AZD2171 and Standard Combination Chemotherapy in Advanced Non-Small Cell Lung Cancer or Colorectal Cancer

OBJECTIVES:

• Determine the recommended phase II dose of AZD2171 when administered with standard combination chemotherapy in patients with advanced non-small cell lung cancer or colorectal cancer.
• Determine the safety, tolerability, toxicity profile, dose-limiting toxicities, and pharmacokinetic profile of this treatment regimen.
• Assess the antitumor activity of this treatment regimen in patients with measurable disease.
• Correlate the toxicity profile with pharmacokinetics.

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

• Group 1 (non-small cell lung cancer): Patients receive gemcitabine hydrochloride IV on days 1 and 8 and cisplatin IV on day 1. Patients also receive oral AZD2171 once daily beginning on day 2. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
• Group 2 (colorectal cancer): Patients receive oxaliplatin IV over 2 hours and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV continuously over 46 hours on days 1 and 2. Patients also receive oral AZD2171 once daily beginning on day 3. Treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.

In both groups, cohorts of 3-6 patients receive escalating doses of AZD2171 until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which at least 2 of 6 patients experience dose-limiting toxicity.

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

PROJECTED ACCRUAL: A total of 30 patients will be accrued for this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed diagnosis of 1 of the following:

• Non-small cell lung cancer (NSCLC), meeting 1 of the following criteria:

• Stage IIIB disease

• No pleural effusion and not a candidate for a combined modality treatment
• Stage IV disease
• Local or metastatic failure after surgery and/or radiotherapy
• Colorectal cancer (CRC)

• Advanced and/or metastatic disease
• Suitable for first-line therapy with oxaliplatin, leucovorin calcium, and fluorouracil (FOLFOX-6)
• Clinically or radiologically documented disease

• No tumor marker elevation as sole evidence of disease
• No necrotic/hemorrhagic metastases or tumor
• No untreated brain or meningeal metastases

• Previously treated, radiologic or clinical evidence of stable brain metastases allowed provided disease is asymptomatic and corticosteroids are not required

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Hemoglobin normal
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Creatinine ≤ 1.5 times upper limit of normal (ULN) OR creatinine clearance ≥ 50 mL/min
• Bilirubin ≤ 1.5 times ULN
• AST or ALT ≤ 2 times ULN (5 times ULN if liver involvement)
• Proteinuria ≤ grade 1
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of other malignancies except adequately treated nonmelanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ≥ 5 years
• No untreated and/or uncontrolled cardiovascular conditions or symptomatic cardiac dysfunction
• No resting blood pressure (BP) consistently higher than systolic BP > 150 mm Hg and diastolic BP > 100 mm Hg (in the presence or absence of a stable dose of antihypertensive medication)
• No poorly controlled hypertension, history of labile hypertension, or poor compliance with antihypertensive medication
• No overt bleeding (≥ 30 mL bleeding/episode) within the past 3 months
• No clinically relevant hemoptysis (≥ 5 mL fresh blood) within the past 4 weeks

• Flecks of blood in sputum allowed
• No active or uncontrolled infections
• No serious illnesses or medical conditions that would preclude compliance with study requirements
• No mean QTc with Bazett's correction > 470 msec
• No history of familial long QT syndrome
• No peripheral neuropathy > grade 1
• No dihydropyrimidine dehydrogenase deficiency or history of severe hand-foot syndrome after fluoropyrimidines (for patients with CRC)

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• Recovered from prior therapy
• At least 6 months since prior adjuvant or neoadjuvant therapy
• At least 6 months since prior adjuvant radiotherapy
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas and mitomycin C) (for patients with NSCLC)
• At least 4 weeks since prior and no concurrent corticosteroids
• At least 3 weeks since prior palliative radiotherapy and recovered

• Concurrent palliative radiotherapy allowed
• At least 2 weeks since prior epidermal growth factor receptor inhibitor therapy
• At least 2 weeks since prior major surgery
• No more than 1 prior single-agent, nonplatinum-containing chemotherapy regimen for metastatic disease (for patients with NSCLC)
• No prior gemcitabine hydrochloride (for patients with NSCLC)
• No prior oxaliplatin (for patients with CRC)
• No prior angiogenesis inhibitor
• No prior chemotherapy for advanced/metastatic disease (for patients with CRC)
• No other concurrent experimental drugs or anticancer therapy