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

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