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

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
NCIC Clinical Trials Group
ClinicalTrials.gov Identifier:
NCT00535353
First received: September 25, 2007
Last updated: February 7, 2014
Last verified: February 2014

September 25, 2007
February 7, 2014
August 2007
September 2012   (final data collection date for primary outcome measure)
  • Recommended phase II dose of AZD2281 and irinotecan hydrochloride [ Time Frame: Nov 2011 ] [ Designated as safety issue: Yes ]
    End of study
  • Safety [ Time Frame: Nov 2011 ] [ Designated as safety issue: Yes ]
    End of study
  • Tolerability [ Time Frame: Nov 2011 ] [ Designated as safety issue: Yes ]
    End of study
  • Dose-limiting toxicities [ Time Frame: 2011-May-28 ] [ Designated as safety issue: Yes ]
    Fatigue, Nausea, Dehydration and Anorexia.
  • Pharmacokinetic profile [ Time Frame: Nov 2011 ] [ Designated as safety issue: No ]
    End of study
  • Correlation, if any, between the toxicity profile and pharmacokinetics [ Time Frame: Nov 2011 ] [ Designated as safety issue: Yes ]
    End of study.
  • Recommended phase II dose of AZD2281 and irinotecan hydrochloride
  • Safety
  • Tolerability
  • Dose-limiting toxicities
  • Pharmacokinetic profile
  • Correlation, if any, between the toxicity profile and pharmacokinetics
Complete list of historical versions of study NCT00535353 on ClinicalTrials.gov Archive Site
  • Efficacy [ Time Frame: Nov 2011 ] [ Designated as safety issue: No ]
    End of study
  • Pharmacodynamic outcomes [ Time Frame: Nov 2011 ] [ Designated as safety issue: No ]
    End of study.
  • Efficacy
  • Pharmacodynamic outcomes
Not Provided
Not Provided
 
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.

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.

Interventional
Phase 1
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Colorectal Cancer
  • Drug: irinotecan hydrochloride
    In Part A, a continuous oral AZD2281 dose will be given in combination with irinotecan given as a 90 minute infusion on day 1 every 21 days. In Part B, AZD2281 will be given on days 1-5 and irinotecan as a 90 minute infusion on day 3 each cycle. Cycles are repeated every 14 days.
  • Drug: olaparib
    In Part A, a continuous oral AZD2281 dose will be given in combination with irinotecan given as a 90 minute infusion on day 1 every 21 days. In Part B, AZD2281 will be given on days 1-5 and irinotecan as a 90 minute infusion on day 3 each cycle. Cycles are repeated every 14 days.
Not Provided
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
26
September 2014
September 2012   (final data collection date for primary outcome measure)

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
Both
18 Years to 70 Years
No
Contact information is only displayed when the study is recruiting subjects
Canada
 
NCT00535353
I187, CAN-NCIC-IND187, IND187, CDR0000565189
No
NCIC Clinical Trials Group
NCIC Clinical Trials Group
Not Provided
Study Chair: Eric X. Chen, MD, PhD Princess Margaret Hospital, Canada
NCIC Clinical Trials Group
February 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP