Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib

Inclusion Criteria:

1. Male or female patients ≥ 18 years of age
2. Histologically confirmed GIST of any anatomical location and confirmed by the RRePS Network ; positive immunohistochemical staining for c-KIT (CD117); or negative staining for KIT, but with either positive staining for DOG1 or an identified mutation of KIT or PDGFRA gene
3. CDKN2A gene deletion assessed by array-comparative genomic hybridization (array-CGH)
4. Unresectable and/or metastatic disease with documented progression according to modified RECIST criteria (see section 7.2.1.5 of protocol) after 1st line imatinib and 2nd line sunitinib. Progression on the last line of treatment should be confirmed by central review with two radiological assessments identical (CT scans or MRI) obtained at less from 4 months interval within the 24 months before inclusion.
5. At least one measurable GIST lesion according to RECIST (v1.1 Appendix 3). A previously irradiated lesion is eligible to be considered as a measurable lesion provided that there is objective evidence of progression of the lesion prior to starting PD-0332991.
6. A performance status of 0, 1 or 2 according to the Eastern Cooperative Oncology Group (ECOG) scale(Appendix 1)
7. Recovery from Grade 2 to 4 toxicity related to prior line of treatment assessed according to NCICTCAE v.4.0 (Appendix 2)
8. Adequate bone marrow function as shown by:

   Blood absolute neutrophil count (ANC) ≥ 1.5 x 109/L
   1. Blood platelets ≥ 100 x 109/L
   2. Blood hemoglobin (Hgb) \> 9 g/dL
9. Adequate liver function as shown by:

   c. Serum or plasma ALT and AST ≤ 3.0 x ULN (regardless of the presence or absence of metastases) d. Serum or plasma total bilirubin: ≤ 1.5 x ULN (excepted for patients with Gilbert's syndrome)
10. Adequate renal function as shown by serum creatinine ≤ 2 x ULN
11. Patients who give a written informed consent obtained according to French and European regulations.
12. Patients affiliated to the French Social Security

Exclusion Criteria:

1. RB1 gene deletion assessed by array-comparative genomic hybridization (array-CGH)
2. Patients who received anti-cancer drugs ≤ 5 days prior to starting PD-0332991
3. Patients who are treated or planned to be treated concomitantly with other cytotoxic or antineoplastic treatments, such as chemotherapy, immunotherapy, biological response modifiers, or radiotherapy
4. Patients with another primary malignancy within 2 years prior to starting the study drug, with the exception of adequately treated in-situ carcinoma of the uterine cervix, or completely excised (R0 resection) basal or squamous cell carcinoma of the skin
5. Patients with a corrected QT interval using Bazett's formula (QTcB) \> 470 msec.
6. Current use or anticipated need for food or drugs that are known strong cytochrome P450 (CYP)3A4 inhibitors (i.e. grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, posaconazole, erythromycin, clarithromycin, tilithromycin, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, atazanavir, amprenavir, fosamprenavir, nefazodone, diltiazem, and delaviridine)
7. Patients with impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of PD-0332991 (e.g. severe ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or extensive (\>1m) small bowel resection, inability to swallow oral medications). Prior partial gastrectomy is not an exclusion criterion.
8. Patients with prior complete gastrectomy
9. Any of the following in the previous 6 months: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism.
10. Patients with any clinically significant medical or surgical condition which, according to investigators' discretion, should preclude participation

    1. i.e. active or uncontrolled infection, uncontrolled diabetes, active or chronic liver disease (cirrhosis, chronic active hepatitis or chronic persistent hepatitis)
    2. hepatitis B or C virus carriers with normal liver function tests, can be included
11. Known diagnosis of human immunodeficiency virus (HIV) infection. HIV testing is not mandatory
12. Patients who are currently receiving anticoagulation treatment with therapeutic doses :

    1. of warfarin or equivalent anticoagulant (e.g. high dose aspirin or clopidogrel or other)
    2. or have an INR \>1.5. Treatment with acetylsalicyclic acid 100 mg daily or low molecular weight heparin (LMWH) is allowed
13. Pregnant or breast-feeding women
14. Women of child-bearing potential not employing two effective methods of birth control. Effective contraception must be used throughout the trial and 24 weeks after the end of PD-0332991 (e.g. condom with spermicidal jelly, foam suppository or film; diaphragm with spermicide; male condom and diaphragm with spermicide, oral, implantable, or injectable contraceptives). Women of child-bearing potential defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months (i.e. who has had menses any time in the preceding 12 consecutive months), must have a negative serum pregnancy test ≤ 21 days prior to starting study drug.
15. Fertile males not willing to use contraception as stated above
16. Patients unwilling or unable to comply with the protocol.