Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib
Condition: Advanced Gastrointestinal Stromal Tumors
MeSH terms: Gastrointestinal Stromal Tumors
Intervention: PD 0332991
Intervention description: PD-0332991 was administrated orally, formulated as gelatin capsules of 100 mg and 25 mg respectively.
PD-0332991 was dosed on a flat scale of 125 mg (1 capsule x 100 mg/day, 1 capsule x25 mg/day) will be administrated orally o.d on a 21 days on / 7 days off dosing schedule. One cycle is considered to consist of 4 weeks of PD-0332991 administration.
Patients should be instructed to administrate PD-0332991 with a sufficient amount of water at least 1 hour prior to a meal or at least 2 hours following a meal and to swallow the required number of capsules at approximately the same time on each day.
Intervention MeSH terms: Palbociclib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 29.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Gastrointestinal Stromal Tumor; PD-0332991; Efficacy; advanced; safety

Summary:

      The treatment of advanced GIST patients is based on imatinib followed with sunitinib in case
      of resistance/intolerance. However, the median progression-free survival (PFS) on sunitinib
      is frequently short, and after failure with both imatinib and sunitinib, treatment remains
      controversial.

      Previous studies on GISTs have linked 9p21 alterations to tumor progression (El-Rifai et al.
      2000; Kim et al., 2000; Schneider-Stock et al., 2003; Schneider-Stock et al., 2005; Romeo et
      al. 2009; Haller et al., 2008) but the driver gene was not positively identified (CDKN2A,
      CDKN2B, or MTAP) (Astolfi et al., 2010; Belinsky et al., 2009; Perrone et al., 2005; Assamaki
      et al. 2007; Huang et al., 2009). A recent study has shown that homozygous 9p21 deletions
      target CDKN2A and more specifically p16INK4a 4. Most of the CINSARC genes are known to be
      under the transcriptional control of E2F. RB1 sequesters E2F, which is released from the
      complex upon RB1 phosphorylation by CDK4. CDK4 is, in turn, inhibited by p16INK4a. Hence, we
      hypothesize that alteration of the restriction point via deletion of p16INK4a (and more
      rarely of RB1: 20% of cases) gene in GISTs is likely to be a causative event that leads to
      the overexpression of CINSARC genes, which in turn induce chromosome instability and
      ultimately metastasis. Low p16INK4a expression was associated with response to PD-0332991 in
      several in vitro tumor model(Konecny et al. 2011; Katsumi et al. 2011; Finn et al. 2009).
      Considering our molecular data, we believed that PD-0332991 warrants clinical investigation
      in advanced gastrointestinal stromal tumors with alteration of p16INK4a. This alteration is
      detectable by comparative genomic hybridization which is a technique highly manageable in the
      context of routine clinical care and clinical trial.

      Main objective was 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.
    

Eligibility 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

               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.