A Phase 1 Study of Dexanabinol in Patients With Advanced Solid Tumours

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 1, Pharmacokinetically-Guided, Dose Escalation Study to Assess the Safety and Tolerability of Dexanabinol in Patients With Advanced Solid Tumours

Conditions
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Solid Tumour

Intervention / Treatment
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* Drug: Dexanabinol
* Other: Cremophor


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients defined by age ≥18 years. Patients with histologically or cytologically confirmed solid tumours that are advanced, metastatic and or progressive, for whom there is no effective standard therapy available. Eastern Collaborative Oncology Group (ECOG) Performance Status of ≤2. 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. 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). 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). If there is a history of treated brain metastases, these must have been clinically stable for ≥4 weeks prior to enrollment. Have a life expectancy of >3 months. 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. Be willing and able to comply with the study protocol procedures. Exclusion Criteria: 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dexanabinol 2 mg/kg<br>Dexanabinol 2 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|
| Experimental: Dexanabinol 3 mg/kg<br>Dexanabinol 3 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|
| Experimental: Dexanabinol 6 mg/kg<br>Dexanabinol 6 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|
| Experimental: Dexanabinol 12 mg/kg<br>Dexanabinol 12 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|
| Experimental: Dexanabinol 15 mg/kg<br>Dexanabinol 15 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|
| Experimental: Dexanabinol 22 mg/kg<br>Dexanabinol 22 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|
| Experimental: Dexanabinol 30 mg/kg<br>Dexanabinol 30 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|
| Experimental: Dexanabinol 36 mg/kg<br>Dexanabinol 36 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|
| Experimental: Dexanabinol Expansion Phase<br>Dexanabinol 30 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.) | Drug: Dexanabinol<br>* Patients will (initially) be given a slow intravenous (i.v.) infusion of Dexanabinol over 3 hours on Days 1, 8 and 15 of a three weekly (21 day) cycle.<br>* Other names: HU-211;Other: Cremophor<br>* Drug vehicle.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 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. | Each patient will be followed for 22 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 | Geometric mean AUC of Dexanabinol (0-infinity) 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. | 
| Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 | Mean Cmax of Dexanabinol on 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. | 
| Number of Adverse Events (AEs) | AEs will be graded according to the NCI CTCAE v4.03 for cancer clinical trials | 30 +/-3 days from the end of the last infusion | 
| Progression Free Survival | Tumour response evaluation using RECIST 1.1. (Assessment by CT scan or MRI). | At Screening and after every 2 cycles of treatment (+/-1 week) | 
| Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 | Geometric mean AUC of Dexanabinol (0-infinity) 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. | 
| Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | Geometric mean AUC of Cremophor (0-27hour) 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. | 
| Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | Geometric mean AUC of Cremophor (0-27hour) 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. | 
| Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 | Mean Cmax of Dexanabinol on 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. | 
| Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | Mean Cmax of Cremophor on 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. | 
| Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | Mean Cmax of Cremophor on 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. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cancer