A randomized phase II non-comparative study of PF-04691502 and gedatolisib (PF-05212384) in patients with recurrent endometrial cancer.
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.
Vall d'Hebron Institute of Oncology (VHIO), Pg. Vall d'Hebron 119-129, Barcelona 08035, Spain. Electronic address: jmcampof2@seom.org.
Josep María
JM
Del Campo
Massachusetts General Hospital, 55 Fruit St # 410, Boston, MA 02114, USA. Electronic address: mbirrer@mgh.harvard.edu.
Michael
M
Birrer
Pfizer Oncology, 10646 Science Center Drive, La Jolla, CA 92121, USA. Electronic address: craig.davis@pfizer.com.
Craig
C
Davis
Saitama Medical University International Medical Center, 1397-1, Yamane, Hidaka, Saitama 350-1298, Japan. Electronic address: fujiwara@saitama-med.ac.jp.
Keiichi
K
Fujiwara
Pfizer Worldwide Research and Development, 35 Cambridge Park Drive, Cambridge, MA 02140, USA. Electronic address: ashwingollerkeri@gmail.com.
Ashwin
A
Gollerkeri
Royal Marsden Hospital, 203 Fullham Road, London SW3 6JJ, UK. Electronic address: Martin.Gore@rmh.nhs.uk.
Martin
M
Gore
Pfizer Oncology, 10646 Science Center Drive, La Jolla, CA 92121, USA.
Brett
B
Houk
McGill University, Jewish General Hospital, 3755 Chemin Cote Ste Catherine, Montreal, QC H3R 1E2, Canada. Electronic address: susie.lau@mcgill.ca.
Susie
S
Lau
Fundación Instituto Valenciano de Oncología, C/ Gregorio Gea, 31, Valencia 46009, Spain. Electronic address: apoveda@fivo.org.
Andres
A
Poveda
M. D. Anderson Cancer Center, Servicio de Oncologia Medica C/ Arturo Soria, 270, Madrid 28033, Spain. Electronic address: agonzalezm@seom.org.
Antonio
A
González-Martín
University of New Mexico Health Sciences Center, MSC07 4025 1201 Camino de Salud Northeast, Albuquerque, NM 87131, USA. Electronic address: cmuller@salud.unm.edu.
Carolyn
C
Muller
Aichi Cancer Center Hospital, 1-1 Kanododen, Chikusa-ku, Nagoya, Aichi 464-8681, Japan. Electronic address: kmuro@aichi-cc.jp.
Kei
K
Muro
Pfizer Oncology, 558 Eastern Point Rd, Groton, CT 06340, USA. Electronic address: kristen.j.pierce@pfizer.com.
Kristen
K
Pierce
Pfizer Japan, 3-22-7, Yoyogi, Shibuya-ku, Tokyo 151-8589, Japan. Electronic address: mie.suzuki@pfizer.com.
Mie
M
Suzuki
Pfizer Oncology, 300 Technology Square, Suite 302, Cambridge, MA 02139, USA. Electronic address: jennifer.vermette@pfizer.com.
Jennifer
J
Vermette
Princess Margaret Cancer Centre, 610 University Avenue, Toronto M5G 2M9, Canada. Electronic address: Amit.Oza@uhn.ca.
Amit
A
Oza
D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009025:Morpholines / Q000009:adverse effects / Q000627:therapeutic use*; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000201:enzymology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014227:Triazines / Q000009:adverse effects / Q000627:therapeutic use*
D014408:Biomarkers, Tumor; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; D014227:Triazines; C570662:2-amino-8-(4-(2-hydroxyethoxy)cyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido(2,3-d)pyrimidin-7(8H)-one; C549060:gedatolisib; C546842:MTOR protein, human
Endometrial cancer; Gedatolisib; PI3K; Stathmin; mTOR