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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
e-Therapeutics PLC
ClinicalTrials.gov Identifier:
NCT01489826
First received: December 7, 2011
Last updated: August 22, 2016
Last verified: August 2016
  Purpose

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 Intervention Phase
Solid Tumour
Drug: Dexanabinol
Other: Cremophor
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: 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

Resource links provided by NLM:


Further study details as provided by e-Therapeutics PLC:

Primary Outcome Measures:
  • Number of Patients Experiencing Dose Limiting Toxicity (DLT) [ Time Frame: Each patient will be followed for 22 days ] [ Designated as safety issue: Yes ]

    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:
  • 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. ] [ Designated as safety issue: No ]
    Geometric mean AUC of Dexanabinol (0-infinity) on Cycle 1 Day 1.

  • 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. ] [ Designated as safety issue: No ]
    Mean Cmax of Dexanabinol on Cycle 1 Day 1

  • Number of Adverse Events (AEs) [ Time Frame: 30 +/-3 days from the end of the last infusion ] [ Designated as safety issue: Yes ]
    AEs will be graded according to the NCI CTCAE v4.03 for cancer clinical trials

  • Tumour Response [ Time Frame: At Screening and after every 2 cycles of treatment (+/-1 week) ] [ Designated as safety issue: No ]
    Tumour response evaluation using RECIST 1.1. (Assessment by CT scan or MRI). An additional scan will be performed to confirm a Complete Response (CR) or Partial Response (PR). Tumour markers may be evaluated where appropriate

  • 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. ] [ Designated as safety issue: No ]
    Geometric mean AUC of Dexanabinol (0-infinity) on Cycle 1 Day 8.

  • 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. ] [ Designated as safety issue: No ]
    Geometric mean AUC of Cremophor (0-27hour) on Cycle 1 Day 1.

  • 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. ] [ Designated as safety issue: No ]
    Geometric mean AUC of Cremophor (0-27hour) on Cycle 1 Day 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. ] [ Designated as safety issue: No ]
    Mean Cmax of Dexanabinol on Cycle 1 Day 8

  • 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. ] [ Designated as safety issue: No ]
    Mean Cmax of Cremophor on Cycle 1 Day 1

  • 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. ] [ Designated as safety issue: No ]
    Mean Cmax of Cremophor on Cycle 1 Day 8


Enrollment: 40
Study Start Date: January 2012
Study Completion Date: July 2015
Primary Completion Date: July 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

  Eligibility

Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01489826

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     History of Changes
Other Study ID Numbers: ETS2101-001 
Study First Received: December 7, 2011
Results First Received: June 10, 2016
Last Updated: August 22, 2016
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by e-Therapeutics PLC:
Cancer

Additional relevant MeSH terms:
HU 211
Dronabinol
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
Hallucinogens
Psychotropic Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Cannabinoid Receptor Agonists
Cannabinoid Receptor Modulators
Hormones
Hormones, Hormone Substitutes, and Hormone Antagonists

ClinicalTrials.gov processed this record on December 02, 2016