Dataset Information

Phase II Trial of Palbociclib in Patients with Advanced Esophageal or Gastric Cancer.

ABSTRACT:

Lessons learned

Palbociclib monotherapy demonstrated minimal clinical activity in patients with previously treated gastroesophageal cancers. Further clinical evaluation of palbociclib monotherapy is not warranted in gastroesophageal cancers, but improved understanding of resistance mechanisms may permit rational combination approaches.

Background

Dysregulation of the cell cycle is a hallmark of cancer. Progression through the G1/S transition requires phosphorylation of retinoblastoma (RB) by cyclin-dependent kinases (CDKs) 4 and 6, which are regulated by cyclins D and E. Amplifications of cyclin D loci and activating mutations in CDKs are frequent molecular aberrations in gastroesophageal malignancies. We conducted a phase II trial of the CDK4/6 inhibitor palbociclib as an initial test of efficacy.

Methods

Patients with previously treated metastatic gastroesophageal cancers with intact RB nuclear expression by immunohistochemistry were treated with 125 mg daily of palbociclib for days 1-21 of 28-day cycles. The primary endpoint was overall response rate.

Results

We screened 29 patients and enrolled 21 patients: 5 with gastric adenocarcinoma, 3 with gastroesophageal junction adenocarcinoma, 8 with esophageal adenocarcinoma, and 5 with esophageal squamous cell carcinoma. All 29 tumors screened had intact nuclear RB expression, and four treated patients tested positive for CCND1 overexpression. No objective responses were seen. Median progression-free survival was 1.8 months, and median overall survival was 3.0 months. All recurrent grade 3 or 4 toxicities were hematologic, with neutropenia in eight patients (38%), anemia in four patients (19%), and thrombocytopenia in two patients (10%).

Conclusion

Palbociclib has limited single-agent activity in gastroesophageal tumors.

SUBMITTER: Karasic TB

PROVIDER: S-EPMC8108046 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND:Gastric cancer is one of the most common malignant tumors worldwide. With the rapid aging of global population, the number of elderly patients with local advanced gastric cancer is increasing. Surgery is the essential treatment for local advanced gastric cancer. However, elderly patients are at high risk of postoperative complications due to reduced functional reserve and increased comorbidities. Laparoscopic gastrectomy may be a promising surgery approach for elderly patients but its benefits remain controversial. We therefore proposed this randomized trial to evaluate the safety and efficacy of laparoscopic versus open gastrectomy for local advanced gastric cancer in patients aged 70 and above. METHODS:The current study has a randomized, parallel controlled, single-center, open-label, superiority design with two arms. A sample of 180 local advanced gastric cancer patients aged 70 and above will be recruited in Peking University Cancer Hospital and Institute. Participants will be randomized to either receive open or laparoscopic gastrectomy. The primary outcome is surgical safety, including complication rate, reoperation rate, readmission rate, and mortality rate within 30 days after surgery. The secondary endpoints include postoperative rehabilitation status, one-year postoperative life quality, three-year overall and disease-free survival. Assessments will take place at baseline (before random assignment), at 30 days, one-year, and three-year after the surgery. The study has been approved by an ethical review board. DISCUSSION:We hypothesized that laparoscopic gastrectomy is superior to open gastrectomy in terms of perioperative safety for local advanced gastric cancer patients aged 70 and above. If this hypothesis is statistically proved, the rational introduction of minimally invasive surgery technique in traditional gastrectomy can help improve the surgical safety for elderly patients, reduce patient financial burden, shorten hospital stay, and improve hospital beds turnover rate. Our research data will also provide high quality clinical evidence and data support for the conduction of multicenter phase III clinical trials. TRIAL REGISTRATION:The study has been prospectively registered in ClinicalTrial.gov ( NCT03564834 ).

Project description:PurposeWe evaluated the activity of regorafenib, an oral multikinase inhibitor, in advanced gastric adenocarcinoma.Patients and methodsWe conducted an international (Australia and New Zealand, South Korea, and Canada) randomized phase II trial in which patients were randomly assigned at a two-to-one ratio and stratified by lines of prior chemotherapy for advanced disease (one v two) and region. Eligible patients received best supportive care plus regorafenib 160 mg or matching placebo orally on days 1 to 21 of each 28-day cycle until disease progression or prohibitive adverse events occurred. The primary end point was progression-free survival (PFS). Final analysis included data to December 31, 2014.ResultsA total of 152 patients were randomly assigned from November 7, 2012, to February 25, 2014, yielding 147 evaluable patients (regorafenib, n = 97; placebo, n = 50). Baseline characteristics were balanced. Median PFS significantly differed between groups (regorafenib, 2.6 months; 95% CI, 1.8 to 3.1 and placebo, 0.9 months; 95% CI, 0.9 to 0.9; hazard ratio [HR], 0.40; 95% CI, 0.28 to 0.59; P < .001). The effect was greater in South Korea than in Australia, New Zealand, and Canada combined (HR, 0.12 v 0.61; interaction P < .001) but consistent across age, neutrophil-to-lymphocyte ratio, primary site, lines of chemotherapy, peritoneal metastasis presence, number of metastatic sites, and plasma vascular endothelial growth factor A. A survival trend in favor of regorafenib was seen (median, 5.8 months; 95% CI, 4.4 to 6.8 v 4.5 months; 95% CI, 3.4 to 5.2; HR, 0.74; P = .147). Twenty-nine patients assigned to placebo received open-label regorafenib after disease progression. Regorafenib toxicity was similar to that previously reported.ConclusionIn this phase II trial, regorafenib was effective in prolonging PFS in refractory advanced gastric adenocarcinoma. Regional differences were found, but regorafenib was effective in both regional groups. A phase III trial is planned.