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

• ClinicalTrials.gov Identifier: NCT01489826
• Recruitment Status: Completed
• First Posted: December 12, 2011
• Results First Posted: October 18, 2016
• Last Update Posted: February 9, 2017
• Sponsor: e-Therapeutics PLC
• Information provided by (Responsible Party): e-Therapeutics PLC

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Solid Tumour	Drug: Dexanabinol; Other: Cremophor	Phase 1

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 40 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1, Pharmacokinetically-Guided, Dose Escalation Study to Assess the Safety and Tolerability of Dexanabinol in Patients With Advanced Solid Tumours
• Study Start Date: January 2012
• Actual Primary Completion Date: July 2015
• Actual Study Completion Date: July 2015

Arms and Interventions

Arm	Intervention/treatment
Experimental: Dexanabinol 2 mg/kg; Dexanabinol 2 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.
Experimental: Dexanabinol 3 mg/kg; Dexanabinol 3 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.
Experimental: Dexanabinol 6 mg/kg; Dexanabinol 6 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.
Experimental: Dexanabinol 12 mg/kg; Dexanabinol 12 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.
Experimental: Dexanabinol 15 mg/kg; Dexanabinol 15 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.
Experimental: Dexanabinol 22 mg/kg; Dexanabinol 22 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.
Experimental: Dexanabinol 30 mg/kg; Dexanabinol 30 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.
Experimental: Dexanabinol 36 mg/kg; Dexanabinol 36 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.
Experimental: Dexanabinol Expansion Phase; Dexanabinol 30 mg/kg formulated in cremophor/ethanol, administered once weekly intravenously (i.v.)	Drug: Dexanabinol; 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.; Other Names: ETS2101; HU-211; Other: Cremophor; Drug vehicle.

Outcome Measures

Primary Outcome Measures :

1. Number of Patients Experiencing Dose Limiting Toxicity (DLT) [ Time Frame: 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 :

1. Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 [ Time Frame: 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.
2. Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 [ Time Frame: 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
3. Number of Adverse Events (AEs) [ Time Frame: 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
4. Progression Free Survival [ Time Frame: At Screening and after every 2 cycles of treatment (+/-1 week) ]
   Tumour response evaluation using RECIST 1.1. (Assessment by CT scan or MRI).
5. Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 [ Time Frame: 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.
6. Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 [ Time Frame: 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.
7. Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 [ Time Frame: 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.
8. Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 [ Time Frame: 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
9. Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 [ Time Frame: 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
10. Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 [ Time Frame: 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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Adult patients defined by age ≥18 years.
2. Patients with histologically or cytologically confirmed solid tumours that are advanced, metastatic and or progressive, for whom there is no effective standard therapy available.
3. Eastern Collaborative Oncology Group (ECOG) Performance Status of ≤2.
4. 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.
5. 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).

6. 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).
7. If there is a history of treated brain metastases, these must have been clinically stable for ≥4 weeks prior to enrollment.
8. Have a life expectancy of >3 months.
9. 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.
10. Be willing and able to comply with the study protocol procedures.

Exclusion Criteria:

1. Patient is pregnant or breast feeding.
2. History of clinically significant cardiac condition, including ischemic cardiac event, myocardial infarction or unstable cardiac disease within 3 months of Cycle 1, Day 1.
3. 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.
4. Major surgery within 6 weeks prior to Cycle 1, Day 1.
5. Known human immunodeficiency virus positivity.
6. Active hepatitis B or C or other active liver disease (other than malignancy).
7. Use of any investigational agents within 4 weeks of Cycle 1, Day 1.
8. Any active, clinically significant, viral, bacterial, or systemic fungal infection within 4 weeks prior to Cycle 1, Day 1.
9. 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.

Contacts and Locations

Locations

United Kingdom

Leeds Cancer Centre at St. James's University Hospital

Leeds, England, United Kingdom, LS9 7TF

Northern Centre for Cancer Care, Freeman Hospital, Newcastle-upon-Tyne, UK

Newcastle-upon-Tyne, Tyne and Wear, United Kingdom, NE7 7DN

The Beatson West of Scotland Cancer Centre,

Glasgow, United Kingdom, G12 0YN

Sponsors and Collaborators

e-Therapeutics PLC

Investigators

• Principal Investigator: Ruth Plummer, MD; Northern Centre for Cancer Care, Freeman Hospital, Newcastle-upon-Tyne, UK
• Principal Investigator: Alan Anthoney, MD; Leeds Cancer Centre at St. James's University Hospital
• Principal Investigator: Jeff Evans, MD; The Beatson West of Scotland Cancer Centre, 1053 Great Western Road, Glasgow

More Information

• Responsible Party: e-Therapeutics PLC
• ClinicalTrials.gov Identifier: NCT01489826
• Other Study ID Numbers: ETS2101-001
• First Posted: December 12, 2011
• Results First Posted: October 18, 2016
• Last Update Posted: February 9, 2017
• Last Verified: October 2016

Keywords provided by e-Therapeutics PLC:

Cancer

Additional relevant MeSH terms:

Neoplasms; HU 211; Anti-Arrhythmia Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Neuroprotective Agents; Protective Agents