Solid Tumour
Conditions
Keywords
Cancer
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.
Interventions
DRUGDexanabinol
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.
OTHERCremophor
Drug vehicle.
Sponsors
e-Therapeutics PLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
| 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 |
| 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 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 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. |
| 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 |
| 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 |
| 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. |
Countries
United Kingdom
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Dexanabinol Dose Escalation - Cohort 1 Open label, dose escalation phase to assess tolerability and pharmacokinetics of dexanabinol in patients with advanced tumours | 3 |
| Dexanabinol Dose Escalation - Cohort 2 Open label, dose escalation phase to assess tolerability and pharmacokinetics of dexanabinol in patients with advanced tumours | 3 |
| Dexanabinol Dose Escalation - Cohort 3 Open label, dose escalation phase to assess tolerability and pharmacokinetics of dexanabinol in patients with advanced tumours | 3 |
| Dexanabinol Dose Escalation - Cohort 4 Open label, dose escalation phase to assess tolerability and pharmacokinetics of dexanabinol in patients with advanced tumours | 7 |
| Dexanabinol Dose Escalation - Cohort 5 Open label, dose escalation phase to assess tolerability and pharmacokinetics of dexanabinol in patients with advanced tumours | 3 |
| Dexanabinol Dose Escalation - Cohort 6 Open label, dose escalation phase to assess tolerability and pharmacokinetics of dexanabinol in patients with advanced tumours | 3 |
| Dexanabinol Dose Escalation - Cohort 7 Open label, dose escalation phase to assess tolerability and pharmacokinetics of dexanabinol in patients with advanced tumours | 9 |
| Dexanabinol Dose Escalation - Cohort 8 Open label, dose escalation phase to assess tolerability and pharmacokinetics of dexanabinol in patients with advanced tumours | 3 |
| Dexanabinol Expansion Phase Open label, expansion phase to assess pharmacodynamics of dexanabinol in patients with advanced tumours at the MTD/MAD (30 mg/kg) | 6 |
| Total | 40 |
Baseline characteristics
| Characteristic | Dexanabinol Dose Escalation - Cohort 2 | Dexanabinol Dose Escalation - Cohort 3 | Dexanabinol Dose Escalation - Cohort 4 | Dexanabinol Dose Escalation - Cohort 5 | Dexanabinol Dose Escalation - Cohort 6 | Dexanabinol Dose Escalation - Cohort 7 | Dexanabinol Dose Escalation - Cohort 8 | Dexanabinol Dose Escalation - Cohort 1 | Dexanabinol Expansion Phase | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 3 Participants | 7 Participants | 3 Participants | 3 Participants | 9 Participants | 3 Participants | 1 Participants | 6 Participants | 38 Participants |
| Age, Continuous | 61.3 years STANDARD_DEVIATION 7.64 | 69.0 years STANDARD_DEVIATION 11.14 | 57.9 years STANDARD_DEVIATION 7.27 | 52.3 years STANDARD_DEVIATION 5.51 | 62.0 years STANDARD_DEVIATION 13.11 | 64.6 years STANDARD_DEVIATION 6.91 | 63.7 years STANDARD_DEVIATION 12.7 | 66.7 years STANDARD_DEVIATION 10.21 | 56.3 years STANDARD_DEVIATION 12.75 | 61.2 years STANDARD_DEVIATION 9.69 |
| Gender Female | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 4 Participants | 12 Participants |
| Gender Male | 2 Participants | 3 Participants | 5 Participants | 2 Participants | 2 Participants | 9 Participants | 1 Participants | 2 Participants | 2 Participants | 28 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 7 / 7 | 3 / 3 | 3 / 3 | 9 / 9 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 3 / 3 | 2 / 3 | 1 / 3 | 2 / 7 | 2 / 3 | 1 / 3 | 5 / 9 | 1 / 3 | 2 / 6 |
Outcome results
Primary
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.
Time frame: Each patient will be followed for 22 days
Population: Patients will be sequentially assigned to increasing doses of Dexanabinol, to establish the MTD (highest dose it is safe to give patients) or alternatively the Maximum Administered Dose(MAD). DLT evaluation in 3 to 6 patients at end of 1 treatment cycle
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dexanabinol 2 mg/kg | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 0 Number of patients with DLT |
| Dexanabinol 3 mg/kg | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 0 Number of patients with DLT |
| Dexanabinol 6 mg/kg | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 0 Number of patients with DLT |
| Dexanabinol 12 mg/kg | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 1 Number of patients with DLT |
| Dexanabinol 15 mg/kg | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 0 Number of patients with DLT |
| Dexanabinol 22 mg/kg | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 0 Number of patients with DLT |
| Dexanabinol 30 mg/kg | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 0 Number of patients with DLT |
| Dexanabinol 36 mg/kg | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 2 Number of patients with DLT |
| Dexanabinol Expansion Phase | Number of Patients Experiencing Dose Limiting Toxicity (DLT) | 0 Number of patients with DLT |
Secondary
Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1
Geometric mean AUC of Cremophor (0-27hour) 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.
Population: This analysis was performed on all patients who received study drug and for whom PK samples were obtained (the PK analysis population). For the purposes of the PK analysis, the results from the expansion phase arm were combined with the 30 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dexanabinol 2 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | NA µL.h/mL | — |
| Dexanabinol 3 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | NA µL.h/mL | — |
| Dexanabinol 6 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | 10.3 µL.h/mL | Geometric Coefficient of Variation 101 |
| Dexanabinol 12 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | 46.2 µL.h/mL | Geometric Coefficient of Variation 69.9 |
| Dexanabinol 15 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | 29.5 µL.h/mL | Geometric Coefficient of Variation 64 |
| Dexanabinol 22 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | 92.4 µL.h/mL | Geometric Coefficient of Variation 40.5 |
| Dexanabinol 30 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | 120 µL.h/mL | Geometric Coefficient of Variation 39.1 |
| Dexanabinol 36 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 1 | 152 µL.h/mL | Geometric Coefficient of Variation 75.8 |
Secondary
Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8
Geometric mean AUC of Cremophor (0-27hour) 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.
Population: This analysis was performed on all patients who received study drug and for whom PK samples were obtained (the PK analysis population). For the purposes of the PK analysis, the results from the expansion phase arm were combined with the 30 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dexanabinol 2 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | NA µL.h/mL | — |
| Dexanabinol 3 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | 3.15 µL.h/mL | Geometric Coefficient of Variation 287 |
| Dexanabinol 6 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | 14.8 µL.h/mL | Geometric Coefficient of Variation 50.1 |
| Dexanabinol 12 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | 43.6 µL.h/mL | Geometric Coefficient of Variation 40 |
| Dexanabinol 15 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | 29.8 µL.h/mL | Geometric Coefficient of Variation 88.3 |
| Dexanabinol 22 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | 97.1 µL.h/mL | Geometric Coefficient of Variation 37 |
| Dexanabinol 30 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | 146 µL.h/mL | Geometric Coefficient of Variation 54.9 |
| Dexanabinol 36 mg/kg | Area Under Curve (AUC) of Cremophor on Cycle 1 Day 8 | 138 µL.h/mL | Geometric Coefficient of Variation 0 |
Secondary
Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1
Geometric mean AUC of Dexanabinol (0-infinity) 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.
Population: Concentrations of dexanabinol were not reported for some patients on Days 1 or 8 (including all patients in the 6 mg/kg arm) because the bioanalytical assay, in these instances, was not appropriately validated on the day of the assay. For the purposes of the PK analysis, the results from the expansion phase arm were combined with the 30 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dexanabinol 2 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 | 2620 ng.h/mL | Geometric Coefficient of Variation 33.9 |
| Dexanabinol 3 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 | 6520 ng.h/mL | Geometric Coefficient of Variation 0 |
| Dexanabinol 6 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 | 25000 ng.h/mL | Geometric Coefficient of Variation 53.3 |
| Dexanabinol 12 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 | 27500 ng.h/mL | Geometric Coefficient of Variation 5.99 |
| Dexanabinol 15 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 | 46900 ng.h/mL | Geometric Coefficient of Variation 41.9 |
| Dexanabinol 22 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 | 110000 ng.h/mL | Geometric Coefficient of Variation 59.9 |
| Dexanabinol 30 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 1 | 219000 ng.h/mL | Geometric Coefficient of Variation 0 |
Secondary
Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8
Geometric mean AUC of Dexanabinol (0-infinity) 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.
Population: Concentrations of dexanabinol were not reported for some patients on Days 1 or 8 (including all patients in the 6 mg/kg arm) because the bioanalytical assay, in these instances, was not appropriately validated on the day of the assay. For the purposes of the PK analysis, the results from the expansion phase arm were combined with the 30 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dexanabinol 2 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 | 2600 ng.h/mL | Geometric Coefficient of Variation 31.5 |
| Dexanabinol 3 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 | 5140 ng.h/mL | Geometric Coefficient of Variation 2.39 |
| Dexanabinol 6 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 | 29500 ng.h/mL | Geometric Coefficient of Variation 47.2 |
| Dexanabinol 12 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 | 45700 ng.h/mL | Geometric Coefficient of Variation 40.4 |
| Dexanabinol 15 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 | 96500 ng.h/mL | Geometric Coefficient of Variation 67.2 |
| Dexanabinol 22 mg/kg | Area Under Curve (AUC) of Dexanabinol on Cycle 1 Day 8 | 145000 ng.h/mL | Geometric Coefficient of Variation 0 |
Secondary
Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1
Mean Cmax of Cremophor on 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.
Population: This analysis was performed on all patients who received study drug and for whom PK samples were obtained (the PK analysis population). For the purposes of the PK analysis, the results from the expansion phase arm were combined with the 30 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dexanabinol 2 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | NA µL/mL | — |
| Dexanabinol 3 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | NA µL/mL | — |
| Dexanabinol 6 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | 1.30 µL/mL | Geometric Coefficient of Variation 21.2 |
| Dexanabinol 12 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | 3.42 µL/mL | Geometric Coefficient of Variation 46.9 |
| Dexanabinol 15 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | 2.72 µL/mL | Geometric Coefficient of Variation 11 |
| Dexanabinol 22 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | 7.78 µL/mL | Geometric Coefficient of Variation 33.3 |
| Dexanabinol 30 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | 8.49 µL/mL | Geometric Coefficient of Variation 33.3 |
| Dexanabinol 36 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 1 | 11.8 µL/mL | Geometric Coefficient of Variation 37.5 |
Secondary
Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8
Mean Cmax of Cremophor on 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.
Population: This analysis was performed on all patients who received study drug and for whom PK samples were obtained (the PK analysis population). For the purposes of the PK analysis, the results from the expansion phase arm were combined with the 30 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dexanabinol 2 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | NA µL/mL | — |
| Dexanabinol 3 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | 0.754 µL/mL | Geometric Coefficient of Variation 44.7 |
| Dexanabinol 6 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | 1.69 µL/mL | Geometric Coefficient of Variation 168 |
| Dexanabinol 12 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | 2.99 µL/mL | Geometric Coefficient of Variation 34.4 |
| Dexanabinol 15 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | 2.22 µL/mL | Geometric Coefficient of Variation 34.2 |
| Dexanabinol 22 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | 8.15 µL/mL | Geometric Coefficient of Variation 6.51 |
| Dexanabinol 30 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | 9.91 µL/mL | Geometric Coefficient of Variation 31.3 |
| Dexanabinol 36 mg/kg | Maximum Concentration (Cmax) of Cremophor Cycle 1 Day 8 | 10.1 µL/mL | Geometric Coefficient of Variation 0 |
Secondary
Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1
Mean Cmax of Dexanabinol on 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.
Population: Concentrations of dexanabinol were not reported for some patients on Days 1 or 8 (including all patients in the 6 mg/kg arm) because the bioanalytical assay, in these instances, was not appropriately validated on the day of the assay. For the purposes of the PK analysis, the results from the expansion phase arm were combined with the 30 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dexanabinol 2 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 | 606 ng/mL | Geometric Coefficient of Variation 20.9 |
| Dexanabinol 3 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 | 1580 ng/mL | Geometric Coefficient of Variation 0.895 |
| Dexanabinol 6 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 | 6950 ng/mL | Geometric Coefficient of Variation 76.8 |
| Dexanabinol 12 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 | 7790 ng/mL | Geometric Coefficient of Variation 24.8 |
| Dexanabinol 15 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 | 13000 ng/mL | Geometric Coefficient of Variation 27.4 |
| Dexanabinol 22 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 | 28800 ng/mL | Geometric Coefficient of Variation 62.3 |
| Dexanabinol 30 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 1 | 45600 ng/mL | Geometric Coefficient of Variation 0 |
Secondary
Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8
Mean Cmax of Dexanabinol on 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.
Population: Concentrations of dexanabinol were not reported for some patients on Days 1 or 8 (including all patients in the 6 mg/kg arm) because the bioanalytical assay, in these instances, was not appropriately validated on the day of the assay. For the purposes of the PK analysis, the results from the expansion phase arm were combined with the 30 mg/kg arm.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Dexanabinol 2 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 | 705 ng/mL | Geometric Coefficient of Variation 2.01 |
| Dexanabinol 3 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 | 1410 ng/mL | Geometric Coefficient of Variation 12.6 |
| Dexanabinol 6 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 | 8600 ng/mL | Geometric Coefficient of Variation 58.3 |
| Dexanabinol 12 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 | 9560 ng/mL | Geometric Coefficient of Variation 49.6 |
| Dexanabinol 15 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 | 14600 ng/mL | Geometric Coefficient of Variation 44 |
| Dexanabinol 22 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 | 27800 ng/mL | Geometric Coefficient of Variation 56.7 |
| Dexanabinol 30 mg/kg | Maximum Concentration (Cmax) of Dexanabinol Cycle 1 Day 8 | 34900 ng/mL | Geometric Coefficient of Variation 0 |
Secondary
Number of Adverse Events (AEs)
AEs will be graded according to the NCI CTCAE v4.03 for cancer clinical trials
Time frame: 30 +/-3 days from the end of the last infusion
Population: The numbers represent the total number of AEs per group. Refer to AE tables for specific information.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dexanabinol 2 mg/kg | Number of Adverse Events (AEs) | 68 Events |
| Dexanabinol 3 mg/kg | Number of Adverse Events (AEs) | 31 Events |
| Dexanabinol 6 mg/kg | Number of Adverse Events (AEs) | 26 Events |
| Dexanabinol 12 mg/kg | Number of Adverse Events (AEs) | 90 Events |
| Dexanabinol 15 mg/kg | Number of Adverse Events (AEs) | 64 Events |
| Dexanabinol 22 mg/kg | Number of Adverse Events (AEs) | 60 Events |
| Dexanabinol 30 mg/kg | Number of Adverse Events (AEs) | 85 Events |
| Dexanabinol 36 mg/kg | Number of Adverse Events (AEs) | 47 Events |
| Dexanabinol Expansion Phase | Number of Adverse Events (AEs) | 62 Events |
Secondary
Progression Free Survival
Tumour response evaluation using RECIST 1.1. (Assessment by CT scan or MRI).
Time frame: At Screening and after every 2 cycles of treatment (+/-1 week)
Population: Patients included in this analysis were from the 'Efficacy population', defined as those with a baseline and at least one post-baseline assessment of efficacy.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dexanabinol 2 mg/kg | Progression Free Survival | 133.0 Days |
| Dexanabinol 3 mg/kg | Progression Free Survival | 70.0 Days |
| Dexanabinol 6 mg/kg | Progression Free Survival | 37.0 Days |
| Dexanabinol 12 mg/kg | Progression Free Survival | 43.0 Days |
| Dexanabinol 15 mg/kg | Progression Free Survival | 176.0 Days |
| Dexanabinol 22 mg/kg | Progression Free Survival | 293.0 Days |
| Dexanabinol 30 mg/kg | Progression Free Survival | 40.5 Days |
| Dexanabinol 36 mg/kg | Progression Free Survival | NA Days |
| Dexanabinol Expansion Phase | Progression Free Survival | 37.0 Days |