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A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent
Josep María Del Campo1, Michael Birrer2, Craig Davis3
1Vall d'Hebron Institute of Oncology (VHIO), Pg. Vall d'Hebron 119-129, Barcelona 08035, Spain.
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.
Insights
Gedatolisib showed moderate activity and acceptable tolerability in recurrent endometrial cancer patients. PF-04691502 was not well tolerated, and stathmin-high expression did not improve efficacy.
Area of Science:
- Oncology
- Pharmacology
Background:
- Recurrent endometrial cancer presents a treatment challenge.
- Dual phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors offer a potential therapeutic strategy.
Purpose of the Study:
- To evaluate the efficacy and safety of PF-04691502 and gedatolisib, dual PI3K/mTOR inhibitors.
- To assess clinical benefit response in patients with recurrent endometrial cancer after platinum-based chemotherapy.
Main Methods:
- Phase II study (B1271004) using a Simon two-stage design.
- Patients stratified into PI3K-basal or PI3K-activated arms based on stathmin expression.
- Treatment with PF-04691502 (oral) or gedatolisib (intravenous).
Main Results:
- PF-04691502 arms discontinued due to toxicity (pneumonia, pneumonitis).
- Gedatolisib demonstrated a 53% clinical benefit response in the stathmin-low arm.
- Common adverse events for gedatolisib included nausea, mucosal inflammation, and decreased appetite.
Conclusions:
- Gedatolisib exhibited acceptable tolerability and moderate activity in recurrent endometrial cancer.
- PF-04691502 was not well tolerated in daily oral dosing.
- Stathmin-high expression did not predict improved treatment efficacy for gedatolisib.
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