AZD2171 + Chemotherapy in Advanced NSCLC, Colorectal Cancer, or Other Cancer Suitable for Treatment With Capecitabine (Non-Small Lung Cancer Patients Closed to Enrollment as 8/9/07)

Sponsor

NCIC Clinical Trials Group (Other)

Overall Status

Completed

CT.gov ID

NCT00107250

Collaborator

(none)

Enrollment

Locations

Arm

72.1

Actual Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

RATIONALE: AZD2171 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy, such as paclitaxel, carboplatin, or capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving AZD2171 together with chemotherapy may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of AZD2171 when given together with chemotherapy in treating patients with advanced non-small cell lung cancer (closed to enrollment as of 8/9/07), colorectal cancer, or other cancer suitable to capecitabine treatment.

Condition or Disease	Intervention/Treatment	Phase
Colorectal Cancer Lung Cancer Unspecified Adult Solid Tumor, Protocol Specific	Drug: capecitabine Drug: carboplatin Drug: cediranib maleate Drug: paclitaxel	Phase 1

Detailed Description

OBJECTIVES:

Determine the maximum tolerated dose and recommended phase II dose of AZD2171 when administered in combination with standard chemotherapy comprising either paclitaxel and carboplatin OR capecitabine in patients with advanced incurable non-small cell lung cancer (closed to accrual as of 8/9/07), colorectal cancer, or other tumor types suitable for treatment with capecitabine.
Determine the safety and tolerability of these regimens in these patients.
Determine the toxicity profile and dose-limiting toxic effects of these regimens in these patients.
Determine the pharmacokinetic profile of these regimens in these patients.
Correlate the toxicity profile with the pharmacokinetic profile of these regimens in these patients.
Determine the antitumor activity of these regimens in patients with measurable disease.
Correlate patient outcome (response) with baseline (using tumor samples) and serial (using urine and plasma samples) biomarkers in patients treated with these regimens.

OUTLINE: This is an open-label, multicenter, dose-escalation study of AZD2171. Patients are assigned to 1 of 2 treatment groups according to diagnosis.

Group 1 (non-small cell lung cancer) (closed to accrual as of 8/9/07): Patients receive paclitaxel IV and carboplatin IV on day 1. Patients also receive oral AZD2171 once daily on days 2-21 of course 1 and on days 1-21 of all subsequent courses. Treatment with paclitaxel and carboplatin repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity. Treatment with AZD2171 repeats every 21 days in the absence of disease progression or unacceptable toxicity.
Group 2 (colorectal or other tumor types): Patients receive oral capecitabine twice daily on days 1-14. Patients also receive oral AZD2171 once daily on days 8-21 of course 1 and on days 1-21 of all subsequent courses. Treatment with capecitabine repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Treatment with AZD2171 repeats every 21 days in the absence of disease progression or unacceptable toxicity.

In both groups, patients achieving a complete response (CR) OR a stable partial response (SPR) receive 2 additional courses beyond CR or SPR.

Cohorts of 3-6 patients per group receive escalating doses of AZD2171 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 6 patients experience dose-limiting toxicity. Up to 30 additional patients (20 in group 1 and 10 in group 2) will be treated at the MTD.

After completion of study treatment, patients are followed at 4 weeks and then every 3 months until disease relapse.

PROJECTED ACCRUAL: A total of 3-35 patients will be accrued for this study.

Study Design

Study Type:

Interventional

Actual Enrollment :

50 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase I, Open-Label, Dose-Seeking Study of AZD2171 Given Daily Orally in Combination With Standard Chemotherapy Regimens (CT) in Patients With Advanced Incurable Non-Small Cell Lung Cancer (NSCLC) or Colorectal Cancer or Other Tumor Types Suitable for Treatment With Capecitabine

Actual Study Start Date :

Jan 13, 2005

Actual Primary Completion Date :

Oct 23, 2009

Actual Study Completion Date :

Jan 18, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: AZD2171 + Standard chemotherpay regimens	Drug: capecitabine 1000 mg/m2 orally twice daily (total of 2000 mg/m2 per day) for the first 14 days of a 21 day cycle for a maximum of 6-8 cycles. Drug: carboplatin AUC 6; IV; 30 minutes; Every 21 days for a maximum of 6-8 cycles Drug: cediranib maleate Given daily; orally with approximately 240 ml of water whilst in an upright position Drug: paclitaxel 200mg/m2; IV; 3 hours; Every 21 days for a maximum of 6-8 cycles

Arm

Intervention/Treatment

Experimental: AZD2171 + Standard chemotherpay regimens

Drug: capecitabine

1000 mg/m2 orally twice daily (total of 2000 mg/m2 per day) for the first 14 days of a 21 day cycle for a maximum of 6-8 cycles.

Drug: carboplatin

AUC 6; IV; 30 minutes; Every 21 days for a maximum of 6-8 cycles

Drug: cediranib maleate

Given daily; orally with approximately 240 ml of water whilst in an upright position

Drug: paclitaxel

200mg/m2; IV; 3 hours; Every 21 days for a maximum of 6-8 cycles

Outcome Measures

Primary Outcome Measures

Dose limiting toxicity [Each dose level]
To recommend phase II dose of AZD2171 when given orally daily in combination with standard chemotherapy in patients with advanced NSCLC or colon cancer or other tumour types suitable for treatment with capecitabine.

Secondary Outcome Measures

Safety [Each dose level]
safety, tolerability, toxicity profile, dose limiting toxicities and pharmacokinetic profile of AZD2171 and standard chemotherapy given in these combinations. The correlation, if any,between the toxicity profile and the pharmacokinetics will be determined.
Anti-tumour activity [Each dose level]
Assessing the anti-tumour activity of AZD2171 in combination with standard chemotherapy regimens in patients with measurable disease.
Tumour Response [Each dose level]
To correlate patient outcomes (response) with baseline (tumour) and serial (urine and plasma) biomarkers

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 120 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

DISEASE CHARACTERISTICS:

Histologically or cytologically confirmed diagnosis of 1 of the following:
Non-small cell lung cancer (NSCLC) (closed to accrual as of 8/9/07) meeting 1 of the following stage criteria:
Stage IIIB disease
Patients without pleural effusion who are not candidates for combined modality treatment OR who were treated at centers where combined modality treatment is not considered standard treatment are eligible
Stage IV disease
Local or metastatic failure after prior surgery and/or radiotherapy
Colorectal cancer
Metastatic disease
Considered suitable for first-line therapy with capecitabine
Other tumor types
Suitable for treatment with capecitabine
No more than 2 prior chemotherapy regimens for advanced or metastatic disease
Incurable by radiotherapy or surgery
Clinically or radiologically documented disease
No tumor marker elevation as the only evidence of disease
No necrotic or hemorrhagic tumor or metastases
No untreated brain or meningeal metastases
Patients with previously treated stable brain metastases (by radiography or clinical exam) are eligible provided they are asymptomatic and do not require corticosteroids

PATIENT CHARACTERISTICS:

Age

18 and over

Performance status

ECOG 0-2

Life expectancy

At least 12 weeks (colorectal cancer patients)

Hematopoietic

Hemoglobin adequate
Anemia allowed provided patient is well compensated with no evidence of recent bleeding
Absolute granulocyte count ≥ 1,500/mm^3
Platelet count ≥ 100,000/mm^3
No overt bleeding (i.e., ≥ 30 mL/episode) within the past 3 months

Hepatic

Bilirubin ≤ 1.5 times upper limit of normal (ULN)
ALT or AST ≤ 2 times ULN (5 times ULN for documented liver metastases)

Renal

Creatinine ≤ 1.5 times ULN OR
Creatinine clearance ≥ 50 mL/min
No proteinuria > grade 1

Cardiovascular

Resting systolic blood pressure ≤ 150 mm Hg AND/OR resting diastolic blood pressure ≤ 100 mm Hg (in the presence or absence of a stable dose of antihypertensive medication)
Mean QTc ≤ 470 msec (with Bazetts correction) by ECG
LVEF > 50% for patients with prior anthracyclines/trastuzumab or cardio-toxic agents
No untreated or uncontrolled cardiovascular condition
No symptomatic cardiac dysfunction
No poorly controlled hypertension
No history of labile hypertension
No history of poor compliance with antihypertensive medication
No history of familial long QT syndrome

Pulmonary

No clinically relevant hemoptysis (i.e., ≥ 5 mL fresh blood) within the past 4 weeks
Patients with only flecks of blood in their sputum are eligible

Other

Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective (double-method for females; barrier method for males) contraception
No prior allergic reaction to drugs containing Cremophor EL® (NSCLC patients [closed to accrual as of 8/9/07])
No peripheral neuropathy > grade 1 (NSCLC patients [closed to accrual as of 8/9/07])
No dihydropyrimidine dehydrogenase deficiency (colorectal cancer patients)
No history of severe hand-foot syndrome after treatment with fluoropyrimidines (colorectal cancer patients)
No other malignancy within the past 5 years except adequately treated nonmelanoma skin cancer or other curatively treated solid tumor
No active or uncontrolled infection
No other serious illness or medical condition that would preclude study participation

PRIOR CONCURRENT THERAPY:

Biologic therapy

No prior antiangiogenesis therapy

Chemotherapy

At least 4 weeks since prior single-agent non-platinum-containing chemotherapy (6 weeks for nitrosoureas or mitomycin) for metastatic disease (NSCLC patients [closed to accrual as of 8/9/07])
No more than 1 prior single-agent non-platinum-containing chemotherapy regimen for metastatic disease
At least 6 months since prior adjuvant or neoadjuvant chemotherapy
No prior taxane therapy (NSCLC patients [closed to accrual as of 8/9/07])
No prior chemotherapy for metastatic disease (colorectal cancer patients)
No prior capecitabine (colorectal cancer patients)

Endocrine therapy

See Disease Characteristics
At least 4 weeks since prior corticosteroids

Radiotherapy

See Disease Characteristics
At least 21 days since prior palliative radiotherapy except for low-dose non-myelosuppressive radiotherapy with approval
At least 6 months since prior adjuvant radiotherapy

Surgery

See Disease Characteristics
At least 14 days since prior major surgery

Other

Recovered from prior therapy
At least 14 days since prior epidermal growth factor receptor inhibitor therapy
Concurrent oral anticoagulants (e.g., warfarin) allowed provided INR is strictly monitored
No other concurrent investigational therapy
No other concurrent anticancer therapy
No concurrent prophylactic pyridoxine (vitamin B_6) for hand-foot syndrome (colorectal or other tumor type patients)
Use of pyridoxine after the onset of hand-foot syndrome allowed at the discretion of the physician