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

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

RATIONALE: 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. Drugs used in chemotherapy 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 standard combination 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 standard combination chemotherapy in treating patients with advanced non-small cell lung cancer (NSCLC) or colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer; Lung Cancer
• Intervention / Treatment: Drug: fluorouracil; Drug: leucovorin calcium; Drug: oxaliplatin; Drug: cisplatin; Drug: gemcitabine hydrochloride; Drug: cediranib maleate

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 31
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Regional Cancer Centre - General Campus
    • Toronto, Ontario, Canada, M5G 2M9
      • Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital - Montreal

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Collaborators and Investigators

• Sponsor: NCIC Clinical Trials Group
• Investigators: Study Chair: Gerald Batist, MD, Jewish General Hospital; Study Chair: Eric X. Chen, MD, PhD, Princess Margaret Hospital, Canada; Study Chair: Glenwood D. Goss, MD, BCh, FCP, FRCPC, Ottawa Regional Cancer Centre

Publications and helpful links

General Publications

• Chen E, Jonker D, Gauthier I, MacLean M, Wells J, Powers J, Seymour L. Phase I study of cediranib in combination with oxaliplatin and infusional 5-Fluorouracil in patients with advanced colorectal cancer. Clin Cancer Res. 2009 Feb 15;15(4):1481-6. doi: 10.1158/1078-0432.CCR-08-0761.

Study record dates

Study Major Dates

• Study Start (Actual): November 29, 2005
• Primary Completion (Actual): September 18, 2007
• Study Completion (Actual): September 22, 2008

Study Registration Dates

• First Submitted: June 22, 2006
• First Submitted That Met QC Criteria: June 22, 2006
• First Posted (Estimated): June 23, 2006

Study Record Updates

• Last Update Posted (Actual): August 4, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: April 1, 2020

More Information

Terms related to this study

• Keywords: recurrent non-small cell lung cancer; stage IIIB non-small cell lung cancer; stage IV non-small cell lung cancer; stage IV rectal cancer; stage IV colon cancer; recurrent colon cancer; recurrent rectal cancer; stage III colon cancer; stage III rectal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Colorectal Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Micronutrients; Protein Kinase Inhibitors; Vitamins; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Fluorouracil; Oxaliplatin; Leucovorin; Calcium; Levoleucovorin; Cediranib; Gemcitabine
• Other Study ID Numbers: I175; CAN-NCIC-IND175 (Other Identifier: PDQ); CDR0000481443 (Other Identifier: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No