NB1011 in Treating Patients With Metastatic or Recurrent Colorectal Cancer

A Phase I/II Study Of NB1011 Administered Intravenously Daily For 5 Days Every 4 Weeks In Fluoropyrimidine-Resistant Metastatic Or Relapsed Colorectal Cancers

RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die.

PURPOSE: Phase I/II trial to study the effectiveness of NB1011 in treating patients who have metastatic or recurrent colorectal cancer that has not responded to previous treatment.

OBJECTIVES:

• Determine the maximum tolerated dose of NB1011 in patients with fluoropyrimidine-resistant metastatic or recurrent colorectal cancer.
• Determine the safety and toxic effects of this drug in these patients.
• Determine the pharmacokinetics of this drug in these patients.
• Determine the efficacy of this drug in these patients.

OUTLINE: This is a phase I dose-escalation study followed by a phase II study.

• Phase I: Patients receive NB1011 IV over 1 hour on days 1-5. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of NB1011 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.

• Phase II: Additional patients receive NB1011 at the MTD as in phase I. Patients are followed at day 30 and then for 5 months.

PROJECTED ACCRUAL: A maximum of 25 patients will be accrued for the phase I portion of this study. A total of 15-25 patients will be accrued for the phase II portion of this study.

DISEASE CHARACTERISTICS:

• Histologically or cytologically confirmed metastatic or recurrent colorectal adenocarcinoma that has progressed during or within 6 months of fluoropyrimidine-based therapy

• Prior treatment with irinotecan with or without fluorouracil

• Evaluable or measurable disease

  • Uni-dimensionally measurable disease allowed provided CEA is at least 2 times the upper limit of normal

• No meningeal or CNS metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

Age:

• 18 and over

Performance status:

• Karnofsky 70-100%

Life expectancy:

• At least 3 months

Hematopoietic:

• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3

Hepatic:

• Bilirubin less than 1.5 mg/dL (regardless of liver metastases)
• AST and ALT less than 1.5 times upper limit of normal (ULN) (3 times ULN if liver metastases present)
• PT and INR normal
• PTT normal

Renal:

• Creatinine less than 1.5 mg/dL OR
• Creatinine clearance greater than 50 mL/min

Other:

• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• HIV negative
• No known hypersensitivity to NB1011 or any excipient or vehicle in its formulation
• No active or uncontrolled serious bacterial, viral, fungal, or parasitic infection
• No prior or concurrent alcohol abuse or dependency
• No other malignancy within the past 2 years except adequately treated basal cell or squamous cell skin cancer or carcinoma in situ of the cervix
• No concurrent medical or psychological condition that would preclude study

PRIOR CONCURRENT THERAPY:

Biologic therapy:

• Not specified

Chemotherapy:

• See Disease Characteristics
• Recovered from prior anticancer chemotherapy
• No concurrent fluoropyrimidine-based or thymidylate synthase inhibitor agents

Endocrine therapy:

• Not specified

Radiotherapy:

• Recovered from prior anticancer radiotherapy
• No concurrent radiotherapy except palliative radiotherapy (to control a fracture or pain) provided index lesions are not involved

Surgery:

• Recovered from prior anticancer surgery

Other:

• At least 30 days since prior investigational agents
• No other concurrent anticancer therapy
• No concurrent disulfiram