Docetaxel With or Without AZD6244 in Melanoma

Phase 2

Completed

Conditions: Melanoma

Interventions: Drug: Docetaxel and AZD6244
Drug: Docetaxel and placebo

Registration Number: NCT01256359

Lead Sponsor: University of Oxford

Brief Summary: This is a randomised, double-blind placebo controlled phase 2 trial. Patient will be randomly assigned 1:1 between 2 treatment arms. They will receive either docetaxel 75mg/m2 IV and placebo given bd, or AZD6244 75mg bd daily with docetaxel 75mg/m2 IV. Docetaxel will be administered every 3 weeks for a maximum 6 cycles, but AZD6244/placebo may be continued beyond this, until disease progression. The objective is to assess whether the combination of AZD6244 with docetaxel is worthy of evaluation in a definitive randomised study, with the null hypothesis being that the combination has activity similar to that of docetaxel alone in this population. After consent has been obtained mutational analysis of tumour BRAF will be performed on archival tumour tissue, where this information is not already known, to assess eligibility for the study. If there is no archival tissue a fresh biopsy will be requested from the patient. A blood sample will also be taken for future genetic analysis. Once taking part in the trial patients will need to attend their oncology unit regularly for monitoring and the delivery of treatment. Patients will undergo complete physical examination at screening, on C1D1, C1D8, C1D15, C2D1, C2D8 and day 1 of every subsequent cycle. Blood for haematology, biochemistry and clotting will be taken at each of these visits. A 12 lead ECG will be performed at screening . Disease assessment will be by CT scanning using modified RECIST criteria after 9 and 18 weeks, then every 3 months until disease progression.

Detailed Description: No further information in addition to what has been provided in the brief summary

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 83

Inclusion Criteria

Aged >/= 16 years
Able to provide evidence from an accredited laboratory of wt BRAF status for their melanoma, or ascertainment of wt BRAF status from a sample of melanoma provided for mutational analysis in Oxford.
Unresectable stage 3 or 4, histologically proven cutaneous or unknown primary melanoma
At least 1 lesion, not previously irradiated, that can be accurately measured on CT or MRI as defined by modified RECIST criteria
ECOG performance score of 0 or 1.
Life expectancy of at least 12 weeks.
The patient is willing to give consent to the main study and able to comply with the protocol for the duration of the study, including scheduled follow-up visits and examinations.
Haematological and biochemical indices within the ranges shown below. Lab Test Value required Haemoglobin (Hb) >10g/dL White Blood Count (WBC) > 3x109/L Platelet count > 100,000/μL Absolute Neutrophil count > 1.5x109/L; Serum bilirubin ≤ 1.2 x ULN AST (SGOT) or ALT ≤ 2.5 x ULN LDH ≤ 2 x ULN Creatinine clearance (Cockcroft-Gault) >50 ml/min

Exclusion Criteria

Any anti-cancer therapy (including radiotherapy and participation in other clinical trials) within 28 days prior to Day 1.
Prior DNA damaging agents or cytotoxic chemotherapy for metastatic melanoma.
Any unresolved toxicity from prior anti-cancer therapy that is greater than CTCAE grade 2.
Pregnancy or breastfeeding women. Female patients must have a negative urinary or serum pregnancy test or have evidence of post-menopausal status (defined as absence of menstruation for > 12 months, bilateral oophrectomy or hysterectomy).
Grade ≥2 peripheral neuropathy at study entry.
Patients of reproductive potential who are not willing to use adequate contraceptive measures for the duration of the study (both male and female patients)
Known severe hypersensitivity reactions to docetaxel or other drugs formulated in polysorbate 80
Ocular or mucosal malignant melanoma
Another active malignancy within the past five years.
Evidence of brain metastases, unless surgically resected/stereotactic radiosurgery treated brain metastasis with no evidence of relapse on cerebral MRI, or treated brain metastasis and stable off treatment, including steroids, for 3 months.
Clinically significant and uncontrolled major medical condition(s): such as active infection, bleeding diathesis.
Patients who are known to be serologically positive for Hepatitis B, Hepatitis C or HIV.
Cardiac conditions, including uncontrolled hypertension (BP>160/100 despite treatment), heart failure NYHA class 2 or above, prior or current cardiomyopathy, myocardial infarction within 6 months or angina requiring nitrate therapy more than once a week.
Previous treatment with EGFR, ras, raf or MEK inhibitors.
Inability to swallow capsules, refractory nausea and vomiting, chronic gastrointestinal diseases (eg, inflammatory bowel disease) or significant bowel resection that would preclude adequate absorption.
Taking medication that significantly induces or inhibits CYP3A4.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Docetaxel and AZD6244	Docetaxel and AZD6244	Docetaxel with AZD6244
Docetaxel and Placebo	Docetaxel and placebo	Docetaxel without AZD6244

Primary Outcome Measures

Name	Time	Method
Progression Free Survival	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.	This is defined as time from date of randomisation to the first of date of progression (using CT scan, x-ray, MRI scan and clinical examination) using modified RECIST (v1.1) criteria or date of death (events). For patients without an event, the time from date of randomisation to date last known alive will be the censored PFS time.

Secondary Outcome Measures

Name	Time	Method
Biochemistry - Phosphate	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - phosphate.
Biochemistry - Sodium	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - sodium.
Objective Response Rate	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.	Objective response rate calculated as number of patients with Complete Response (CR) or Partial response (PR) over all patients randomised. The numerator of the objective response rate is the number of patients achieving a CR or PR. The denominator is all patients randomised. RECIST(v1.1) criteria was used for assessment.
Biochemistry - LDH	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - LDH.
Physical Exam - Skin	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - skin.
Physical Exam - Abdomen	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - abdomen.
Physical Exam - Extremities	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - extremities.
Physical Exam - Neurological	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - neurological.
Physical Exam - Other	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - other.
Overall Survival	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.	This is defined as the time from randomisation to death (event) or time from randomisation to date last known alive (censored time).
Overall Survival Results - Post Final Analysis	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.	OS analysis was carried out at the final analysis time point on data taken on 01Oct2012. Another data extraction was taken on 05Mar2013 in order to carry out posthoc analyses, OS was analysed again on this data. OS is time from randomisation to death (event) or time from randomisation to date last known alive (censored time).
Vital Signs - Temperature	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Vital signs - temperature.
Vital Signs - Pulse Rate	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Vital signs - pulse rate.
Vital Signs - Systolic Blood Pressure	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Vital signs - systolic blood pressure.
Vital Signs - Diastolic Blood Pressure	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Vital signs - diastolic blood pressure.
Haematology - Haemoglobin	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Haematology - haemoglobin.
Weight	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Weight.
Physical Exam - Cardiovascular	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - cardiovascular.
Physical Exam - Musculoskeletal	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - musculoskeletal.
Progression Free Survival Rate at 6 Months	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months.	PFS at 6 months is defined as the percentage progression free survival at 6 months from the PFS Kaplan Meier graph. This would allow all patients randomised to be included. progression was diagnosed using CT scan, x-ray, MRI scan and clinical examination using modified RECIST(v1.1) criteria.
Haematology - White Cell Count	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are median values across all time-points for all patients in that arm.	Haematology - white cell count.
Haematology - Neutrophils	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Haematology - neutrophils.
Haematology - Platelets	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Haematology - platelets.
Biochemistry - Calcium	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - calcium.
Biochemistry - Potassium	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - potassium.
Biochemistry - ALT	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - ALT.
Biochemistry - AST	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - AST.
Biochemistry - Albumin	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - albumin.
Physical Exam - Head and Neck	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - head and neck.
ECG - Post-dose	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	ECG - post-dose.
Urinalysis	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Urinalysis.
Biochemistry - GGT	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - GGT.
Physical Exam - Chest	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - chest.
Physical Exam - Lymph Nodes	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical exam - lymph nodes.
ECG - Pre-dose	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	ECG - pre-dose.
Biochemistry - Urea	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - urea.
Biochemistry - Bilirubin	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - bilirubin.
Biochemistry - Alkaline Phosphatase	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - alkaline phosphatase.
Biochemistry - Total Protein	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - total protein.
Biochemistry - Creatinine	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported value for each arm is median value across all time-points for all patients in that arm.	Biochemistry - creatinine.
Physical Assessment - General Appearance	From randomisation date to date of PFS event, if they did not have an event by the end of trial datalock (01Oct2012), an average of 9.3 months. Reported values for each arm are total counts across all time-points for all patients in that arm.	Physical assessment - general appearance.