Title

DOC-MEK

Chief Investigator: 

Sponsor: University of Oxford
EudraCT number: 2009-018153-23

A double blind randomised phase 2 trial of docetaxel with or without AZD6244 in wt BRAF advanced melanoma.  To determine the efficacy and tolerability of the combination of the selective MEK inhibitor AZD6244 with docetazel in patients with wild-type BRAF metastatic melanoma.
 

Study Status

Target recruitment of 80 patients was achieved in May 2012. Recruitment is closed and the patients have been unblinded. A small number of patients in the active treatment arm who have not experienced disease progression remain on open label drug.

The trial results were published in Annals of Oncology in May 2014 and the manuscript can be accessed from the link below. The trial results have also been presented at the Society for Melanoma Research (2012) and ASCO (2013).

Number of active sites:

2 (April 2015). Trial has been closed at all other participating Trusts.

 

DOC-MEK Publication: Gupta et al 2014, Annals of Oncology May 2014; 25(5):968-74 – PDF-File, 186.3 KB

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.

Objectives

Primary:

  • To assess the efficacy of AZD6244 in combination with docetaxel, compared with docetaxel alone, in first line patients with wild type BRAF advanced malignant melanoma.

Secondary:

  • To further assess the efficacy of AZD6244 in combination with docetaxel, compared with docetaxel alone, in first line patients with wild type BRAF advanced malignant melanoma.
  • To assess the safety and tolerability of AZD6244 in combination with docetaxel compared with docetaxel alone.

Exploratory:

  • To assess the impact of tumour characteristics on response to docetaxel therapy with or without AZD6244.
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