AZD2171 in Treating Patients With Recurrent or Stage IV Melanoma

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00243061
• Collaborator: (none)
• Enrollment: 24
• Location: 1
• Arm: 1
• Duration (Months): 74
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This phase II trial is studying how well AZD2171 works in treating patients with recurrent or stage IV melanoma. AZD2171 may stop the growth of tumor cells by blocking blood flow to the tumor and by blocking some of the enzymes needed for cell growth.

Condition or Disease	Intervention/Treatment	Phase
Acral Lentiginous Malignant Melanoma; Ciliary Body and Choroid Melanoma, Medium/Large Size; Ciliary Body and Choroid Melanoma, Small Size; Extraocular Extension Melanoma; Intraocular Melanoma; Iris Melanoma; Lentigo Maligna Malignant Melanoma; Recurrent Melanoma; Stage, Intraocular Melanoma; Stage IV Melanoma; Superficial Spreading Malignant Melanoma	Drug: cediranib maleate	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess the objective tumor response rate of AZD2171 administered to patients with recurrent or metastatic malignant melanoma.

2. To assess the toxicity, median survival time, 1-year survival rate, response or stable disease duration, time to disease progression and clinical benefit response of AZD2171 administered to patients with recurrent or metastatic malignant melanoma.

3. To measure baseline and post-treatment levels of angiogenic growth factors and receptors, as well as circulating endothelial cells, and to explore the relationship between these potential correlative endpoints and clinical outcome.

4. To assess changes in blood flow and vessel permeability using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) pre- and post-treatment, and to explore the relationship between these potential imaging endpoints and clinical outcome.

5. To look for polymorphisms of kdr/flk-1, and other genes in this pathway, by performing pharmacogenetic analysis of pbmc's, and correlate genotype with VEGF levels and response to therapy.

OUTLINE: This is an open-label, multicenter study.

Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed for survival.

Study Design

• Study Type: Interventional
• Actual Enrollment: 24 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Study of AZD2171 in Previously Untreated Patients With Metastatic or Recurrent Malignant Melanoma
• Study Start Date: Jan 1, 2006
• Actual Primary Completion Date: Mar 1, 2012
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (cediranib maleate) Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: cediranib maleate; Given orally; Other Names: AZD2171

Outcome Measures

Primary Outcome Measures

1. Objective Tumor Response (Partial or Complete Response) According to RECIST [Up to 6 years]

   Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [J Nat Cancer Inst 92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions, assessed by CT or MRI; Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR."

2. Prolonged Stable Disease According to RECIST [Up to 6 months]

Secondary Outcome Measures

1. Median Survival Time [Up to 6 years]

2. Survival Rate [At 1 year]

3. Response Duration [From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 6 years]

4. Stable Disease Duration [From the start of the treatment until the criteria for progression are met, assessed up to 6 years]

5. Highest Toxicity Grade Assessed by NCI CTCAE Version 3.0 [Up to 6 years after completion of treatment]

6. Time to Disease Progression [Up to 6 years]

7. Clinical Benefit Response [Up to 6 years]

8. Changes in Levels of Soluble Angiogenic Factors [From baseline to up to 6 years]

9. Change in Vessel Permeability and Blood Flow by DCE-MRI [From baseline to up to 28 days after starting daily oral dosing]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Histologically/cytologically confirmed recurrent/metastatic malignant melanoma (stage IV acral lentiginous, lentigo maligna, superficial spreading or ocular malignant melanoma)

• Measurable disease- at least 1 lesion accurately measured in at least 1 dimension (longest diameter) as >=20mm with conventional techniques or >=10mm with spiral CT scan

• Previously irradiated lesions not considered measurable unless they demonstrated progression prior to study entry

• No prior chemotherapy (including regional therapy); prior adjuvant immunotherapy permitted if completed >3 months prior to study entry; patients may have received prior radiation therapy if completed >=4 weeks prior to study entry

• Previous surgery permissible if performed >=4 weeks prior to study entry

• Life expectancy >12 weeks

• ECOG performance status=< 2 (Karnofsky>=60%)

• Leukocytes>=3,000/mcL

• Absolute neutrophil count>=1,500/mcL

• Platelets>=100,000/mcL

• Hemoglobin>=8g/dL

• Total bilirubin<1.5x institutional ULN (IULN)

• AST/ALT=<3 x IULN (5xULN if liver metastases)

• Creatinine within IULN

• Creatinine within IULN OR

• Creatinine clearance>=60mL/min/m^2 if creatinine levels above IULN

• Baseline blood pressure <140/90mmHg; may be taking antihypertensive medications

• AZD2171 has shown to terminate fetal development in rat as expected for process dependent on VEGF signaling; women of childbearing potential must have negative pregnancy test prior to study entry; women of childbearing potential/men must agree to use adequate contraception (hormonal/barrier method of birth control; abstinence) prior to study entry and for duration of study

• Ability to understand/willingness to sign written informed consent

Exclusion Criteria:

• Any previous chemotherapy or immunotherapy for recurrent/metastatic disease; patients who have had radiotherapy or major surgery within 4 weeks prior to entering study or those who have not recovered from AEs due to treatment received more than 4 weeks earlier

• May not be concurrently receiving other investigational agents nor have participated in an investigational trial of bio-, chemo- or immunotherapy agents

• Known brain metastases because of their poor prognosis and because patients often develop progressive neurologic dysfunction that would confound evaluation of neurologic and other AEs

• History of allergic reactions attributed to compounds of similar chemical/biologic composition to AZD2171

• Mean QTc>470msec (Bazett's correction) in screening electrocardiogram or history of familial long QT syndrome

• +1 proteinuria on 2 consecutive dipsticks taken no less than 1 week apart

• Uncontrolled intercurrent illness including but not limited to hypertension, ongoing/active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

• Pregnant women excluded from study because AZD2171 is a VEGF inhibitor with known abortifacient effects; breastfeeding should be discontinued if mother is treated with AZD2171

• HIV-positive patients on combination antiretroviral therapy are ineligible because of potential for PK interactions with AZD2171; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated

• Any significant abnormality noted in ECG within 14 days of treatment

• A NYHA classification of III or IV (NOTE: Patients classified as class II controlled with treatment may continue with increase monitoring)

• Conditions requiring concurrent use of drugs/biologics with proarrhythmic potential; these drugs are prohibited during studies with AZD2171

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Princess Margaret Hospital Phase 2 Consortium	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Elaine McWhirter, Princess Margaret Hospital Phase 2 Consortium

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00243061
• Other Study ID Numbers: NCI-2012-03026; PHL-038; N01CM62203; N01CM62201
• First Posted: Oct 21, 2005
• Last Update Posted: Aug 27, 2018
• Last Verified: Jul 1, 2018

• Additional relevant MeSH terms: Melanoma; Uveal Neoplasms; Hutchinson's Melanotic Freckle; Lentigo; Recurrence; Cediranib

Study Results

Participant Flow

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
Period Title: Overall Study
STARTED	24
COMPLETED	24
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
Overall Participants	24
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	67
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	11 45.8%
>=65 years	13 54.2%
Sex: Female, Male (Count of Participants)
Female	7 29.2%
Male	17 70.8%
Region of Enrollment (participants) [Number]
Canada	10 41.7%
United States	14 58.3%

Outcome Measures

1. Primary Outcome

Title	Objective Tumor Response (Partial or Complete Response) According to RECIST
Description	Response and progression will be evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [J Nat Cancer Inst 92(3):205-216, 2000]. Changes in only the largest diameter (unidimensional measurement) of the tumor lesions, assessed by CT or MRI; Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR."
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

Out of 24 patients analyzed, 0 patients had objective response of PR or CR as defined by RECIST

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
Measure Participants	24
Number [participants]	0 0%

2. Primary Outcome

Title	Prolonged Stable Disease According to RECIST
Time Frame	Up to 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally
Measure Participants	24
Number [participants]	9 37.5%

3. Secondary Outcome

Title	Median Survival Time
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally
Measure Participants	24
Median (95% Confidence Interval) [months]	9.9

4. Secondary Outcome

Title	Survival Rate
Time Frame	At 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally
Measure Participants	24
Number (95% Confidence Interval) [percentage of participants]	41 170.8%

5. Secondary Outcome

Title	Response Duration
Time Frame	From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 6 years

Outcome Measure Data

Analysis Population Description

None of the patients had Partial or complete response

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally
Measure Participants	24
Number [months]	0

6. Secondary Outcome

Title	Stable Disease Duration
Time Frame	From the start of the treatment until the criteria for progression are met, assessed up to 6 years

Outcome Measure Data

Analysis Population Description

Only 17 of the 24 accrued patients were evaluable for response

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
Measure Participants	17
Median (95% Confidence Interval) [months]	4.6

7. Secondary Outcome

Title	Highest Toxicity Grade Assessed by NCI CTCAE Version 3.0
Time Frame	Up to 6 years after completion of treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
Measure Participants	23
Number [highest grade]	4

8. Secondary Outcome

Title	Time to Disease Progression
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

9 patients developed progressive disease

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally
Measure Participants	24
Median (95% Confidence Interval) [months]	4.1

9. Secondary Outcome

Title	Clinical Benefit Response
Time Frame	Up to 6 years

Outcome Measure Data

Analysis Population Description

data were not collected

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
Measure Participants	0

10. Secondary Outcome

Title	Changes in Levels of Soluble Angiogenic Factors
Time Frame	From baseline to up to 6 years

Outcome Measure Data

Analysis Population Description

data were not collected

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
Measure Participants	0

11. Secondary Outcome

Title	Change in Vessel Permeability and Blood Flow by DCE-MRI
Time Frame	From baseline to up to 28 days after starting daily oral dosing

Outcome Measure Data

Analysis Population Description

data were not collected

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
Measure Participants	0

Adverse Events

Arm/Group Title	Treatment (Cediranib Maleate)
Arm/Group Description	Patients receive oral AZD2171 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. cediranib maleate: Given orally laboratory biomarker analysis: Correlative studies dynamic contrast-enhanced magnetic resonance imaging: Correlative studies
All Cause Mortality
	Treatment (Cediranib Maleate)
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Treatment (Cediranib Maleate)
	Affected / at Risk (%)	# Events
Total	9/24 (37.5%)
Eye disorders
Blurred vision	1/24 (4.2%)
Gastrointestinal disorders
Abdominal pain	1/24 (4.2%)
Anorexia	1/24 (4.2%)
Nausea	1/24 (4.2%)
Vomiting	1/24 (4.2%)
Diarrhea	1/24 (4.2%)
General disorders
Non-cardiac chest pain	1/24 (4.2%)
Fatigue	1/24 (4.2%)
Infections and infestations
Infections and infestations - Other, specify	1/24 (4.2%)
Investigations
Aspartate aminotransferase increased	1/24 (4.2%)
Metabolism and nutrition disorders
Dehydration	3/24 (12.5%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/24 (4.2%)
Nervous system disorders
Dizziness	1/24 (4.2%)
Dysphasia	1/24 (4.2%)
Vascular disorders
Hypertension	3/24 (12.5%)
Other (Not Including Serious) Adverse Events
	Treatment (Cediranib Maleate)
	Affected / at Risk (%)	# Events
Total	24/24 (100%)
Gastrointestinal disorders
Diarrhea	18/24 (75%)
General disorders
Fatigue	19/24 (79.2%)
Metabolism and nutrition disorders
Hyperglycemia	15/24 (62.5%)
Vascular disorders
Hypertension	17/24 (70.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.