Abstract CT329: Phase I study of the PI3Kβ/δ inhibitor AZD8186 in patients with advanced castration resistant prostate cancer, triple negative breast cancer, squamous non-small cell lung cancer or PTEN deficient solid tumors: update from dose-finding
Bibliographic record
Abstract
Abstract Background: A frequent mechanism of dysregulation of the PI3K/AKT/mTOR pathway, commonly altered in cancer, is loss of function of the tumour suppressor PTEN, leading to increased PI3K signalling, particularly through the PI3Kβ isoform. AZD8186 is a potent and selective inhibitor of PI3Kβ/δ with significant activity in PTEN-deficient preclinical models. We report the dose-finding portion of the study, assessing the safety/tolerability of an intermittent dosing schedule of AZD8186. Trial design and eligibility criteria: AZD8186 tablets were administered twice daily 5 days on treatment, 2 days off (5/2 schedule) in 3 week cycles. Escalating doses of AZD8186 were evaluated in cohorts of 3-6 evaluable patients treated until confirmed disease progression, unacceptable toxicity, or withdrawal of consent. A safety review committee reviewed all available safety data and dose limiting toxicities (DLTs) prior to each dose modification. The dose/schedule finding, safety and activity will be updated at time of presentation. Adult patients were recruited with tumor types known to be PTEN deficient or to have prevalent PTEN loss, such as castration-resistant prostate cancer (CRPC), triple negative breast cancer, squamous non-small cell lung cancer or, that had relapsed and/or were refractory to suitable therapies. Results: As of 25 Oct, 32 patients have received treatment (30 mg n = 7, 60 mg n = 6, 120 mg n = 5; 240 mg n = 6, 360 mg n = 6; 300 mg n = 2). Pharmacokinetic parameters show that systemic exposures to parent drug and its major active metabolite increased in a dose proportional manner and exceeded preclinical exposures that have demonstrated robust anti-tumour activity in PTEN deficient xenograft models. DLTs of maculopapular rash (CTCAE Grade 3) were observed at 360 mg (in 2/6 patients) and at 300 mg (2/2 patients). Additional AEs occurring in >10% of patients included diarrhea, nausea, vomiting, fatigue, rash, decreased appetite and QTc prolongation. AEs of ≥ grade 3 included: rash, hypophosphatemia, hypokalemia, diarrhea elevated aspartate transaminase and 1st degree atrioventricular block; there were no grade 5 events. Overall, 11 patients remained on study for at least 60 days; one CRPC patient remained on study for more than 160 days with minor PSA response, symptomatic improvement and stable disease by CT and bone scan. Conclusions: AZD8186 is a potent oral inhibitor of PI3Kβ/δ, with potential for treatment of PTEN-deficient tumors. Investigation of the safety/tolerability of the 5/2 schedule is continuing. This agent may hold potential for treatment of PTEN deficient tumors. Citation Format: Lillian L. Siu, Johann De Bono, Kari B. Wisinski, Celestia S. Higano, Natalie Cook, Maria Jose De Miguel Luken, Rajiv Kumar, Joshua Lang, Gurkamal S. Chatta, Sara M. Tolaney, Stefan M. Symeonides, Gilmour Morrison, Patrick D. Mitchell, David G. Brooks, Geoffrey I. Shapiro. Phase I study of the PI3Kβ/δ inhibitor AZD8186 in patients with advanced castration resistant prostate cancer, triple negative breast cancer, squamous non-small cell lung cancer or PTEN deficient solid tumors: update from dose-finding. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT329. doi:10.1158/1538-7445.AM2015-CT329
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".