AZD2281 and Irinotecan in Treating Patients With Locally Advanced or Metastatic Colorectal Cancer

A Phase I Study of AZD2281 in Combination With Irinotecan in Patients With Locally Advanced or Metastatic Incurable Colorectal Cancer

RATIONALE: AZD2281 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as irinotecan, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving AZD2281 together with irinotecan may kill more tumor cells.

PURPOSE: This phase I trial is studying the side effects and best dose of AZD2281 and irinotecan in treating patients with locally advanced or metastatic colorectal cancer.

Study Overview

• Status: Completed
• Conditions: Colorectal Cancer
• Intervention / Treatment: Drug: irinotecan hydrochloride; Drug: olaparib

Detailed Description

OBJECTIVES:

• To determine the recommended phase II dose of AZD2281 and irinotecan hydrochloride in patients with locally advanced or metastatic colorectal cancer.
• To determine the safety, tolerability, toxicity profile, dose-limiting toxicities, and pharmacokinetic profile of this regimen.
• To assess the correlation, if any, between the toxicity profile and pharmacokinetics of this regimen.
• To assess, preliminarily, the antitumor activity of this regimen in patients with measurable disease.
• To demonstrate the pharmacodynamic activity of this regimen by establishing its effects in tumor biopsies, cheek swabs, and blood samples.
• To assess the correlation, if any, between patients with tumors demonstrating microsatellite instability and antitumor activity and pharmacodynamic effects of this regimen.
• To investigate the impact of common genetic polymorphisms of genes of relevant pathways (drug metabolism, DNA repair, and apoptosis) on outcome and toxicity as well as other pharmacodynamic effects.

OUTLINE: This is a multicenter, dose-escalation study of AZD2281 and irinotecan hydrochloride.

• Part I: Patients receive oral AZD2281 twice a day on days -7 to 21 in course 1 and on days 1-21 in all subsequent courses. Patients also receive irinotecan hydrochloride IV over 90 minutes on day 1. Courses repeat every 21 days (course 1 is 28 days) until the maximum tolerated dose is determined in the absence of disease progression or unacceptable toxicity.
• Part II: Patients then receive oral AZD2281 once daily on days 1-5 and irinotecan hydrochloride IV over 90 minutes on day 3 at the maximum tolerated dose determined in Part I. Courses repeat every 14 days in the absence of disease progression or unacceptable toxicity.

Patients undergo cheek swabs, tumor tissue, and blood sample collection periodically for pharmacokinetic, pharmacodynamic, and correlative studies.

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

• Study Type: Interventional
• Enrollment (Actual): 26
• Phase: Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Health Research Institute - General Division
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed colorectal cancer

  • Locally advanced and/or metastatic disease
  • Disease considered incurable
• Suitable for treatment with single agent irinotecan hydrochloride as a palliative intervention, as determined by the investigator

• Must have clinically and/or radiologically documented disease

  • Patients whose only evidence of disease progression is tumor marker elevation are not eligible

• Must have received no more than one prior oxaliplatin- and/or irinotecan hydrochloride-based chemotherapy regimen given either with adjuvant, neoadjuvant, or palliative intent

  • One additional adjuvant fluoropyrimidine (fluorouracil or capecitabine) regimen may have been given for relapsed or metastatic disease
• No untreated brain or meningeal metastases (CT scan required if there is a clinical suspicion of CNS disease)

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Absolute granulocyte count ≥ 1,500/mm³
• Platelet count ≥ 100,000/mm³
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• ALT and AST ≤ 2 times ULN (≤ 5 times ULN if liver metastasis is present)
• Serum creatinine ≤ 1.5 x ULN OR creatinine clearance ≥ 50 mL/min
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception during and for 90 days after completion of study therapy
• Must reside within a 1½ hour drive from participating center
• No other invasive malignancies, unless curatively treated with no evidence of disease

• No GI tract disease resulting in an inability to absorb oral medication, including the following:

  • Uncontrolled inflammatory GI disease (e.g., Crohn's disease or ulcerative colitis)

  • Post-surgical malabsorption characterized by uncontrolled diarrhea that results in weight loss and vitamin deficiency or requires IV hyperalimentation

    • Pancreatic enzyme supplementation is allowed
• No untreated and/or uncontrolled hypertension, cardiovascular conditions, and/or symptomatic cardiac dysfunction
• No active or uncontrolled infections
• No serious illnesses or medical conditions that would preclude study participation
• No known hypersensitivity to the study drugs or their components, atropine, or loperamide
• Not known to be homozygous for the UGT1A1*28 allele
• No known deficiency in glucuronidation of bilirubin, such as Gilbert's syndrome

• No neuropathy ≥ grade 2

  • Patients with persistent, stable, grade 3 sensory neuropathy, who meet other eligibility criteria may be allowed at the discretion of the investigator

PRIOR CONCURRENT THERAPY:

• Recovered from all prior therapy
• No prior PARP inhibitor
• No prior radical pelvic irradiation
• No prior radiotherapy to ≥ 25% of bone marrow stores
• Prior irinotecan hydrochloride allowed provided the drug was not discontinued due to toxic effects and the patient did not have severe irinotecan hydrochloride-related toxicity (grade 4 or requiring hospitalization)
• At least 21 days since prior radiotherapy (exceptions may be made for low-dose, nonmyelosuppressive radiotherapy)
• At least 30 days since prior chemotherapy
• At least 21 days since prior hormonal, immunologic, biologic, or signal transduction inhibitor therapies
• More than 3 weeks since prior and no other concurrent investigational drugs or anticancer therapy

• At least 14 days since prior major surgery

  • Wound healing must have occurred

• At least 14 days since prior and no concurrent CYP3A4 enzyme-inducing or -inhibiting drugs, including enzyme-inducing anticonvulsants, rifampin, rifabutin, St. John's wort, atazanavir, or ketoconazole

  • Dexamethasone is allowed for antiemetic prophylaxis

Study Plan

How is the study designed?

Design Details

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended phase II dose of AZD2281 and irinotecan hydrochloride	End of study	Nov 2011
Safety	End of study	Nov 2011
Tolerability	End of study	Nov 2011
Dose-limiting toxicities	Fatigue, Nausea, Dehydration and Anorexia.	2011-May-28
Pharmacokinetic profile	End of study	Nov 2011
Correlation, if any, between the toxicity profile and pharmacokinetics	End of study.	Nov 2011

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Efficacy	End of study	Nov 2011
Pharmacodynamic outcomes	End of study.	Nov 2011

Collaborators and Investigators

• Sponsor: NCIC Clinical Trials Group
• Collaborators: AstraZeneca
• Investigators: Study Chair: Eric X. Chen, MD, PhD, Princess Margaret Hospital, Canada

Publications and helpful links

General Publications

• Chen EX, Jonker DJ, Siu LL, McKeever K, Keller D, Wells J, Hagerman L, Seymour L. A Phase I study of olaparib and irinotecan in patients with colorectal cancer: Canadian Cancer Trials Group IND 187. Invest New Drugs. 2016 Aug;34(4):450-7. doi: 10.1007/s10637-016-0351-x. Epub 2016 Apr 13.

Study record dates

Study Major Dates

• Study Start (Actual): January 2, 2008
• Primary Completion (Actual): September 25, 2012
• Study Completion (Actual): February 13, 2015

Study Registration Dates

• First Submitted: September 25, 2007
• First Submitted That Met QC Criteria: September 25, 2007
• First Posted (Estimated): September 26, 2007

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: 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; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase Inhibitors; Poly(ADP-ribose) Polymerase Inhibitors; Topoisomerase I Inhibitors; Olaparib; Irinotecan
• Other Study ID Numbers: I187; CAN-NCIC-IND187 (Registry Identifier: NCI US - Physician Data Query); IND187 (Other Identifier: NCIC CTG); CDR0000565189 (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