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Study Summary
No. 2005-0842:.......Colorectal......Scott Kopetz......Gastrointestinal Medical Oncology
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Study Summary Title
Study Summary
Number:
2005-0842
Study Title:Dual Inhibition of EGFR and c-Src by Cetuximab and Dasatinib Combined with FOLFOX Chemotherapy in Metastatic Colorectal Cancer (CA180048)
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Physician New Patient Referral
Name:Scott KopetzPatients Call:800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Dept:Gastrointestinal Medical OncologyReferring MD
Call:
800-392-1611 (in U.S.A.) 713-792-6161 (outside U.S.A.)
Phone:713-792-2828
Contact us about clinical trials
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General Information
Disease Group:ColorectalSupported By:N/A
Phase of Study:Phase IReturn
Visit:
Patients will return to MDACC on a weekly basis to receive treatment
Treatment
Agents:
5-FU
Cetuximab
Dasatinib
Leucovorin
Oxaliplatin
Home Care:Home care will not be required for this protocol
Treatment Loc:Only at MDACC
Estimated
Length of Stay
in Houston:
This protocol will not require hospitalization for the patient.
Description/
Intervention:
The goal of the Phase I part of this clinical research study is to find the
highest tolerable dose of a combination of dasatinib, cetuximab, and FOLFOX
(5-fluorouracil [5-FU], leucovorin [LV], and Eloxatin [oxaliplatin]) that can
be given to patients with metastatic colorectal cancer. The safety of these
drugs in combination will also be studied.

The goal of the Phase II part of this clinical research study is to learn if
dasatinib given in combination with FOLFOX with or without cetuximab can help
to control metastatic colorectal cancer.
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Study Objectives / Outcomes
1. Primary Objective [Phase IB]
  • To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of the combination of dasatinib, cetuximab and FOLFOX in adult patients with metastatic colorectal cancer.
  • To demonstrate biological activity of the combination regimen on c-Src activity at the MTD in the expansion cohort.

2. Primary Objective [Phase II]
  • To determine the response-rate distribution of dasatinib and FOLFOX with or without cetuximab.

3. Secondary Objectives [Phase IB]
  • To demonstrate the feasibility of peripheral blood biomarkers of Src inhibition.
  • To determine the safety profile and tolerability of this regimen in this patient population;
  • To document the antitumor effects of this regimen in this patient population.

4. Secondary Objectives [Phase II]
  • To determine time to treatment failure (TTF) and ratio of current TTF to TTF of immediate prior regimen.
  • To determine overall survival (OS).
  • To determine the safety profile and tolerability of this regimen in this patient population.
  • To qualitatively determine changes in quality of life on treatment for patients, as measured utilizing the MD Anderson Symptom Inventory (MDASI-GI) instrument.
  • To determine changes in serum cytokines and angiogenic proteins (including VEGF, IL-8, bFGF, PlGF, PDGF, caveolin) during treatment and at the time of progression.
  • To determine duration and extent of phosphorylation changes in peripheral blood mononuclear cells (PBMCs) in patients treated with dasatinib.
  • To determine the PFS, RR, and OS for the subset of patients with adequate Src inhibition at the first restaging, defined as <50% of baseline activity in peripheral blood mononuclear cells

In order to minimize the error of estimates for response rate, TTF, and overall survival, the combined outcomes of patients in the Phase IB and Phase II portions will also be analyzed and presented for patients refractory to prior oxaliplatin and cetuximab.
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Study Status Information
Study Activation / Registration Date:04/23/2007
IRB Review and Approval Date:12/06/2006
Study Type:Phase I
Recruitment Status:Open
Projected Accrual:N/A
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Enrollment Eligibility
If you do not meet the enrollment eligibility, there may be other treatment options for you. Please Contact the Referral Office for more information.

Inclusion Criteria:1) Patient must have histologically or cytologically confirmed colorectal adenocarcinoma with metastatic disease documented on diagnostic imaging studies

2) Phase IB: Patient must have wild type KRAS.

3) Phase IB: For the expansion cohort, only patients with liver metastases >/= 2.0 cm amenable to percutaneous CT or U/S guided biopsy and who agree to having 2 liver biopsies done are eligible.

4) Phase II: Patient must have known KRAS (exon 1, codon 12, 13) or sufficient available tumor tissue from the primary tumor or metastatic site for KRAS mutation analysis [Phase II only].

5) Patient must have previously progressed on systemic therapy for metastatic colorectal cancer, with no limit on the number of prior regimens. For patients in the Phase II cohort, they must have progressed on 5-FU or capecitabine and oxaliplatin [patients with KRAS mutated tumors], and either cetuximab or panitumumab [patients with KRAS wild type tumors].

6) (Continued from # 5) The following criteria must be met for progression. • Baseline imaging was performed 1 month or less prior to starting regimen. • Average treatment intensity (number of cycles received/number of cycles anticipated in absence of delays) of greater than 70%. • Restaging study demonstrating progression 6 weeks or less from last dose of oxaliplatin and EGFR inhibitor (if applicable). • Progression may be by RECIST criteria or, with PI approval, clinical progression.

7) Written informed consent obtained

8) Age >/= 18 years to provide a uniform oncologic phenotype of adult-onset colorectal cancer.

9) ECOG performance status 0-1 (Appendix E)

10) Patients must have adequate organ and marrow function defined as: ANC >/= 1,500/mm^3; platelets >/= 100,000/ mm^3; hemoglobin >/= 9 gm/dL (may be transfused to maintain or exceed this level); total bilirubin </= 1.5 mg/dL; AST (SGOT)/ALT(SGPT) </= 2.5 times institution's upper limit of normal (IULN), or </= 5 times IULN if known liver metastases; · Creatinine clearance > 60mL/min using Cockroft-Gault formula.

11) Women of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to the start of study medications. Childbearing potential is defined as a woman who is not post-menopausal for 12 months or longer or is not surgically sterile. Patients must agree to practice acceptable contraceptive methods as outlined in the protocol.

Exclusion Criteria:1) Recent (within 4 weeks of the first infusion of study drugs on this study), or planned participation in another experimental therapeutic drug study. Patients who have had any systemic chemotherapy, radiotherapy, or major surgery within 21 days prior to the first infusion of study drugs.

2) Patients who have not recovered to </= grade 2 for neuropathy or </= grade 1 for other side effects due to prior treatment.

3) Patients with radiographic evidence of pleural effusions in the last 30 days prior to enrollment.

4) Patients with known brain metastases because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events.

5) Female patients who are pregnant or lactating or men and women of reproductive potential not willing to employ an effective method of birth control during treatment and for 3 weeks after discontinuing study treatment

6) Patients with known dihydropyrimidine dehydrogenase deficiency.

7) Patients with a history of significant bleeding disorder unrelated to cancer, including: Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease); Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies)

8) Patients currently taking the following drugs that are generally accepted to have a risk of causing Torsades de Pointes:haloperidol, methadone, amiodarone, sotalol, erythromycins, clarithromycin cisapride, chlorpromazine, bepridil, droperidol, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine, quinidine, procainamide, disopyramide, ibutilide, dofetilide. Subjects who have discontinued any of these medications must have a wash-out of at least 5 days (or 14 days for amiodarone) prior to the first dose of dasatinib.

9) Patients with wild type KRAS tumors with a history of allergic reactions attributed to cetuximab, oxaliplatin, 5-FU, capecitabine, or leucovorin that, previously, have not been adequately prevented with premedications.

10) Current use of full-dose warfarin (except as required to maintain patency of preexisting, permanent indwelling IV catheters). For subjects receiving warfarin for catheter patency, INR should be < 1.5.

11) Current or recent (<2 week) use of aspirin (at a dose greater than 81 mg/day) or clopidogrel.

12) Diagnosed or suspected congenital long QT syndrome

13) Any history of clinically significant ventricular arrhythmias (such as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).

14) Previous allergic reaction to a human monoclonal antibody.

15) Prolonged QTc interval on pre-entry electrocardiogram (> 450 msec) on both the Fridericia [QTc = QT/RR^1/3] and Bazett's [QTc = QT/sqrtRR] correction. Bazett's correction is calculated automatically by institutional EKG machines

16) Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: Uncontrolled high blood pressure (systolic blood pressure >/= 140 and diastolic blood pressure >/= 90), history of labile hypertension, or history of poor compliance with an antihypertensive regimen. Unstable angina or stable angina markedly limiting ordinary physical activity. (Angina occurs on walking one to two blocks on the level and climbing one flight of stairs in normal conditions and at a normal pace) .

17) Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: New York Heart Association (NYHA) >/= grade 2 congestive heart failure; Myocardial infarction within 6 months of study enrollment; History of stroke within 6 months of study enrollment; Unstable symptomatic arrhythmia requiring medication (Patients with chronic atrial arrhythmia, i.e., atrial fibrillation or paroxysmal SVT are eligible); Clinically significant peripheral vascular disease; Uncontrolled diabetes; Serious active or uncontrolled infection

18) History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of a study drug or that might affect the interpretation of the results of the study or render the subject at high risk from treatment complications

19) Inability to take oral medications.

20) Inability to comply with study and/or follow-up procedures

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Links
Registration Number: NCT00501410
Study Information on Clinical Trials Registry (clinicaltrials.gov)

Other Links:
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Results


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