is a Phase IB, open-label, dose-finding study. A de-escalation process has been selected for the study with a 3+3 design to establish the Maximum Tolerated Dose (MTD).

The first group of 3 subjects (within each arm), where all 3 subjects may be started at the same time, will receive 2-OHOA at the starting dose of 12 g/day (4 g tid). If 0-1 Dose-Limiting Toxicities (DLTs) in the first 3 patients, then a new cohort with 3 more patients is started at 12 g/day (4 g tid). If 2 or more patients out of 3 or 6 patients experience DLT(s) the dose is deescalated.

De-escalation doses are from 12 g/day (4 g tid) to 8 g/day (4 g bid) and from 8 g/day (4 g bid) to 4 g/day (4 g od). This procedure must be applied to the two arms of the study described below. Both arms will be independent, and will run in parallel, therefore none of the patients from Arm 1 may enter Arm 2.

• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Glioblastoma (GBM)

Intervention

• Drug: 2-OHOA
  Arm 1: Daily for 6 weeks. Arm 2: daily, two 28-day cycles
  Other Name: 2-Hydroxyoleic acid, sodium salt, 2OHOA
• Radiation: RT
  In Arm 1: Fractionated focal irradiation of 1.8-2 Gy/fraction/day, 5 days/week, 6 weeks. Total dose up to 60 Gy
  Other Name: radiotherapy
• Drug: TMZ
  Arm 1: 75 mg/m2/day, daily, 6 weeks Arm 2: 200 mg/m2/day, daily the first 5 days of two 28-day cycles (in case of toxicity, TMZ dose may be reduced to 150 mg/m2/day at Cycle 3 to allow for recovery)
  Other Name: temozolomide

Study Arms

• Experimental: Arm 1 (chemoradiation phase)

  Radiotherapy (RT) + temozolomide (TMZ) + 2-OHOA (during Concurrent phase - duration 6 weeks)*:

  2-OHOA will be initiated at the start of the concurrent phase and will be administered on a continuous daily basis together with TMZ and RT for 6 weeks at the selected dose, either 12 g/day (4 g tid), 8 g/day (4 g bid) or 4 g/day (4 g od).

  RT will be administered only during the concurrent phase, consisting of fractionated focal irradiation administered using 1.8- 2 Gy/fraction, daily for 5 days/week for 6 weeks, for a total dose of up to 60 Gy.

  TMZ will be administered during the concurrent phase at a starting dose of 75 mg/m2/day given daily for 6 weeks.

  * One extra week may be allowed.

  Interventions:

  • Drug: 2-OHOA
  • Radiation: RT
  • Drug: TMZ
• Experimental: Arm 2 (maintenance phase)

  TMZ + 2-OHOA (during Maintenance phase with TMZ 200 mg/m2/day at Cycle 2 - duration 8 weeks):

  2-OHOA will be initiated on day 2 of Cycle 2 of the maintenance phase, when TMZ 200 mg/m2/day is given and administered on a continuous basis for two 28-day cycles. 2-OHOA will be administered at the selected dose, either 12 g/day (4 g tid), 8 g/day (4 g bid) or 4 g/day (4 g od).

  TMZ will be administered at 200 mg/m2/day given daily the first 5 days for two 28-day cycles (if no toxicity is seen). In case of toxicity, TMZ dose may be reduced to 150 mg/m2/day at Cycle 3 to allow for recovery.

  Both arms will be followed by a 4-week safety follow-up

  Interventions:

  • Drug: 2-OHOA
  • Drug: TMZ

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 6, 2019): 12
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: September 2023
• Estimated Primary Completion Date: June 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Glioblastoma (GBM) according to 2016 World Health Organization (WHO) Classification.
2. Must have had a partial or complete surgical resection of the Grade 4 astrocytic tumor.
3. Subjects in Arm 1 must have had no previous treatment except surgery (ie, no previous RT, local CT, or systemic therapy). Subjects must meet certain other eligibility requirements.
4. Subjects in Arm 2 must have completed a standard first line regimen of concurrent TMZ and RT for newly diagnosed GBM patients, followed by a rest phase, and have not had any other previous CT except surgery (including any other regimens of RT and local or systemic CT). Progression and/or pseudoprogression should have been ruled out before starting Arm 2 as per usual clinical practice, with correct laboratory results (absolute neutrophile count ≥1.5 x 109/L, platelet count ≥ 100 x 109/L, non-haematological toxicity grade ≤ 2) at screening. Subjects must meet certain other eligibility requirements.
5. Subjects must be able to undergo serial MRIs (computerized tomography may not be a substitute for magnetic resonance imaging [MRI]).
6. Male or female ≥ 18 years old.
7. Must have a Karnofsky performance status of ≥ 70% and the ability to swallow oral medication.
8. Must have no other diagnosis of cancer malignancy (except surgically excised nonmelanoma skin cancer or carcinoma in situ of the cervix, or treated early stage prostate cancer, or a malignancy diagnosed ≥ 5 years previously with no current evidence of disease and no therapy within two years prior to enrolment on this study).
9. Must be capable of understanding and complying with the protocol requirements.
10. Contraception: All female patients will be considered to be of childbearing potential unless they are postmenopausal (at least 12 months consecutive amenorrhea, in the appropriate age group and without other known or suspected cause), or have been sterilized surgically. Female patients of childbearing potential must agree to use two forms of highly effective contraception methods (a primary and a secondary method) during the study and for a period of 6 months following the last administration of the study drug. Male patients and their female partners, who are of childbearing potential and are not practicing total abstinence, must agree to use two forms of highly effective contraception methods (a primary and a secondary method) during the study and for a period of 6 months following the last administration of the study drug These contraception methods include oral, transdermal, systemic or implant contraception birth control, intra-uterine devices (IUD), abstinence and double barrier method such as diaphragm with spermicidal gel or other recommended double barrier methods screening.
11. Written informed consent form signed before any study test or procedure.

Exclusion Criteria:

1. Subject has received prior systemic CT or RT (Arm 1) or prior systemic CT other than TMZ (Arm 2), biologic agents, or any other type of investigational agent for the treatment of brain tumors.
2. Subjects who have progressed on TMZ are not eligible (pseudoprogression ruled out as per usual clinical practice).
3. Subject has evidence of acute intracranial or intratumoral hemorrhage > Grade 1 by MRI. Subjects with resolving hemorrhage changes, punctate hemorrhage, or hemosiderin may enter the study.
4. Subject has serious intercurrent illness such as: hypertension despite optimal treatment, or significant cardiac arrhythmias; or a recent history of serious disease such as symptomatic congestive heart failure, or abdominal fistula or gastrointestinal (GI) perforation within 6 months, prior to starting study treatment.
5. Subject has had major surgery within 28 days prior to starting study treatment (except cancer resection surgery in arm 1), or had non water-tight dural closure during previous surgery, or has unhealed wounds from previous surgery.
6. Subject has inherited bleeding diathesis or coagulopathy with the risk of bleeding.
7. Subject is pregnant or breastfeeding.
8. Subject is known to be positive for the human immunodeficiency virus (HIV) (a test for HIV at screening is not required).
9. Subject has a previously-identified allergy or hypersensitivity to components of either the 2-OHOA or TMZ formulations.
10. Subject is unable or unwilling to abide by the study protocol or cooperate fully with the investigator or designee.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Vicenc Tur, MBA; +34 971439886; v.tur@lipopharma.com

Contact: Antoine Perier, MSc; +34 971439886; clinical.dev@lipopharma.com

• Listed Location Countries: Spain

Administrative Information

• NCT Number: NCT03867123
• Other Study ID Numbers: MIN-002-1801; 2018-000317-21 ( EudraCT Number )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Responsible Party: Laminar Pharmaceuticals
• Study Sponsor: Laminar Pharmaceuticals
• Collaborators: Not Provided

Investigators

• Study Director: Jordi Roma, MD; cro

• PRS Account: Laminar Pharmaceuticals
• Verification Date: May 2019