Palbociclib and Cetuximab in Metastatic Colorectal Cancer

Inclusion Criteria:

4.1.1 Written informed consent obtained to participate in the study and HIPAA authorization for release of personal health information.

4.1.2 Age ≥ 18 years at the time of consent.

4.1.3 ECOG Performance Status of 0-2

4.1.4 Histologically-confirmed metastatic CRC

4.1.5 Measurable disease according to RECIST v1.1 for solid tumors.

4.1.6 Documented wild-type in KRAS and NRAS (codons 12, 13, 59, 61, 117, and 146) and in BRAF codon 600, based on tumor tissue taken from primary or metastatic site and tested for biomarkers

4.1.7 Previously treated with at least two prior regimens of systemic chemotherapy for metastatic or locally advanced, unresectable disease, including fluoropyrimidines (5-fluorouracil and/or capecitabine), oxaliplatin, and irinotecan.

A maintenance regimen of 5-fluorouracil or capecitabine, with or without bevacizumab, should not be counted as a separate line of treatment For patients who experienced disease recurrence during or within 6 months of completion of adjuvant chemotherapy with fluoropyrimidine and oxaliplatin, only one regimen of systemic chemotherapy for metastatic disease is required

4.1.8 Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained prior to initiating study medications.

System Laboratory Value Hematological* Hemoglobin (Hgb) ≥ 9 g/dL Absolute Neutrophil Count (ANC) ≥ 1500/mm3 Platelets ≥ 100,000/mm3

Renal* Creatinine OR Calculated creatinine clearance ≤1.5 x ULN

60 mL/min by Cockcroft-Gault formula Hepatic* Bilirubin ≤ 1.0 × upper limit of normal (ULN) Aspartate aminotransferase (AST) ≤ 3 × ULN OR

5 × ULN (if liver metastases present) Alanine aminotransferase (ALT) ≤ 3 × ULN OR

5 × ULN (if liver metastases present)

Note: Hematology and other lab parameters that are ≤ grade 2 BUT still meet criteria for study entry are allowed. Furthermore, changes in laboratory parameters during the study should not be considered adverse events unless they meet criteria for dose modification(s) of study medication outlined by the protocol and/or worsen from baseline during therapy.

4.1.9 Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to initiating study medications. NOTE: Females are considered of childbearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months. Documentation of postmenopausal status must be provided.

4.1.10 Females of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 6 months after treatment discontinuation. The two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method or an intrauterine device that meets <1% failure rate for protection from pregnancy in the product label.

4.1.11 Male patients with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 6 months after the last dose of study therapy.

4.1.12 Subjects is willing and able to comply with study procedures based on the judgement of the investigator or protocol designee.

4.1.13 Able to swallow capsules, with no surgical or anatomic condition that will preclude the patient from swallowing and absorbing oral medications.

4.1.14 Has not undergone any major surgical procedures for at least 4 weeks, with full healing of all surgical wounds

4.1.15 At sites in the Southeastern U.S., subject must have negative serum test for galactose-alpha-1,3-galactose IgE See Appendix 12.5 for map (Note: positive test result is predictive of immediate-onset anaphylaxis reaction during first exposure to cetuximab, which is prevalent predominantly in limited geographic region of the Southeastern U.S. (Clin Mol Allergy 2012;10:1-11).

4.1.16 For Study Cohort A, has not had prior treatment with cetuximab, panitumumab, or other anti-EGFR therapy.

4.1.17 For Study Cohort B, must have had previous treatment with cetuximab or panitumumab with disease control (defined as complete response, partial response, or stable disease) lasting for ≥ 4 months in duration and completed their last anti-EGFR therapy 8 weeks prior to initiating treatment.

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Exclusion Criteria:

4.2.1 Active infection requiring systemic therapy.

4.2.2 Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).

4.2.3 Presence of known, active central nervous system (CNS) metastases.

4.2.4 Treatment with any investigational drug within 28 days prior to initiating study medications.

4.2.5 Prior treatment with drug targeting cyclin-dependent kinase (CDK) family.

4.2.6 Subject is receiving prohibited medications or treatments as listed in section 5.5 of the protocol that cannot be discontinued/replaced by an alternative therapy.

4.2.7 Known hypersensitivity to the components of study drugs or analogs of study drugs.

4.2.8 Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years.

4.2.9 Uncontrolled, severe concomitant comorbidity (e.g. uncontrolled hypertension, uncontrolled diabetes mellitus, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection).

4.2.10 History of interstitial lung disease or pneumonitis.

4.2.11 Any other clinically significant heart disease, including angina pectoris, resting bradycardia, left bundle branch block, ventricular tachyarrhythmia, unstable atrial fibrillation, acute myocardial infarction, or heart disease requiring cardiac pacemaker or implantable cardioverter/defibrillator

4.2.12 Known psychiatric or substance abuse disorder that would interfere with the ability of the patient to comply with trial requirements.

4.2.13 History of long-QT syndrome.

4.2.14 Baseline QTcF ≥ 470 msec.

4.2.15 Concomitant use of drugs known to cause QT prolongation as defined in Appendix 12.4 and in section 5.5 (Note: Ondansetron at doses ≤ 16 mg or less is allowed)

4.2.16 History of any of the following cardiovascular conditions within the past 6 months:

Class III or IV congestive heart failure as defined by the New York Heart Association Criteria
Cardiac angioplasty or stenting
Myocardial infarction
Unstable angina
Symptomatic peripheral vascular disease or other clinically significant cardiac disease