A Multi-Arm Phase I Study of the PI3K/mTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer
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BACKGROUND: This phase I, four-arm, open-label study (NCT01347866) evaluated the PI3K/mTOR inhibitors PF-04691502 (arms A, B) and gedatolisib (PF-05212384; arms C, D) in combination with the MEK inhibitor PD-0325901 (arm A, D) or irinotecan (arm B, C) in patients with advanced solid tumors. OBJECTIVES: Primary endpoint was dose-limiting toxicity with each combination. Secondary endpoints included safety, pharmacokinetics and preliminary antitumor activity. PATIENTS AND METHODS: Dose escalation followed a 3 + 3 design in arm C and a zone-based design in arm D. RESULTS: was estimated to be 110 mg weekly and for the combination with PD-0325901 was not reached at the highest dose evaluated (gedatolisib 154 mg weekly). Plasma concentrations of gedatolisib were generally similar across dose groups in arm C (with irinotecan) and arm D (with PD-0325901). Frequent dose delays or dose reductions were required for both combinations, potentially preventing sustained therapeutic drug concentrations. Gedatolisib plus irinotecan produced a response rate of ~5% and clinical benefit in 16% of patients with advanced colorectal cancer (progression-free survival, 2.8 months). Preliminary evidence of clinical activity was observed with gedatolisib plus PD-0325901 in patients with ovarian cancer (three partial responses, n = 5) or endometrial cancer (one partial response, n = 1) and KRAS mutations. CONCLUSIONS: Further evaluations of gedatolisib are warranted in patients with advanced solid malignancies.
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Horizontal combination, targeting parallel pathways, invariably leads to resistance or unacceptable toxicity.
“Targeting parallel pathways (‘horizontal combination’) also invariably leads to resistance or unacceptable toxicity94,95.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [94]
Combination strategies for horizontal inhibition of parallel pathways are marred by resistance and toxicity.
“In addition, we describe combination strategies for horizontal inhibition of parallel pathways, an approach also marred by resistance in addition to toxicity94,95.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [94]
The combination of MEK and PI3K inhibitors in clinical practice has been limited in effectiveness and identified as having high toxicity.
“However, the combination of MEK and PI3K inhibitors in clinical practice has been limited in effectiveness and identified as having high toxicity [77].”
From RAS Mutations in Advanced Colorectal Cancer: Mechanisms, Clinical Implications, and Novel Therapeutic Approaches (2025) · cites this paper as [77]
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References 33 · Cited by 98
- Authors
- Wainberg, Z. A., Alsina, M., Soares, H. P., Braña, I., Britten, C. D., Del Conte, G., Ezeh, P., Houk, B., Kern, K. A., Leong, S., Pathan, N., Pierce, K. J., Siu, L. L., Vermette, J., & Tabernero, J.
- Affiliations
- University of California, Los Angeles (US)
- Moffitt Cancer Center (US)
- Princess Margaret Cancer Centre (CA)
- Medical University of South Carolina (US)
- Pfizer (United States) (US)
- University of Colorado Anschutz (US)
- Universitat Autònoma de Barcelona (ES)
- Corresponding author
- Wainberg, Zev A.
- ORCID
- Venue
- Targeted Oncology
- Published
- 2017-10-24
- Volume
- 12
- Issue
- 6
- Pages
- 775-785
- ISSN
- 1776-2596 (ISSN-L)
- 1776-260X
- PMC
- PMC5700209
- OpenAlex
- W2765084883
- Cited by
- 98
- References
- 33
- Citations by year
- 2026: 4 · 2025: 17 · 2024: 18 · 2023: 6 · 2022: 10 · 2021: 13 · 2020: 14 · 2019: 11 · 2018: 5
- FWCI
- 3.35
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Targeted Oncology (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Dipòsit Digital de Documents de la UAB (Universitat Autònoma de Barcelona) (submittedVersion, cc-by-nc)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc)
- Funders
- Pfizer (Not applicable)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- PI3K/mTOR inhibitors, gedatolisib, PF-04691502, irinotecan, MEK inhibitors, PD0325901, advanced solid tumors, dose-limiting toxicity, colorectal cancer, ovarian cancer, endometrial cancer, KRAS mutation, combination therapy, pharmacokinetics
- MeSH terms
- Irinotecan, Phosphoinositide-3 Kinase Inhibitors, Antineoplastic Combined Chemotherapy Protocols, Antineoplastic Agents, Phytogenic, Benzamides, Camptothecin, Diphenylamine, Female, Humans, Male, Morpholines, Neoplasms, Triazines, TOR Serine-Threonine Kinases
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