A Phase I Study of the CDK4/6 Inhibitor PD-0332991, 5-Fluorouracil, and Oxaliplatin in Patients With Advanced Refractory Colorectal Cancer
- Retinoblastoma-positive, histologically proven colorectal cancer with measurable
- Progression on, or intolerance of, or ineligibility for all standard therapies
(including regimens containing fluoropyrimidine, oxaliplatin, irinotecan,
bevacizumab, and an anti-EGFR antibody (where appropriate).
- Biopsy accessible tumor deposits
- Corrected QT interval less than 500 milliseconds by EKG
- ECOG preformance status 0-2
- Subjects with no brain metastases or a history of previously treated brain metastases
who have been treated by surgery or stereotactic radiosurgery at least 4 weeks prior
to enrollment and have a baseline MRI that shows no evidence of active intracranial
disease and have not had treatment with steroids within 1 week of study enrollment.
- Adequate hepatic, bone marrow, and renal function
- Partial thromboplastin time must be = 1.5 x upper limit normal range and INR < 1.5.
Subjects on anticoagulant will be permitted to enroll as long as the INR is in
acceptable therapeutic range.
- Life expectancy > 12 weeks
- Women of childbearing potential must have a negative serum pregnancy test within 14
days prior to initiation of treatment and/or postmenopausal women must be amenorrheic
for at least 12 months.
- Subject is capable of understanding and complying with parameters of the protocol and
able to sign and date the informed consent.
- Intolerant of, or ineligible for 5-FU, oxaliplatin and/or the combination of both
- CNS metastases that do not meet the criteria outlined in the inclusion criteria
- Peripheral neuropathy >/= Grade 2 at baseline or peripheral neuropathy >/= Grade 1
with neuropathic pain
- Active severe infection or known chronic infection with HIV or hepatitis B virus
- Cardiovascular disease problems including unstable angina, therapy for
life-threatening ventricular arrhythmia or myocardial infarction, stroke, or
congestive heart failure within the last 6 months.
- Life-threatening visceral disease or other severe concurrent disease
- Women who are pregnant or breastfeeding
- Anticipated patient survival under 3 months
- Concurrent use of known CYP 3A4 inhibiting or activating medications
- Clinically significant and uncontrolled major medical condition(s)