Phase 2
N=29
Efficacy and Safety of PD-0332991 in Advanced Gastrointestinal Stromal Tumors Refractory to Imatinib and Sunitinib
Advanced Gastrointestinal Stromal Tumors
Bottom Line
View on ClinicalTrials.gov: NCT01907607 ↗Enrolled (actual)
29
Serious AEs
41.4%
Results posted
Jan 2021
Primary outcome: Primary: Number of Participants With Non Progression at 4 Months — 3 Participants
Study Design & Population
- Study type
- Interventional
- Phase
- Phase 2
- Interventions
- PD 0332991 (Drug)
- Age
- Adult, Older Adult · 18+ yrs
- Sex
- All
- Sponsor
- Institut Bergonié
- Primary completion
- Dec 2016
Outcome Measures
| Outcome | Result | p-value |
|---|---|---|
| PRIMARY Number of Participants With Non Progression at 4 Months |
3 | — |
| SECONDARY Number of Participants With Objective Response at 4 Months |
— | — |
| SECONDARY Efficacy Assessment of PD-0332991 in Terms of Progression-free Survival Time |
1.74 | — |
| SECONDARY Efficacy Assessment of PD-0332991 in Terms of Overall Survival Time |
19.52 | — |
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
- Male or female patients ≥ 18 years of age
- 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
- CDKN2A gene deletion assessed by array-comparative genomic hybridization (array-CGH)
- 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.
- 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.
- A performance status of 0, 1 or 2 according to the Eastern Cooperative Oncology Group (ECOG) scale(Appendix 1)
- Recovery from Grade 2 to 4 toxicity related to prior line of treatment assessed according to NCICTCAE v.4.0 (Appendix 2)
- 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
- 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)
- Adequate renal function as shown by serum creatinine ≤ 2 x ULN
- Patients who give a written informed consent obtained according to French and European regulations.
- Patients affiliated to the French Social Security
Exclusion Criteria
- RB1 gene deletion assessed by array-comparative genomic hybridization (array-CGH)
- Patients who received anti-cancer drugs ≤ 5 days prior to starting PD-0332991
- 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
- 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
- Patients with a corrected QT interval using Bazett's formula (QTcB) > 470 msec.
- 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)
- 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.
- Patients with prior complete gastrectomy
- 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.
- 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 d
Data sourced from ClinicalTrials.gov (NCT01907607). Outcome figures and adverse-event rates are extracted automatically from the registry's posted results and are provided for clinician reference, not as a substitute for the primary publication.