Adult patients with Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib MedDRA version: 18.0 Level: LLT Classification code 10062427 Term: Gastrointestinal stromal tumor System Organ Class: 100000004864
Conditions
Interventions
Product Code: PD-0332991
Pharmaceutical Form: Capsule
Sponsors
Institut Bergonié
Eligibility
Sex/Gender
All
Inclusion criteria
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 · Blood platelets = 100 x 109/L · Blood hemoglobin (Hgb) > 9 g/dL 9. Adequate liver function as shown by: · Serum or plasma ALT and AST = 3.0 x ULN (regardless of the presence or absence of metastases) · 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 Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 63 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range
Exclusion criteria
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 - i.e. active or uncontrolled infection, uncontrolled diabetes, active or chronic liver disease (cirrhosis, chronic active hepatitis or chronic persistent hepatitis) - 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 • of warfarin or equivalent anticoagulant (e.g. high dose aspirin or clopidogrel or other) • 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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To assess the antitumor activity of PD-0332991 in terms of non-progression at 16 weeks (after centralized review) in patients with documented disease progression while on therapy with imatinib and sunitinib for unresectable and/or metastatic GIST.;Secondary Objective: To assess the antitumor activity of PD-0332991 in terms of : -Objective response rate (ORR) (as per RECIST v1.1 criteria Appendix 3) -Progression-free survival (PFS) (as per RECIST v1.1 criteria Appendix 3) -Non progression rate and ORR assessed using CHOI criteria (Appendix 4 ) -Overall survival To assess correlation between ORR-RECIST and ORR- CHOI To assess the safety of PD-0332991: Incidence of adverse events (AEs), seriousadverse events (SAEs) and abnormal laboratory results (hematology, blood chemistry) will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE), v4.0. (Appendix 4) To assess the pharmacodynamic (PD) effect of PD-0332991 on gene expression profile in patient consenting to research biopsies (Optional study) before starting treatment and on treatment.;Primary end point(s): Efficacy is assessed based on 4-month non progression. Non progression is defined as complete or partial response (CR, PR) or stable disease (SD), using the Response Evaluation Criteria in Solid Tumors (RECISTv1.1). Non-progression rate will be calculated as the number of alive and progression free patients divided by the number of eligible and assessable patients for the efficacy analysis. Eligible and assessable populations are described in corresponding section of protocol. As recommended by RECIST v1.1, all claimed response will be centrally reviewed by an expert of the study. The results of the centralized radiological review will be used for the analysis of the primary endpoint. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): -Objective response is defined as complete response (CR) or partial response (PR) according to RECIST v1.1. -Progression-free survival is defined as the time from the first administration of treatment to progression (as per RECIST v1.1) or death of any cause, whichever occurs first - Overall survival is defined as the time from the first administration of treatment to death. - Progression will also be assessed using CHOI criteria - Safety of PD-0332991 will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE), v4.0 | — |
Countries
France
Contacts
Public ContactClaire Jouffroy
UNICANCER
Outcome results
None listed