Comparison of AZD6244 in Combination With Dacarbazine Versus (vs) Dacarbazine Alone in BRAF Mutation Positive Melanoma Patients

• Sponsor: AstraZeneca (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00936221
• Collaborator: (none)
• Enrollment: 385
• Locations: 38
• Arms: 2
• Duration (Months): 64
• Patients Per Site: 10.1
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

To assess the efficacy in terms of overall survival of AZD6244 in combination with dacarbazine, compared with dacarbazine alone, in first line patients with BRAF mutation positive advanced cutaneous or unknown primary melanoma

Condition or Disease	Intervention/Treatment	Phase
Melanoma	Drug: AZD6244; Drug: Dacarbazine; Drug: Placebo	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 385 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase II, Double-blind, Randomised Study to Assess the Efficacy of AZD6244 in Combination With Dacarbazine Compared With Dacarbazine Alone in First Line Patients With BRAF Mutation Positive Advanced Cutaneous or Unknown Primary Melanoma
• Study Start Date: Jul 1, 2009
• Actual Primary Completion Date: Nov 1, 2011
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: 1 AZD6244 in combination with dacarbazine	Drug: AZD6244; oral capsules, 75mg twice daily; Other Names: selumetinib ; Drug: Dacarbazine; 1000 mg/m2 iv infusion over at least 60 min. on day 1 of each 21 cycle; Other Names: DTIC
Placebo Comparator: 2 Placebo in combination with dacarbazine	Drug: Dacarbazine; 1000 mg/m2 iv infusion over at least 60 min. on day 1 of each 21 cycle; Other Names: DTIC ; Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Overall Survival [From date of randomization until death, withdrawal of consent or the end of the study. The end of the study was defined as the date all AZD6244 patients had been followed for a minimum of 12 months, or the date of final analysis, whichever was later]

   Following progression survival data was collected until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurred first.

Secondary Outcome Measures

1. Progression Free Survival [From randomization until evidence of RECIST-defined objective disease progression or data cut off, for a minimum of 12 months since start of treatment]

   PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression). Progression is defined using RECIST (v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm.

2. Objective Response Rate [From randomization until evidence of RECIST-defined objective disease progression or data cut off, for a minimum of 12 months since start of treatment]

   ORR rate is defined as the number (%) of subjects with at least one visit response of Complete Response (CR) or Partial Response (PR) , as defined by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions and assessed by CT or MRI. CR, Disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions. Data obtained up until progression, or last evaluable assessment in the absence of progression, was included in the assessment of ORR

3. Change in Target Lesion Tumour Size at Week 12 [randomization to week 12]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 130 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histological or cytological confirmation of advanced (inoperable stage III and stage

1. cutaneous or unknown primary melanoma

• Tumor sample confirmed as BRAF mutation positive

Exclusion Criteria:

• Diagnosis of uveal or mucosal melanoma

• Any prior Investigational therapy comprising inhibitors of Ras, Raf or MEK

• Having received an investigational drug within 30 days of starting treatment, or have not recovered from side effects of an investigational drug

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Site	Aurora	Colorado	United States
2	Research Site	Boston	Massachusetts	United States
3	Research Site	Belo Horizonte		Brazil
4	Research Site	Ijuí		Brazil
5	Research Site	Porto Alegre		Brazil
6	Research Site	Sao Paulo		Brazil
7	Research Site	Brno		Czech Republic
8	Research Site	Novy Jicin		Czech Republic
9	Research Site	Praha 2		Czech Republic
10	Research Site	Lille Cedex		France
11	Research Site	Marseille		France
12	Research Site	Villejuif Cedex		France
13	Research Site	Berlin		Germany
14	Research Site	Essen		Germany
15	Research Site	Hannover		Germany
16	Research Site	Kiel		Germany
17	Research Site	Tübingen		Germany
18	Research Site	Budapest		Hungary
19	Research Site	Györ		Hungary
20	Research Site	Székesfehérvár		Hungary
21	Research Site	Amsterdam		Netherlands
22	Research Site	Nijmegen		Netherlands
23	Research Site	Oslo		Norway
24	Research Site	Barcelona		Spain
25	Research Site	Houston		Spain
26	Research Site	Málaga		Spain
27	Research Site	Palma de Mallorca		Spain
28	Research Site	Göteborg		Sweden
29	Research Site	Malmö		Sweden
30	Research Site	Stockholm		Sweden
31	Research Site	Zürich		Switzerland
32	Research Site	Cambridge		United Kingdom
33	Research Site	Chelmsford		United Kingdom
34	Research Site	London		United Kingdom
35	Research Site	Manchester		United Kingdom
36	Research Site	Newcastle upon Tyne		United Kingdom
37	Research Site	Oxford		United Kingdom
38	Research Site	Sutton		United Kingdom

Sponsors and Collaborators

• AstraZeneca

Investigators

• Principal Investigator: Mark Middleton, Dr, Churchil Hospital, Oxford, UK
• Principal Investigator: Caroline Robert, Dr, Institute Gustave Roussy, France
• Study Director: Ian Smith, Dr, AstraZeneca, Alderley Park, UK

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info
• D1532C00006.pdf

Publications

None provided.

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT00936221
• Other Study ID Numbers: D1532C00006
• First Posted: Jul 9, 2009
• Last Update Posted: Mar 14, 2016
• Last Verified: Feb 1, 2016

• Keywords provided by AstraZeneca: BRAF mutation positive; advanced melanoma; Advanced cutaneous melanoma; Unknown primary melanoma
• Additional relevant MeSH terms: Melanoma; Dacarbazine

Study Results

Participant Flow

Arm/Group Title	Selumetinib 75mg BD +Dacarbazine	Placebo BD + Dacarbazine
Arm/Group Description	selumetinib 75mg twice daily + Dacarbazine	Placebo twice daily + Dacarbazine
Period Title: Overall Study
STARTED	45	46
Received Treatment	44	45
COMPLETED	44	45
NOT COMPLETED	1	1

Baseline Characteristics

Arm/Group Title	Selumetinib 75mg BD +Dacarbazine	Placebo BD + Dacarbazine	Total
Arm/Group Description	selumetinib 75mg twice daily + Dacarbazine	Placebo twice daily + Dacarbazine	Total of all reporting groups
Overall Participants	45	46	91
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	55.7 (14.89)	51.6 (16.21)	53.6 (15.62)
Sex: Female, Male (Count of Participants)
Female	23 51.1%	18 39.1%	41 45.1%
Male	22 48.9%	28 60.9%	50 54.9%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	Following progression survival data was collected until documentation of death, withdrawal of consent, loss to follow-up or the final data cut-off, whichever occurred first.
Time Frame	From date of randomization until death, withdrawal of consent or the end of the study. The end of the study was defined as the date all AZD6244 patients had been followed for a minimum of 12 months, or the date of final analysis, whichever was later

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT)

Arm/Group Title	Selumetinib 75mg BD + Dacarbazine	Placebo + Dacarbazine
Arm/Group Description	selumetinib 75mg twice daily + dacarbazine	Matched Placebo + dacarbazine
Measure Participants	45	46
Median (Full Range) [Days]	424	321

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Selumetinib 75mg BD + Dacarbazine, Placebo + Dacarbazine
	Comments	If the true hazard ratio (HR) is 0.57, 58 deaths provides at least 80% power to demonstrate a statistically significant difference for OS, assuming a 1-sided 10% significance level.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.3873
	Comments	1-sided p-value
	Method	Regression, Cox
	Comments	Cox model adjusting for treatment, WHO performance status, LDH, M status and tumour sub-type.
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 80%; 0.67 to 1.28
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Progression Free Survival
Description	PFS is the time from randomisation until the date of objective disease progression as defined by Response Evaluation Criteria In Solid Tumours (RECIST version 1.1) or death (by any cause in the absence of progression). Progression is defined using RECIST (v1.1), as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm.
Time Frame	From randomization until evidence of RECIST-defined objective disease progression or data cut off, for a minimum of 12 months since start of treatment

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT)

Arm/Group Title	Selumetinib 75mg BD + Dacarbazine	Placebo + Dacarbazine
Arm/Group Description	selumetinib 75mg twice daily + dacarbazine	Matched Placebo + dacarbazine
Measure Participants	45	46
Median (Full Range) [Days]	169	92

3. Secondary Outcome

Title	Objective Response Rate
Description	ORR rate is defined as the number (%) of subjects with at least one visit response of Complete Response (CR) or Partial Response (PR) , as defined by Response Evaluation Criteria in Solid Tumours (RECIST v1.1) for target lesions and assessed by CT or MRI. CR, Disappearance of all target lesions; PR, ≥30% decrease in the sum of the longest diameter of target lesions. Data obtained up until progression, or last evaluable assessment in the absence of progression, was included in the assessment of ORR
Time Frame	From randomization until evidence of RECIST-defined objective disease progression or data cut off, for a minimum of 12 months since start of treatment

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT)

Arm/Group Title	Selumetinib 75mg BD + Dacarbazine	Placebo + Dacarbazine
Arm/Group Description	selumetinib 75mg twice daily + dacarbazine	Matched Placebo + dacarbazine
Measure Participants	45	46
Response	18 40%	12 26.1%
Complete Response	1 2.2%	1 2.2%
Partial Response	17 37.8%	11 23.9%
Non-response	27 60%	34 73.9%
Stable Disease >=6 weeks	13 28.9%	10 21.7%
Progression	14 31.1%	24 52.2%

4. Secondary Outcome

Title	Change in Target Lesion Tumour Size at Week 12
Time Frame	randomization to week 12

Outcome Measure Data

Analysis Population Description

Intention to Treat (ITT)

Arm/Group Title	Selumetinib 75mg BD + Dacarbazine	Placebo + Dacarbazine
Arm/Group Description	selumetinib 75mg twice daily + dacarbazine	Matched Placebo + dacarbazine
Measure Participants	45	46
Median (Full Range) [% change]	-8.85	0.22

Adverse Events

Arm/Group Title	Selumetinib 75mg BD +Dacarbazine		Placebo BD + Dacarbazine
Arm/Group Description	selumetinib 75mg twice daily + Dacarbazine		Placebo twice daily + Dacarbazine
All Cause Mortality
	Selumetinib 75mg BD +Dacarbazine		Placebo BD + Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Selumetinib 75mg BD +Dacarbazine		Placebo BD + Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	22/44 (50%)		8/45 (17.8%)
Blood and lymphatic system disorders
Disseminated intravascular coagulation	1/44 (2.3%)		0/45 (0%)
Febrile neutropenia	1/44 (2.3%)		0/45 (0%)
Neutropenia	1/44 (2.3%)		0/45 (0%)
Thrombocytopenia	1/44 (2.3%)		1/45 (2.2%)
Anaemia	0/44 (0%)		1/45 (2.2%)
Cardiac disorders
Left atrial dilatation	1/44 (2.3%)		0/45 (0%)
Eye disorders
Periorbital oedema	1/44 (2.3%)		0/45 (0%)
Ocular hypertension	0/44 (0%)		1/45 (2.2%)
Retinal tear	0/44 (0%)		1/45 (2.2%)
Gastrointestinal disorders
Abdominal pain	3/44 (6.8%)		1/45 (2.2%)
Vomiting	2/44 (4.5%)		1/45 (2.2%)
Diarrhoea	1/44 (2.3%)		0/45 (0%)
Constipation	0/44 (0%)		1/45 (2.2%)
General disorders
Chest pain	1/44 (2.3%)		0/45 (0%)
Pyrexia	1/44 (2.3%)		0/45 (0%)
Asthenia	0/44 (0%)		1/45 (2.2%)
Fatigue	0/44 (0%)		2/45 (4.4%)
Infections and infestations
Erysipelas	2/44 (4.5%)		0/45 (0%)
Cellulitis	1/44 (2.3%)		0/45 (0%)
Clostridium difficile colitis	1/44 (2.3%)		0/45 (0%)
Device related infection	1/44 (2.3%)		0/45 (0%)
Infection	1/44 (2.3%)		0/45 (0%)
Lower respiratory tract infection	1/44 (2.3%)		0/45 (0%)
Sepsis	1/44 (2.3%)		2/45 (4.4%)
Neutropenic sepsis	0/44 (0%)		1/45 (2.2%)
Pneumonia	0/44 (0%)		1/45 (2.2%)
Investigations
Alanine aminotransferase increased	1/44 (2.3%)		0/45 (0%)
Aspartate aminotransferase increased	1/44 (2.3%)		0/45 (0%)
Musculoskeletal and connective tissue disorders
Groin Pain	1/44 (2.3%)		0/45 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Intracranial tumour haemorrhage	1/44 (2.3%)		0/45 (0%)
Prostate cancer	1/44 (2.3%)		0/45 (0%)
Colon cancer	0/44 (0%)		1/45 (2.2%)
Nervous system disorders
Syncope	1/44 (2.3%)		0/45 (0%)
Psychiatric disorders
Completed suicide	0/44 (0%)		1/45 (2.2%)
Renal and urinary disorders
Renal colic	1/44 (2.3%)		0/45 (0%)
Reproductive system and breast disorders
Prostatitis	1/44 (2.3%)		0/45 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional	1/44 (2.3%)		0/45 (0%)
Pulmonary embolism	1/44 (2.3%)		1/45 (2.2%)
Skin and subcutaneous tissue disorders
Rash	1/44 (2.3%)		0/45 (0%)
Vascular disorders
Arterial thrombosis limb	1/44 (2.3%)		0/45 (0%)
Venous thrombosis limb	1/44 (2.3%)		0/45 (0%)
Deep vein thrombosis	0/44 (0%)		1/45 (2.2%)
Other (Not Including Serious) Adverse Events
	Selumetinib 75mg BD +Dacarbazine		Placebo BD + Dacarbazine
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/44 (100%)		44/45 (97.8%)
Blood and lymphatic system disorders
ANAEMIA	4/44 (9.1%)		2/45 (4.4%)
LEUKOPENIA	1/44 (2.3%)		3/45 (6.7%)
NEUTROPENIA	7/44 (15.9%)		7/45 (15.6%)
Thrombocytopenia	11/44 (25%)		6/45 (13.3%)
Eye disorders
EYELID OEDEMA	3/44 (6.8%)		0/45 (0%)
PERIORBITAL OEDEMA	4/44 (9.1%)		1/45 (2.2%)
Gastrointestinal disorders
Abdominal Pain	9/44 (20.5%)		4/45 (8.9%)
Abdominal Pain Upper	4/44 (9.1%)		4/45 (8.9%)
Constipation	12/44 (27.3%)		13/45 (28.9%)
DIARRHOEA	21/44 (47.7%)		13/45 (28.9%)
DRY MOUTH	6/44 (13.6%)		0/45 (0%)
DYSPEPSIA	6/44 (13.6%)		2/45 (4.4%)
FLATULENCE	1/44 (2.3%)		5/45 (11.1%)
GASTROOESOPHAGEAL REFLUX DISEASE	3/44 (6.8%)		0/45 (0%)
NAUSEA	28/44 (63.6%)		25/45 (55.6%)
STOMATITIS	8/44 (18.2%)		5/45 (11.1%)
VOMITING	20/44 (45.5%)		14/45 (31.1%)
General disorders
ASTHENIA	12/44 (27.3%)		5/45 (11.1%)
CHILLS	3/44 (6.8%)		1/45 (2.2%)
FACE OEDEMA	3/44 (6.8%)		1/45 (2.2%)
FATIGUE	16/44 (36.4%)		15/45 (33.3%)
GENERALISED OEDEMA	6/44 (13.6%)		2/45 (4.4%)
LOCALISED OEDEMA	3/44 (6.8%)		0/45 (0%)
OEDEMA PERIPHERAL	19/44 (43.2%)		3/45 (6.7%)
PYREXIA	5/44 (11.4%)		5/45 (11.1%)
Infections and infestations
FOLLICULITIS	5/44 (11.4%)		0/45 (0%)
NASOPHARYNGITIS	3/44 (6.8%)		6/45 (13.3%)
PARONYCHIA	6/44 (13.6%)		0/45 (0%)
RASH PUSTULAR	6/44 (13.6%)		0/45 (0%)
UPPER RESPIRATORY TRACT INFECTION	4/44 (9.1%)		2/45 (4.4%)
URINARY TRACT INFECTION	5/44 (11.4%)		0/45 (0%)
Investigations
ALANINE AMINOTRANSFERASE INCREASED	4/44 (9.1%)		3/45 (6.7%)
ASPARTATE AMINOTRANSFERASE INCREASED	5/44 (11.4%)		1/45 (2.2%)
BLOOD CREATININE PHOSPHOKINASE INCREASED	7/44 (15.9%)		0/45 (0%)
BLOOD PRESSURE INCREASED	4/44 (9.1%)		0/45 (0%)
WEIGHT INCREASED	3/44 (6.8%)		0/45 (0%)
Metabolism and nutrition disorders
DECREASED APPETITE	10/44 (22.7%)		11/45 (24.4%)
HYPOKALAEMIA	3/44 (6.8%)		0/45 (0%)
Musculoskeletal and connective tissue disorders
ARTHRALGIA	4/44 (9.1%)		3/45 (6.7%)
BACK PAIN	7/44 (15.9%)		3/45 (6.7%)
MYALGIA	3/44 (6.8%)		1/45 (2.2%)
PAIN IN EXTREMITY	3/44 (6.8%)		4/45 (8.9%)
Nervous system disorders
DIZZINESS	6/44 (13.6%)		2/45 (4.4%)
DYSGEUSIA	4/44 (9.1%)		4/45 (8.9%)
HEADACHE	5/44 (11.4%)		12/45 (26.7%)
LETHARGY	2/44 (4.5%)		4/45 (8.9%)
PARAESTHESIA	3/44 (6.8%)		4/45 (8.9%)
SYNCOPE	4/44 (9.1%)		0/45 (0%)
Psychiatric disorders
ANXIETY	5/44 (11.4%)		5/45 (11.1%)
BRADYPHRENIA	0/44 (0%)		3/45 (6.7%)
DEPRESSION	3/44 (6.8%)		2/45 (4.4%)
INSOMNIA	3/44 (6.8%)		3/45 (6.7%)
Respiratory, thoracic and mediastinal disorders
COUGH	3/44 (6.8%)		4/45 (8.9%)
DYSPNOEA EXERTIONAL	8/44 (18.2%)		6/45 (13.3%)
EPISTAXIS	3/44 (6.8%)		1/45 (2.2%)
DYSPNOEA	3/44 (6.8%)		2/45 (4.4%)
Skin and subcutaneous tissue disorders
DERMATITIS ACNEIFORM	23/44 (52.3%)		1/45 (2.2%)
DRY SKIN	10/44 (22.7%)		2/45 (4.4%)
ECZEMA	5/44 (11.4%)		1/45 (2.2%)
ERYTHEMA	4/44 (9.1%)		1/45 (2.2%)
EXFOLIATIVE RASH	3/44 (6.8%)		1/45 (2.2%)
HAIR COLOUR CHANGES	4/44 (9.1%)		0/45 (0%)
NIGHT SWEATS	3/44 (6.8%)		4/45 (8.9%)
PALMAR-PLANTAR ERYTHRODYSAESTHESIA SYNDROME	5/44 (11.4%)		0/45 (0%)
PRURITUS	3/44 (6.8%)		2/45 (4.4%)
SKIN CHAPPED	4/44 (9.1%)		0/45 (0%)
SKIN FISSURES	3/44 (6.8%)		0/45 (0%)
ALOPECIA	6/44 (13.6%)		2/45 (4.4%)
Vascular disorders
HYPERTENSION	8/44 (18.2%)		1/45 (2.2%)
LYMPHOEDEMA	11/44 (25%)		2/45 (4.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.