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Dose-Dense and Dose-Intense Alternating Irinotecan/Capecitabine and Oxaliplatin/Capecitabine: Phase I in Solid Tumors and Phase II With Bevacizumab a First-Line Therapy of Advanced Colorectal Cancer


Phase 1
18 Years
N/A
Not Enrolling
Both
Colorectal Cancer, Unspecified Adult Solid Tumor, Protocol Specific

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Trial Information

Dose-Dense and Dose-Intense Alternating Irinotecan/Capecitabine and Oxaliplatin/Capecitabine: Phase I in Solid Tumors and Phase II With Bevacizumab a First-Line Therapy of Advanced Colorectal Cancer


The study was originally intended to be Phase I/Phase II but it was terminated early because
of toxicity of treatment and therefore never moved to the Phase II portion of the study.

OBJECTIVES:

- Determine the maximum tolerated dose (MTD) and dose-limiting toxicity of dose-dense and
dose-intense capecitabine in combination with alternating full-dose irinotecan
hydrochloride and oxaliplatin in patients with metastatic or locally advanced
unresectable solid tumors. (phase I)

- Characterize the safety of the MTD in patients ≥ 65 years of age treated with this
regimen. (phase I)

- Characterize the pharmacokinetics of this regimen in patients ≥ 65 years of age. (phase
I)

- Characterize the functional status of patients ≥ 65 years of age at baseline and after
study treatment, in terms of performance status, independence in activities,
comorbidities, risk of malnutrition, and underlying depression. (phase I)

- Characterize the neurological status of all patients, in terms of muscle strength and
sensation, at baseline and after study treatment. (phase I)

- Determine the clinical antitumor response in patients treated with this regimen. (phase
I)

- Determine whether the addition of bevacizumab to dose-intense capecitabine in
combination with alternating full-dose irinotecan hydrochloride and oxaliplatin as
first-line treatment leads to an improved response rate in patients with metastatic
colorectal cancer compared to that of published results of
fluoropyrimidine/oxaliplatin, fluoropyrimidine/irinotecan/bevacizumab, and
fluoropyrimidine/irinotecan regimens. (phase II)

- Determine the toxicity of bevacizumab in combination with this regimen in patients with
metastatic colorectal cancer. (phase II)

OUTLINE: This is a multicenter, phase I dose-escalation study of capecitabine followed by a
phase II study.

- Phase I (all solid tumor patients): Patients receive oral capecitabine twice daily on
days 1-7 and 15-21. Patients also receive irinotecan hydrochloride IV over 90 minutes
on days 1 and 15 during course 1 and all subsequent odd-numbered courses and
oxaliplatin IV over 2 hours on days 1 and 15 during course 2 and all subsequent
even-numbered courses. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity Cohorts of 3-6 patients receive escalating doses
of capecitabine (during both odd- and even-numbered courses) until the maximum
tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at
which 2 of 3 or 2 of 6 patients (with at least 1 patient < 65 years of age) experience
dose-limiting toxicity. At least 6 patients are treated at the MTD.

- Phase II (colorectal cancer patients): Patients receive capecitabine (at the MTD
determined in phase I) in combination with irinotecan hydrochloride (during
odd-numbered courses) and oxaliplatin (during even-numbered courses) as in phase I.
Patients also receive bevacizumab IV over 30-90 minutes on days 1 and 15 of each
course.

After completion of study treatment, patients are followed periodically.

PROJECTED ACCRUAL: A total of 50 patients will be accrued for this study.

Inclusion Criteria


DISEASE CHARACTERISTICS:

- Phase I:

- Histologically or cytologically confirmed solid tumor

- Metastatic OR locally advanced unresectable disease

- No curative therapy exists

- Measurable or evaluable disease

- Measurable disease is defined as ≥ 1 lesion that can be accurately measured
in ≥ 1 dimension as ≥ 20 mm with conventional techniques OR ≥ 10 mm with
spiral CT scan

- No known brain metastases

- Phase II:

- Histologically or cytologically confirmed colorectal cancer

- Metastatic OR locally advanced unresectable disease

- Measurable disease (as defined in phase I)

- No tumor involving major blood vessels

- No evidence of CNS disease, including primary brain tumor or brain metastases

PATIENT CHARACTERISTICS:

- Karnofsky performance status 70-100%

- Life expectancy ≥ 12 weeks

- Absolute neutrophil count (ANC) ≥ 1,500/mm^3

- ANC < 1,500/mm^3 allowed, if in the opinion of the investigator, this represents
an ethnic or racial variation of normal

- Platelet count ≥ 100,000/mm^3

- Hemoglobin > 10.0 g/dL

- Bilirubin ≤ 1.5 mg/dL

- AST/ALT ≤ 2 times upper limit of normal (ULN)

- Creatinine ≤ 1.5 mg/dL OR creatinine clearance ≥ 60 mL/min

- Urine protein:creatinine ratio < 1.0 OR protein < 1 g by 24-hour urine collection
(phase II)

- PT/INR ≤ 1.5 unless on full-dose anticoagulants (phase II)

- Not pregnant or nursing

- Negative pregnancy test

- Fertile female patients must use effective double-barrier contraception during and
for 28 days (phase I) or 3 months (phase II) after completion of study treatment

- Fertile male patients must use effective contraception during and for 6 months after
completion of study treatment

- No history of allergic reaction attributed to compounds of similar chemical or
biologic composition to capecitabine, irinotecan hydrochloride, oxaliplatin, or
bevacizumab

- No other uncontrolled illness including, but not limited to, any of the following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness or social situation that would preclude study compliance

- No cardiac ischemia within the past 6 months (phase I)

- No New York Heart Association class II-IV congestive heart failure or symptomatic
arrhythmia (phase II)

- No arterial thrombotic events within the past 6 months including, but not limited to,
any of the following (phase II):

- Transient ischemic attack

- Cerebrovascular accident

- Unstable angina or angina requiring surgical or medical intervention

- Myocardial infarction

- No clinically significant peripheral vascular disease (phase II)

- No history of hypertension unless well controlled (< 150/90 mm Hg) on an
antihypertensive regimen (phase II)

- No evidence of bleeding diathesis or coagulopathy (phase II)

- No gastrointestinal (GI) perforation, abdominal fistula, or intra-abdominal abscess
within the past 30 days (phase II)

- No significant history of bleeding events (phase II)

- Patients with a history of significant bleeding episodes (e.g., hemoptysis or
upper or lower GI bleeding) within the past 6 months are not eligible unless the
source of bleeding has been resected

- No significant traumatic injury within the past 28 days (phase II)

- No serious or nonhealing wound, ulcer, or bone fracture (phase II)

- No peripheral neuropathy > grade 1

PRIOR CONCURRENT THERAPY:

- At least 3 weeks since prior chemotherapy (6 weeks for nitrosoureas) and recovered
(phase I)

- At least 2 weeks since prior immunotherapy or biologic therapy and recovered (phase
I)

- No prior treatment for advanced or metastatic colorectal cancer (phase II)

- More than 12 months since prior adjuvant chemotherapy and/or biologic therapy (e.g.,
bevacizumab or cetuximab) and recovered (phase II)

- At least 4 weeks since prior radiotherapy and recovered

- No prior radiotherapy to the only site of measurable disease unless there is
measurable disease progression within the radiation port after completion of
radiotherapy

- No prior radiotherapy to ≥ 20% of the bone marrow

- More than 28 days since prior major surgical procedure* or open biopsy and recovered
(phase II)

- More than 14 days since prior minor surgery* and recovered (phase II)

- Concurrent full-dose anticoagulation (e.g., warfarin) allowed provided the following
criteria are met (phase II):

- Patient has an in-range INR (between 2 and 3) and is on a stable dose of oral
anticoagulants or a stable dose of low molecular weight heparin

- No active bleeding or pathological condition that carries a high risk of
bleeding (e.g., known varices)

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No other concurrent investigational agents

- No concurrent sargramostim (GM-CSF) NOTE: *Insertion of a vascular device is not
considered major or minor surgery

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Phase II: Bevacizumab plus dose-intense capecitabine in combination with alternating full-dose irinotecan hydrochloride and oxaliplatin as first-line treatment leads to an improved response rate in patients with metastatic colorectal cancer

Outcome Time Frame:

Courses repeat every 28 days in the absence of unacceptable toxicity.

Safety Issue:

Yes

Principal Investigator

Smitha Krishnamurthi, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center

Authority:

United States: Federal Government

Study ID:

CASE1205

NCT ID:

NCT00296062

Start Date:

March 2006

Completion Date:

May 2011

Related Keywords:

  • Colorectal Cancer
  • Unspecified Adult Solid Tumor, Protocol Specific
  • unspecified adult solid tumor, protocol specific
  • stage III colon cancer
  • stage IV colon cancer
  • stage III rectal cancer
  • stage IV rectal cancer
  • recurrent colon cancer
  • recurrent rectal cancer
  • Colorectal Neoplasms
  • Neoplasms

Name

Location

Case Medical Center, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer CenterCleveland, Ohio  44106-5065