A Trial to Assess the Activity and Safety of Palbociclib in Patients With Well and Moderately Differentiated Metastatic Pancreatic Neuroendocrine Tumors (pNET)
A Trial to Assess the Activity and Safety of Palbociclib in Patients With Well and Moderately Differentiated Metastatic Pancreatic Neuroendocrine Tumors (pNET)
A phase II trial to assess the activity and safety of PD0332991 in patients with well- and
 moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET) with
 overexpression of cell cycle markers (Cdk4 and/or phospho-Rb1 and/or cyclin D1)
The purpose of this study is to evaluate the activity and safety of PD0332991 in patients
 with well- and moderately-differentiated metastatic pancreatic neuroendocrine tumors (pNET)
 with overexpression of cell cycle markers (Cdk4 and/or phospho-Rb1 and/or cyclin D1)
Inclusion Criteria:

 1. Histologically or cytologically proven diagnosis of pancreatic neuroendocrine tumors
 (pNET) with Ki67 assessment of < or = 20% (well and moderately differentiated) with
 evidence of unresectable disease or metastatic disease. Locally advanced disease must
 not be amendable to resection or radiation therapy with curative intent.

 2. Overexpression of Cdk4 and/or phospho-Rb1 and/or cyclin D1 in tumor tissue sample from
 tumor biopsy or prior primary tumor resection (Molecular study will be conducted at
 CNIO and logistic is described later). Therefore availability of paraffin-embedding
 tumor tissue sample is needed.

 3. Documented progression of the disease by CT scan, MRI, or Octreoscan within 12 months
 prior to baseline.

 4. Previous treatments with chemotherapy, antiangiogenics, or interferon are permitted
 providing that toxicity has resolved to < grade 1 at study entry and that last
 treatment was at least 4 weeks prior to baseline assessment. Patients may be treated
 with somatostatin analogues during the trial. Concomitant interferon treatment is not
 permitted.

 5. Measurable disease as per RECIST. Measurable lesions that have been previously
 radiated will not be considered target lesions unless increase in size has been
 observed following completion of radiation therapy.

 6. Able to swallow oral compound

 7. Male or female, 18 years of age or older.

 8. ECOG performance status less than 2.

 9. Life expectancy greater than 12 weeks.

 10. The definitions of minimum adequacy for organ function required prior to study entry
 are as follows. In addition, safety precautions provided in the product labeling for
 the anticipated control arm chemotherapy must be observed.

 -  Serum aspartate transaminase (AST) and serum alanine transaminase (ALT) 2.5 x
 upper limit of normal (ULN), or AST and ALT 5 x ULN if liver function
 abnormalities are due to underlying malignancy

 -  Total serum bilirubin 1.5 x ULN

 -  Serum albumin 3.0 g/dL

 -  Absolute neutrophil count (ANC) 1500/L

 -  Platelets 100,000/L

 -  Hemoglobin 9.0 g/dL

 -  Creatinin clearance < 40 mL/min

 11. Signed and dated informed consent document indicating that the patient (or legally
 acceptable representative) has been informed of all the pertinent aspects of the trial
 prior to enrollment.

 12. Willingness and ability to comply with scheduled visits, treatment plans, laboratory
 tests, and other study procedures.

 Exclusion Criteria:

 1. Prior chemotherapy regimen or biological treatment for locally advanced or metastatic
 transitional cell carcinoma of the urinary tract.

 2. Prior treatment on Cdk4 inhibitor under clinical trial.

 3. Creatinine clearance < 40 ml/min using Cockroft and Gault formula.

 4. Major surgery, radiation therapy, or systemic therapy within 3 weeks of study
 randomization except palliative radiotherapy to non-target metastatic lesions.

 5. Prior high-dose chemotherapy requiring hematopoietic stem cell rescue.

 6. Immunosuppressive drugs such as cyclosporine, tacrolimus, azathioprine, or long-term
 oral glucocorticoids taken concurrently or within last 3 months prior to randomization

 7. Prior radiation therapy to >25% of the bone marrow.

 8. Current treatment on another clinical trial.

 9. Uncontrolled brain metastases, spinal cord compression, carcinomatous meningitis, or
 leptomeningeal disease. Patients should have completed surgery or radiation therapy
 for existing brain metastases, should not have documented increase in size over the
 previous 3 months prior to first dose of treatment on study and should be
 asymptomatic.

 10. Diagnosis of any second malignancy within the last 3 years, except for adequately
 treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.

 11. Any of the following within the 12 months prior to starting study treatment:
 myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass
 graft, congestive heart failure, cerebrovascular accident including transient ischemic
 attack, or pulmonary embolus.

 12. Ongoing cardiac dysrhythmias of NCI CTCAE grade 2, atrial XML File Identifier:
 3xAP+CVEwV9UnEoC7xvloFQA/XQ=Page 20/34 fibrillation of any grade, or QTc interval >450
 msec for males or >470msec for females.

 13. Hypertension that cannot be controlled by medications (>150/100mmHg despite optimal
 medical therapy)

 14. Current treatment with therapeutic doses of Coumadin (low dose Coumadin up to 2 mg PO
 daily for deep vein thrombosis prophylaxis is allowed).

 15. Known human immunodeficiency virus infection.

 16. Pregnancy or breastfeeding. All female patients with reproductive potential must have
 a negative pregnancy test (serum or urine) prior to randomization.

 17. Other severe acute or chronic medical or psychiatric condition, or laboratory
 abnormality that would impart, in the judgment of the investigator, excess risk
 associated with study participation or study drug administration, or which, in the
 judgment of the investigator, would make the patient inappropriate for entry into this
 study.