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A phase I study of AZD8186 in combination with docetaxel in patients with PTEN-mutated or PIK3CB-mutated advanced
A M Schram1, N Takebe2, A Chen2
1Memorial Sloan Kettering Cancer Center, New York, USA; Weill Cornell Medical College, New York, USA.
Background:
Loss of PTEN activity is common in solid tumors and promotes cancer growth through activation of the PI3K pathway. PTEN-deficient tumors have increased dependence on PI3Kβ and are sensitive to PI3Kβ inhibition in preclinical models. Efficacy is further enhanced by the addition of taxane chemotherapy. We conducted a phase I trial of AZD8186, a small molecule inhibitor of PI3Kβ and PI3Kδ, in combination with docetaxel (Taxotere) (NCI 10131; NCT03218826).
Material And Methods:
Patients with advanced PTEN- or PIK3CB-mutated solid tumors identified through local testing were eligible. Treatment included docetaxel intravenously every 21 days and AZD8186 orally twice daily, 5 days on and 2 days off. Primary objectives were safety, tolerability, and maximum tolerated dose (MTD) as determined by a 3 + 3 dose-escalation design. Secondary objectives included assessment of antitumor activity.
Results:
Twenty-three patients were enrolled with 11 distinct tumor types across 5 dose levels. Clinically significant neutropenia led to dose-level adjustment and the addition of prophylactic growth factor. The MTD was not reached and AZD8186 120 mg twice daily with docetaxel 75 mg/m2 was named the recommended phase II dose. The most common treatment-emergent adverse events (TEAEs) were anemia (57%), diarrhea (43%), and fatigue (43%). The most common grade ≥3 TEAE was neutropenia (30%). One patient with docetaxel-naive prostate cancer had a prolonged partial response (overall response ratio 5.6%); clinical benefit rate was 22.2%.
Conclusions:
The combination of AZD8186 and docetaxel was generally well tolerated, with the exception of neutropenia, which was effectively managed with the use of growth factor. Limited clinical activity was observed.
Insights
This phase I trial combined AZD8186, a PI3K inhibitor, with docetaxel chemotherapy in advanced solid tumors. The combination showed manageable toxicity, with neutropenia being the main concern, and limited clinical activity observed.
Area of Science:
- Oncology
- Clinical Pharmacology
- Drug Development
Background:
- Loss of PTEN activity is prevalent in solid tumors, activating the PI3K pathway and driving cancer growth.
- PTEN-deficient tumors exhibit heightened dependence on PI3Kβ, showing sensitivity to PI3Kβ inhibition in preclinical studies.
- Combining PI3K inhibitors with taxane chemotherapy may enhance efficacy in PTEN-altered cancers.
Purpose of the Study:
- To evaluate the safety, tolerability, and maximum tolerated dose (MTD) of AZD8186 in combination with docetaxel in patients with advanced solid tumors.
- To determine the recommended Phase II dose (RP2D) for this combination therapy.
- To assess the preliminary antitumor activity of the combination treatment.
Main Methods:
- A Phase I, 3+3 dose-escalation study involving patients with advanced PTEN- or PIK3CB-mutated solid tumors.
- AZD8186 was administered orally twice daily (5 days on, 2 days off) concurrently with intravenous docetaxel every 21 days.
- Safety endpoints included dose-limiting toxicities, MTD, and treatment-emergent adverse events (TEAEs); antitumor activity was a secondary endpoint.
Main Results:
- Twenty-three patients with 11 tumor types were enrolled across 5 dose levels.
- The MTD was not reached; the RP2D was determined as AZD8186 120 mg BID plus docetaxel 75 mg/m².
- Common TEAEs included anemia (57%) and diarrhea (43%). Grade ≥3 neutropenia (30%) required prophylactic growth factor support.
- One patient with prostate cancer achieved a partial response; the overall clinical benefit rate was 22.2%.
Conclusions:
- The combination of AZD8186 and docetaxel was generally well-tolerated, with neutropenia managed by growth factors.
- Limited clinical activity was observed in this Phase I trial.
- Further investigation may be warranted to optimize the combination strategy in specific PTEN-altered tumor types.
