A Phase 1 Study of Dexanabinol in Patients With Advanced Solid Tumours
- Registration Number
- NCT01489826
- Lead Sponsor
- e-Therapeutics PLC
- Brief Summary
This study is a trial of Dexanabinol in patients with advanced solid tumours. The purposes of this protocol are to study different doses of the study drug to determine the maximum safe dose and to further understand the safety of the study drug; to understand what the body does to the study drug; to understand what the study drug does to the body and to measure any reduction in size of patients' cancer tumour(s).
Dexanabinol is a synthetic cannabinoid derivative with reduced psychotropic potential which was initially investigated as a neuroprotective agent. Because of its method of action however it is thought that it may have the effect of destroying cancer cells by reducing the level of control on networks that prevent cancer cells dying.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 40
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Adult patients defined by age ≥18 years.
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Patients with histologically or cytologically confirmed solid tumours that are advanced, metastatic and or progressive, for whom there is no effective standard therapy available.
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Eastern Collaborative Oncology Group (ECOG) Performance Status of ≤2.
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Any acute or chronic adverse effects of prior chemotherapy or radiotherapy have resolved to < Grade 2 as determined by Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, with the exception of alopecia.
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Evaluable disease, either measurable on imaging, or with informative tumour marker(s), as assessed by Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 (Eisenhauer, et al. 2009).
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Laboratory values at Screening:
- Absolute neutrophil count ≥1.5 x 109/L;
- Platelets ≥100 x 109/L;
- Total bilirubin <1.5 times the upper limit of normal;
- Aspartate aminotransferase (AST) ≤2.5 times the upper limit of normal;
- Alanine aminotransferase (ALT) ≤2.5 times the upper limit of normal;
- Estimated glomerular filtration rate (GFR) of >50 mL/min (based on the Wright formula (Wright, et al. 2001); and
- Negative human chorionic gonadotropin (hCG) test in women of childbearing potential (defined as women ≤50 years of age or history of amenorrhea for ≤12 months prior to study entry). Sexually active male and female patients of childbearing potential must agree to use an effective method of birth control (e.g. barrier methods with spermicides, oral or parenteral contraceptives and/or intrauterine devices) during the entire duration of the study and for 1 month after final administration of Dexanabinol, or the patient must be surgically sterile (with documentation in the patient's medical records).
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If there is a history of treated brain metastases, these must have been clinically stable for ≥4 weeks prior to enrollment.
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Have a life expectancy of >3 months.
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Ability to give written, informed consent prior to any study-specific Screening procedures, with the understanding that the consent may be withdrawn by the patient at any time without prejudice.
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Be willing and able to comply with the study protocol procedures.
- Patient is pregnant or breast feeding.
- History of clinically significant cardiac condition, including ischemic cardiac event, myocardial infarction or unstable cardiac disease within 3 months of Cycle 1, Day 1.
- Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to Cycle 1, Day 1. Localised palliative radiotherapy is permitted for symptom control.
- Major surgery within 6 weeks prior to Cycle 1, Day 1.
- Known human immunodeficiency virus positivity.
- Active hepatitis B or C or other active liver disease (other than malignancy).
- Use of any investigational agents within 4 weeks of Cycle 1, Day 1.
- Any active, clinically significant, viral, bacterial, or systemic fungal infection within 4 weeks prior to Cycle 1, Day 1.
- History of significant chronic or recurrent infections requiring treatment or any uncontrolled intercurrent illness that would jeopardize patient safety, interfere with the objectives of the protocol, or limit patient compliance with study requirements, as determined by the Investigator.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SINGLE_GROUP
- Arm && Interventions
Group Intervention Description Dexanabinol 12 mg/kg Cremophor Dexanabinol 12 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 15 mg/kg Cremophor Dexanabinol 15 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 36 mg/kg Cremophor Dexanabinol 36 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 6 mg/kg Cremophor Dexanabinol 6 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 3 mg/kg Cremophor Dexanabinol 3 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 22 mg/kg Cremophor Dexanabinol 22 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 2 mg/kg Cremophor Dexanabinol 2 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 30 mg/kg Cremophor Dexanabinol 30 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol Expansion Phase Cremophor Dexanabinol 30 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 6 mg/kg Dexanabinol Dexanabinol 6 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol Expansion Phase Dexanabinol Dexanabinol 30 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 2 mg/kg Dexanabinol Dexanabinol 2 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 3 mg/kg Dexanabinol Dexanabinol 3 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 12 mg/kg Dexanabinol Dexanabinol 12 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 15 mg/kg Dexanabinol Dexanabinol 15 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 22 mg/kg Dexanabinol Dexanabinol 22 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 30 mg/kg Dexanabinol Dexanabinol 30 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) Dexanabinol 36 mg/kg Dexanabinol Dexanabinol 36 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)
- Primary Outcome Measures
Name Time Method Number of Patients Experiencing Dose Limiting Toxicity (DLT) Each patient will be followed for 22 days Patients will be sequentially assigned to increasing doses of Dexanabinol, to establish the maximum tolerated dose (MTD) (highest dose it is safe to give patients) or alternatively the maximum administered dose (MAD).
3 patients will be enrolled to a cohort to assess each dose level. Dose escalation to a cohort of 3 new patients will occur when all patients in the previous cohort have completed the first cycle i.e. the first 3 doses followed by observation through to Day 22, and no DLT has occurred. Upon occurrence of the first DLT within a cohort, an additional 3 patients were to be added to that cohort. For a six patient cohort, all 6 patients were to have completed their first dexanabinol treatment cycle with no more than 1 DLT before dose escalation to the next cohort. If 2 or more DLTs occur in a cohort, the next lower dose level will be declared the MTD.
DLTs will be graded for severity based on the National Cancer Institute (NCI) Common Terminology Criteria version 4.03.
- Secondary Outcome Measures
Name Time Method Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 Cycle1 - Day 1: pre-dose (0h); 1, 2, 3 h post start of infusion; 5, 10, 15, 30 min post-end infusion; 1, 2, 3, 4, 6, 8, 10 and 24 h post-end infusion. Mean Cmax of Cremophor on Cycle 1 Day 1
Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 Cycle1 - Day 8: pre-dose (0h); 1, 2, 3 h post start of infusion; 5, 10, 15, 30 min post-end infusion; 1, 2, 3, 4, 6, 8, 10 and 24 h post-end infusion. Mean Cmax of Cremophor on Cycle 1 Day 8
Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 Cycle1 - Day 1: pre-dose (0h); 1, 2, 3 h post start of infusion; 5, 10, 15, 30 min post-end infusion; 1, 2, 3, 4, 6, 8, 10 and 24 h post-end infusion. Mean Cmax of Dexanabinol on Cycle 1 Day 1
Progression Free Survival At Screening and after every 2 cycles of treatment (+/-1 week) Tumour response evaluation using RECIST 1.1. (Assessment by CT scan or MRI).
Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 Cycle 1- Day 1: pre-dose (0h); 1, 2, 3 h post start of infusion; 5, 10, 15, 30 min post-end infusion; 1, 2, 3, 4, 6, 8, 10 and 24 h post-end infusion. Geometric mean AUC of Cremophor (0-27hour) on Cycle 1 Day 1.
Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 Cycle 1- Day 1: pre-dose (0h); 1, 2, 3 h post start of infusion; 5, 10, 15, 30 min post-end infusion; 1, 2, 3, 4, 6, 8, 10 and 24 h post-end infusion. Geometric mean AUC of Dexanabinol (0-infinity) on Cycle 1 Day 1.
Number of Adverse Events (AEs) 30 +/-3 days from the end of the last infusion AEs will be graded according to the NCI CTCAE v4.03 for cancer clinical trials
Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 Cycle 1- Day 8: pre-dose (0h); 1, 2, 3 h post start of infusion; 5, 10, 15, 30 min post-end infusion; 1, 2, 3, 4, 6, 8, 10 and 24 h post-end infusion. Geometric mean AUC of Dexanabinol (0-infinity) on Cycle 1 Day 8.
Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 Cycle 1- Day 8: pre-dose (0h); 1, 2, 3 h post start of infusion; 5, 10, 15, 30 min post-end infusion; 1, 2, 3, 4, 6, 8, 10 and 24 h post-end infusion. Geometric mean AUC of Cremophor (0-27hour) on Cycle 1 Day 8.
Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 Cycle1 - Day 8: pre-dose (0h); 1, 2, 3 h post start of infusion; 5, 10, 15, 30 min post-end infusion; 1, 2, 3, 4, 6, 8, 10 and 24 h post-end infusion. Mean Cmax of Dexanabinol on Cycle 1 Day 8
Trial Locations
- Locations (3)
Northern Centre for Cancer Care, Freeman Hospital, Newcastle-upon-Tyne, UK
🇬🇧Newcastle-upon-Tyne, Tyne and Wear, United Kingdom
The Beatson West of Scotland Cancer Centre,
🇬🇧Glasgow, United Kingdom
Leeds Cancer Centre at St. James's University Hospital
🇬🇧Leeds, England, United Kingdom