A Phase 1/2A Study of Minerval in Adult Patients With Advanced Solid Tumours

• ClinicalTrials.gov Identifier: NCT01792310
• Recruitment Status: Completed
• First Posted: February 15, 2013
• Last Update Posted: December 6, 2016
• Sponsor: Laminar Pharmaceuticals
• Collaborators: Specialized Medical Services (SMS)-Oncology BV; Royal Marsden NHS Foundation Trust; Northern Institute for Cancer Research, Newcastle; Vall d'Hebron Institute of Oncology; Instituto Oncológico IMQ, Clínica IMQ Zorrotzaurre. Bilbao; Onkologikoa, San Sebastián.
• Information provided by (Responsible Party): Laminar Pharmaceuticals

Tracking Information

• First Submitted Date: December 24, 2012
• First Posted Date: February 15, 2013
• Last Update Posted Date: December 6, 2016
• Study Start Date: May 2013
• Actual Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 13, 2013)

Number of patients with adverse events [ Time Frame: From the first dose of study drug until 30 days after the last dose of study drug ]

All adverse events will be recorded including clinically significant physical examinations and vital signs, laboratory safety tests and 12-lead electrocardiograms

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: November 25, 2015)

• Concentration of 2-OHOA in blood measured by LC-MS/MS [ Time Frame: 21 days ]
  Full profiles on Day 1 and Day 21 (dose escalation phase only), trough measurements on Day 8, 15 and 21
• Concentration of biomarkers in blood or tumour tissue [ Time Frame: First 22 days then every 9 cycles until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another "general" discontinuation criterion) ]
  Effect on glial fibrillary acidic protein in glioma patients and effect on sphingomyelin and dihydrofolate reductase in patients with other solid tumours
• Concentration of micro RNA in blood [ Time Frame: First 22 days then every 9 cycles until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another "general" discontinuation criterion) ]
  Blood samples for future analysis of micro RNA
• Radiological disease progression [ Time Frame: Every 6 weeks until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another "general" discontinuation criterion) ]
  Measurement by CT or MRI scan. Changes scored according to Response Assessment in Neuro-oncology (RANO) criteria (for glioma patients) or Response evaluation criteria in solid tumours (RECIST v1.1) (for other solid tumour patients).
• Clinical disease progression [ Time Frame: until any criterion for discontinuation is met (clinical or radiological progression of disease, clinically unacceptable toxicity, or another "general" discontinuation criterion ]

Original Secondary Outcome Measures (submitted: February 13, 2013)

• Concentration of 2-OHOA in blood measured by LC-MS/MS [ Time Frame: 21 days ]
  Full profiles on Day 1 and Day 21 (dose escalation phase only), trough measurements on Day 8, 15 and 21
• Concentration of biomarkers in blood or tumour tissue [ Time Frame: 22 days ]
  Effect on glial fibrillary acidic protein in glioma patients and effect on sphingomyelin and dihydrofolate reductase in patients with other solid tumours
• Radiological disease progression [ Time Frame: Every 6 weeks ]
  Measurement by CT or MRI scan. Changes scored according to Response Assessment in Neuro-oncology (RANO) criteria (for glioma patients) or Response evaluation criteria in solid tumours (RECIST v1.1) (for other solid tumour patients).
• Clinical disease progression [ Time Frame: 126 days (based upon 6 cycles) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1/2A Study of Minerval in Adult Patients With Advanced Solid Tumours
• Official Title: A Phase 1/2A Dose Escalation Study of 2-hydroxyoleic Acid (2-OHOA; Minerval®) in Adult Patients With Advanced Solid Tumours Including Malignant Glioma
• Brief Summary: This is a phase 1/2A, open label, non-randomized study in patients with advanced solid tumours including malignant glioma

Detailed Description

This is an open label, non-randomized study in patients with advanced solid tumours including malignant glioma. The study will be performed in two phases - a dose escalation phase following a standard "3+3" design to establish dose-limiting toxicity (DLT) and a safe dose of 2-OHOA followed by two expanded safety cohorts (approximately 10 of whom have malignant glioma and approximately 10 of whom have other advanced solid tumours that are suitable for biopsy) treated at the maximum tolerated dose (MTD). If the MTD is well tolerated in the expanded safety cohorts, that dose becomes the recommended phase 2 dose (RP2D). During each dose cohort, at least one week must elapse between the first and subsequent patients receiving treatment with 2-OHOA. Patients may receive palliative localized radiotherapy, if needed (however, this lesion cannot be a target lesion for evaluation of the treatment response).

Safety, pharmacokinetics (PK), pharmacodynamics and efficacy will be evaluated during the study at pre-defined timepoints

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Glioma
• Other Solid Tumours

Intervention

Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)

Patients will receive treatment cycles of 21 days, until any criterion for discontinuation (clinical or radiological progression of disease, clinically unacceptable toxicity, or another "general" discontinuation criterion) is met.

Patients are expected to receive between one and 6 cycles of treatment. The treatment period may be extended if clinical benefit is shown.

In the event of significant GI toxicity, the treatment schedule may be modified from continuous dosing to an intermittent regime In the case of toxicity, the dose of 2-OHOA may be reduced or delayed by up to 14 days at the discretion of the Investigator. A maximum of two dose reductions will be permitted per patient. Treatment "holidays" of no more than 14 days are also permitted for reasons other than toxicity. Intra-patient dose escalation may be permitted in certain specific circumstances.

Other Name: Minerval®

Study Arms

• Experimental: Dose Cohort 1
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA). 7 dose cohorts of up to 6 patients have been performed in the dose escalation phase. The starting dose cohort received 250 mg twice daily.
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)
• Experimental: Dose Cohort 2
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA). 500 mg twice daily
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)
• Experimental: Dose Cohort 3
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA). 1g twice daily
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)
• Experimental: 2-OHOA Dose Cohort 4
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA). 2g twice daily
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)
• Experimental: 2-OHOA Dose Cohort 5
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA). 4g twice daily
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)
• Experimental: 2-OHOA Dose Cohort 6
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA). 4g three times daily
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)
• Experimental: 2-OHOA Dose Cohort 7
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA). 8g twice daily
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)
• Experimental: 2-OHOA Dose Expansion cohort. Glioma
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA) at the MTD: 4g three times daily. Up to 10 patients with malignant glioma.
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)
• Experimental: 2-OHOA Dose Expansion cohort. Non-glioma
  Intervention: 2-hydroxyoleic acid (2-OHOA/2OHOA) at the MTD: 4g three times daily. Up to 10 patients with other advanced solid tumours that are suitable for biopsy.
  Intervention: Drug: 2-hydroxyoleic acid (2-OHOA/2OHOA)

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: December 5, 2016): 54
• Original Estimated Enrollment (submitted: February 13, 2013): 50
• Actual Study Completion Date: September 2016
• Actual Primary Completion Date: September 2016 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

• Males or females providing written, informed consent
• Histologically- or cytologically-confirmed advanced solid malignancy that is refractory to standard-of-care treatment, or for which there is no standard therapy. If this is glioma:Grade III / Grade IV malignant glioma recurring or progressing after first or second line standard-of-care treatment and true progressive disease, confirmed according to the RANO criteria 4.
• Life-expectancy of at least 12 weeks
• Eastern cooperative oncology group (ECOG) performance status of 0-2
• Safety laboratory tests and ECGs within specified limits.
• Using adequate contraception, where applicable
• Presence of lesions suitable for biopsy (mandatory for non-glioma patients enrolled in the expanded safety cohort and highly desirable for non-glioma patients enrolled in the dose escalation phase)

Exclusion Criteria

• Anti cancer therapy within 4 weeks (6 weeks for mitomycin and nitrosureas and 2 weeks for palliative radiotherapy)
• NCI Common terminology criteria for adverse events (CTCAE) >Grade 1 toxicities from prior chemotherapy or radiotherapy that could impact on safety outcome assessment
• Recent >Grade 1 intracranial or intratumoural haemorrhage either by CT or MRI scan. Patients with resolving haemorrhage changes, punctuate haemorrhage or haemosiderin may enter the study
• Significant or uncontrolled cardiovascular disease, unstable angina or myocardial infarction within the preceding 6 months
• Known impairment of GI function that could alter the absorption of study drug
• History of uncontrolled hyperlipidemia and/or the need for concurrent lipid lowering therapy
• Concurrent severe and/or uncontrolled other medical disease that could compromise participation in the study
• Taking warfarin, phenytoin or sulphonylureas (glibenclamide, glimepiride, glipizide, glyburide or nateglanide)
• Pregnant or breast feeding Other protocol specific criteria may apply

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Spain, United Kingdom
• Removed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT01792310
• Other Study ID Numbers: MIN-001-1203; EudraCT 2012-001527-13 ( Registry Identifier: EudraCT NUMBER: 2012-001527-13 )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Laminar Pharmaceuticals
• Study Sponsor: Laminar Pharmaceuticals

Collaborators

• Specialized Medical Services (SMS)-Oncology BV
• Royal Marsden NHS Foundation Trust
• Northern Institute for Cancer Research, Newcastle
• Vall d'Hebron Institute of Oncology
• Instituto Oncológico IMQ, Clínica IMQ Zorrotzaurre. Bilbao
• Onkologikoa, San Sebastián.

Investigators

• Study Chair: Professor Johann de Bono, MB ChB FRCP MSc PhD; The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG
• Principal Investigator: Prof. Ruth Plummer, BMBCh, MRCP, Cert Me; Northern Institute for Cancer Research, Newcastle
• Principal Investigator: Dr Jordi Rodon; Vall d'Hebron Institute of Oncology
• Principal Investigator: Dr Juanita Lopez; The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey, United Kingdom SM2 5NG
• Principal Investigator: Dr Ricardo Fernandez Rodriguez; Instituto Oncológico IMQ, Clínica IMQ Zorrotzaurre. Bilbao
• Principal Investigator: Dr Ander Urruticoechea Ribate; Onkologikoa, San Sebastián.

• PRS Account: Laminar Pharmaceuticals
• Verification Date: December 2016