A Phase I Dose-Finding Study and a Randomized Phase II Study of ALIMTA Plus Oxaliplatin Versus Oxaliplatin Plus 5-Fluorouracil and Leucovorin (FOLFOX 4 Regimen) in the First-Line Treatment of Patients With Locally Advanced Unresectable or Stage IV Colorectal Cancer
3.11 Phase I and II Required Characteristics
3.111 Pathologic or cytologic diagnosis of adenocarcinoma of the colon or rectum. Patients
must have locally advanced unresectable or Stage IV colorectal cancer that is not amenable
to curative therapy. See Protocol Appendix VI, American Joint Committee on Cancer Staging
Criteria for Colorectal Cancer.
3.112 Measurable disease as defined by RECIST criteria (see Section 11.0). Patients who
do not have measurable disease, but who do have evaluable disease, may be enrolled in the
Ph I portion of the study only.
3.113 Prior radiation therapy allowed to <25% of the bone marrow (see Protocol Appendix
VII, Distribution of Active Bone Marrow in the Adult), and patients must have recovered
from the toxic effects of the treatment prior to study enrollment (except for alopecia).
Patients are allowed to have received standard postoperative adjuvant radiation therapy
for rectal cancer. Prior radiotherapy must be completed < 30 days before study entry.
Lesions that have been radiated in the advanced setting cannot be included as sites of
measurable disease unless clear tumor progression has been documented in these lesions
since the end of radiation therapy.
3.114 ECOG performance status (PS) of 0, 1or 2 (see Protocol Appendix IV).
3.115 Estimated life expectancy of greater than or equal to 12 weeks.
3.116 Ability and willingness to comply with adequate follow-up.
3.117 Adequate organ function including the following less than or equal to 7 days prior
to study entry:
- Adequate bone marrow reserve:
- ANC greater than or equal to 1500
- PLT greater than or equal to 100,000
- Hgb greater than or equal to 9 g/dL.
- Total bilirubin less than or equal to 1.5 x ULN
- Alk Phos (AP), AST less than or equal to 3.0 x ULN (AP and AST less than or equal to
5 ULN is acceptable if liver has tumor involvement).
- Renal: calculated creatinine clearance (CrCl) >= 45 mL/min based on the standard
Cockcroft and Gault formula (see table below) or on measured glomerular filtration
rate (GFR) using the appropriate radiolabeled method (51-CrEDTA or Tc99m-DTPA).
Enrollment and dosing decisions based on creatinine clearance may be made using local
lab values (calculated using the standard Cockcroft and Gault formula [see below])
The serum creatinine must be assayed at the same local lab each time for that
- Cockcroft and Gault Equation Creatinine clearance for males = (140 - age)(weight
in kg) (72)(serum creatinine in mg/dL) Creatinine clearance for females = 140 -
age)(weight in kg)(0.85) (72)(serum creatinine in mg/dL) Moderate renal
impairment is calculated creatinine clearance 30-50 mL/min (32). Mild renal
impairment is calculated creatinine clearance 51-80 mL/min (32).
3.118 Ability to sign informed consent.
3.119 Age greater than or equal to 18 years.
3.12 Phase I and II Contraindications
3.121 Evidence of peripheral neuropathy >CTCAE v3.0 Grade 1 (for example, diabetic
3.122 Prior chemotherapy for advanced disease. Only one prior adjuvant therapy including
CPT-11, or 5-fluorouracil-leucovorin, Capecitabine but not oxaliplatin is allowed if it
has been >= 6 months since the last treatment. Patients enrolling in the Phase I portion
of the trial may have received one advanced disease regimen that does not include either
ALIMTA or oxaliplatin.
3.123 Treatment less than or equal to 30 days with any chemotherapy as well as
non-cytotoxic cancer therapy such as immunotherapy.
3.124 Serious concomitant systemic disorders (including active infections or
uncontrolled/brittle diabetes) that would compromise the safety of the patient or
compromise the patients ability to complete the study.
3.125 Second primary malignancy (except in situ carcinoma of the cervix or adequately
treated nonmelanomatous carcinoma of the skin or other malignancy treated >= 5 years
previously with no evidence of recurrence; prior low grade [Gleason score £ 6] localized
prostate cancer is allowed).
3.126 Inability to interrupt aspirin or other nonsteroidal anti-inflammatory agents 2 days
before, the day of, and 2 days after each dose of ALIMTA (5 days prior for long-acting
agents such as piroxicam). (See Appendix VIII for list of NSAIDs.)
3.127 Clinically symptomatic central nervous system metastases. Metastases that have been
previously treated and are stable are allowed as judged by the investigator.
3.128 Any of the following as this regimen may be harmful to a developing fetus or nursing
- Pregnant women
- Nursing women
- Women of childbearing potential or their sexual partners who are unwilling to employ
adequate contraception (condoms, diaphragm, birth control pills, injections,
intrauterine device (IUD), surgical sterilization, subcutaneous implants, or
3.129a Presence of clinically relevant third-space fluid collections. Fluid collections
may be drained to allow the patient to enroll in the study.
3.129b Weight loss ³10% - 6 weeks prior to study entry.
3.129c Inability or unwillingness to take folic acid or vitamin B12.
3.129d Previous completion or withdrawal from this study or any other study investigating
3.129e Prior treatment with oxaliplatin.
3.129f Concurrent therapy or treatment - 30 days with another experimental agent for
cancer or other diseases.