AZD0530 (NSC 735464) in Treating Patients With Previously Treated Metastatic Colon Cancer or Rectal Cancer

Phase 2

Terminated

Conditions: Adenocarcinoma of the Rectum
Stage IV Rectal Cancer
Recurrent Rectal Cancer
Stage IV Colon Cancer
Adenocarcinoma of the Colon
Recurrent Colon Cancer

Interventions: Drug: saracatinib
Other: laboratory biomarker analysis

Registration Number: NCT00397878

Lead Sponsor: National Cancer Institute (NCI)

Brief Summary: This phase II trial is studying how well AZD0530 works in treating patients with previously treated metastatic colon cancer or rectal cancer. AZD0530 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.

Detailed Description: PRIMARY OBJECTIVES:

I. Determine the progression-free survival (PFS) at 4 months in metastatic colorectal carcinoma patients receiving daily doses of AZD0530.

SECONDARY OBJECTIVES:

I. Evaluate the objective response rate (RR) and overall survival (OS) of patients with metastatic colorectal cancer who are treated with AZD0530.

II. In patients who consent, both blood and tissue samples will be collected for laboratory correlates. Assess in a preliminary manner the association between correlative markers and the potential downstream effects of AZD0530 on IL-8, VEGF, specific Src-regulated markers in focal adhesions, adherens junctions, and angiogenesis on clinical outcome in pre- and post-treatment tumor samples.

OUTLINE:

Patients receive oral AZD0530 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

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

PROJECTED ACCRUAL: A total of 35 patients will be accrued for this study.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 10

Inclusion Criteria

Patients must have histologically or cytologically confirmed adenocarcinoma of the colon or rectum that is metastatic
Patients must have measurable disease, defined (per RECIST criteria) as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 20 mm with conventional techniques or >= 10 mm with spiral CT scan
Patients must have received one and only one prior chemotherapy regimen for metastatic colorectal cancer; patients may have received biologic therapy (e.g., bevacizumab) in combination with chemotherapy as part of their prior chemotherapy
ECOG performance status 0-2
Absolute neutrophil count (ANC) >= 1,500/mcL
Platelets >= 100,000/mcL
Hemoglobin >= 9 g/dL
Total bilirubin =< 1.5 x institutional ULN
AST(SGOT)/ALT(SGPT) =< 3.0 x institutional ULN
Creatinine within normal institutional limits OR estimated CrCl (Cockcroft-Gault) or 24 hr urine collection of >= 50 mL/min
The effects of AZD0530 on the developing human fetus at the recommended therapeutic dose are unknown; however, AZD0530 has been shown to cause gross fetal malformations and to negatively impact embryo fetal survival in rats; for this reason and because many tyrosine kinase inhibitors are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and up to 30 days following removal from the study; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately; women of child-bearing potential will have serum beta-Hcg levels drawn up to 7 days prior to receiving study treatment
Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD0530, breastfeeding should be discontinued if the mother is treated with AZD0530
Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to study registration or those who have not recovered from treatment related adverse events > grade 1 (except for neuropathy [ies] which may be =< grade 2) due to agents administered more than 4 weeks earlier
Use of specifically prohibited CYP3A4-active agents or substances are not permitted during protocol treatment, and patients who must continue treatment with these agents are not eligible; prohibited drugs should be discontinued seven (7) days or 5 half-lives (whichever is the longer time period) prior to the administration of the first dose of AZD0530 and for 7 days or 5 half-lives (which ever is the longer time period) following discontinuation of AZD0530
Patients may not be receiving any other investigational agents
Patients with greater than +1 proteinuria on two consecutive readings taken no less than 24 hours apart are ineligible
Patients with QTc prolongation (defined as a QTc interval greater than or equal to 480 msecs) are ineligible
Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection (requiring parenteral antibiotics at the time of registration), cardiac disease NYHA class III or IV, unstable angina pectoris, unstable cardiac arrhythmia or tachycardia (heart rate >= 100 beats per minute), poorly controlled hypertension (systolic blood pressure >= 140 mmHg or diastolic blood pressure >= 90 mmHg)
Patients with any condition (e.g., gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for IV alimentation, prior surgical procedures affecting absorption, or active peptic ulcer disease) that impairs their ability to swallow AZD0530 tablets are excluded
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
Pregnant women are excluded from this study because AZD0530 has the potential for teratogenic or abortifacient effects as shown by the gross fetal malformation and effects on embryofetal survival seen in reproductive toxicity studies in the rat
Patients with a history of another primary malignancy within the last 5 years, with the exception of non-melanoma skin cancer, and carcinoma in situ of uterine cervix
Patient who are known to be HIV-positive are ineligible because of the potential for pharmacokinetic interactions with AZD0530 and antiretroviral therapy (HAART)

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (saracatinib)	laboratory biomarker analysis	Patients receive oral AZD0530 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Treatment (saracatinib)	saracatinib	Patients receive oral AZD0530 once daily on days 1-28. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Median Progression Free Survival (PFS)	Time from start of treatment to time of progression, up to 4 months	Time period of metastatic colorectal patients with one previous chemotherapy treatment for metastatic disease who are alive and progression free after commencing the experimental therapy. A 95% posterior credible intervals used.

Secondary Outcome Measures

Name	Time	Method
Overall Survival	Up to 5 years	Number of participants who survived up to 5 years
Time to Progression	within 54 days	Number of participants who progressed on treatment within less than or equal to 2 cycles (cycle=28 days; within 54 days PD).