A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.
View/ Open
Date
2016-07ICR Author
Author
Del Campo, JM
Birrer, M
Davis, C
Fujiwara, K
Gollerkeri, A
Gore, M
Houk, B
Lau, S
Poveda, A
González-Martín, A
Muller, C
Muro, K
Pierce, K
Suzuki, M
Vermette, J
Oza, A
Type
Journal Article
Metadata
Show full item recordAbstract
Objective PF-04691502 and gedatolisib (PF-05212384) are potent, dual PI3K/mTOR inhibitors. This phase II study (B1271004) was conducted in patients with recurrent endometrial cancer following platinum-containing chemotherapy. The primary endpoint was to assess clinical benefit response (complete or partial response, or stable disease for ≥16weeks) following treatment with PF-04691502 or gedatolisib.Methods The main study consisted of four independent arms based on a Simon two-stage design. Patients were assigned to putative PI3K-basal (PF-04691502 or gedatolisib) or PI3K-activated (PF-04691502 or gedatolisib) arms based on stathmin-low or stathmin-high tumor expression, respectively. Japanese patients were also enrolled in a separate lead-in cohort.Results In stage 1 (main study), eighteen patients were randomized to PF-04691502 and 40 to gedatolisib. The two PF-04691502 arms were discontinued early due to unacceptable toxicity, including pneumonia and pneumonitis. The most common treatment-related adverse events associated with gedatolisib were nausea (53%), mucosal inflammation (50%), decreased appetite (40%), diarrhea (38%), fatigue (35%), and dysgeusia and vomiting (each 30%). Clinical benefit response rate was 53% (10/19) in the gedatolisib/stathmin-low arm and 26% (5/19) in the gedatolisib/stathmin-high arm. Safety profile and pharmacokinetic characteristics of both drugs in the Japanese lead-in cohort were comparable to the Western population.Conclusions Gedatolisib administered by weekly intravenous infusion demonstrated acceptable tolerability and moderate activity in patients with recurrent endometrial cancer. PF-04691502 daily oral dosing was not well tolerated. Clinical benefit response criteria for proceeding to stage 2 were only met in the gedatolisib/stathmin-low arm. Stathmin-high expression did not correlate with greater treatment efficacy. ClinicalTrials.gov registration ID: NCT01420081.
Collections
Subject
Humans
Endometrial Neoplasms
Neoplasm Recurrence, Local
Morpholines
Pyridones
Pyrimidines
Triazines
Protein Kinase Inhibitors
Aged
Aged, 80 and over
Middle Aged
Female
Phosphatidylinositol 3-Kinases
TOR Serine-Threonine Kinases
Biomarkers, Tumor
Phosphoinositide-3 Kinase Inhibitors
Language
eng
Date accepted
2016-04-16
License start date
2016-07
Citation
Gynecologic oncology, 2016, 142 (1), pp. 62 - 69