A phase I trial of liposomal doxorubicin (D), bevacizumab (A), and temsirolimus (T) in advanced malignancy

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e13508 Background: Liposomal doxorubicin (D) and bevacizumab (A) are active drugs in multiple malignancies. Unfortunately, resistance mechanisms have been described for each that limit their efficacy following repeated exposure. These include aberrant activation of alternate signaling pathways, such as PI3K/AKT/mTOR and upregulation of hypoxia inducible factor (HIF-1α). We therefore added temsirolimus (T), an agent known to inhibit mTOR and to downregulate HIF-1α, to the combination of D and A. The objectives of this trial were to assess the safety of this combination, obtain preliminary efficacy data and to identify biologic correlates for treatment response. Methods: D, A and T were administered intravenously on a 21 day cycle. D, A and T were given day 1, and T was administered alone weeks 2 and 3. A standard 3+3 trial design was used for dose escalation; 6 dose levels are planned. Patient serum and biopsies were also collected pre- and post-treatment for batched analysis to assess biologic response correlates. Results: 6/12 treated patients are evaluable (remaining patients have not yet completed 1st restaging). 5 patients are male; median age (all patients) 53, range 12 to 59. Median number of prior treatments = 5, range 2 - 8. At first restaging, 2/2 patients with endometrial cancer were found to have ≥ 25% decrease in tumor size (RECIST), and one patient with colorectal carcinoma had a 15% decrease. 1 patient had stable disease. One of the patients with endometrial cancer and extensive intra-abdominal disease who showed rapid tumor regression (≥ 25% decrease at 2 months) developed an entero-colonic fistula, and chose hospice care. Grade 2 stomatitis and fatigue (CTCAEv3)have also been seen. The current doses being used are 20mg/m2 of D and 5mg/m2 of A every 21 days, and 25mg of T every 7 days (dose level 3). Conclusions: Preliminary data indicate that the combination of D, A and T has anti-tumor activity and is well tolerated at the doses used. Patients with intra-abdominal disease who experience rapid tumor regression may be at risk for fistula formation. Biomarker analysis for modulation of the mTOR signal (via PI3K mutations or other aberrations) and the HIF-1α pathway is ongoing. No significant financial relationships to disclose.