Jennifer Squires

Combination therapy: intermittent sorafenib with bevacizumab yields activity and decreased toxicity

Background:We previously reported preliminary results of our phase I study of continuous daily sorafenib with bevacizumab every other week for solid tumours. Toxicity was moderate, leading to additional dose levels (DL) testing intermittent sorafenib dosing.Methods:Seventeen patients with advanced solid tumours were treated on three additional DLs testing sorafenib days 1–5 per week. Dose level 4 was sorafenib 200 mg twice daily (b.i.d.) and bevacizumab 5 mg kg−1. DL5 alternated between bevacizumab 10 mg kg−1-sorafenib 200 mg b.i.d. (A) and sorafenib 400 mg b.i.d. with bevacizumab 5 mg kg−1 (B). Outcome and toxicity data from 19 epithelial ovarian cancer (EOC) patients from DL 1–5 were analysed.Results:Fewer patients required sorafenib dose reduction with the intermittent schedule (41 vs 74% daily, P=0.01). Hand–foot skin reaction (HFSR) remained the primary cause of dose reduction (n=5). Partial responses (12%) or disease stabilisation ⩾4 months (53%; median 6 (4–26)) occurred in most patients on the intermittent schedule. Partial response occurred in 47% EOC patients treated in pooled analysis of duration 4–37 months.Conclusion:Intermittent sorafenib dosing with bevacizumab has promising clinical activity and less sorafenib dose reduction and side effects, but does not ameliorate HFSR. We are conducting a phase II clinical trial with intermittent sorafenib and bevacizumab in patients with EOC.

Feasibility and safety of sequential research-related tumor core biopsies in clinical trials.

There has been increasing interest in serial research biopsies in studies of targeted therapies. Definition of patient characteristics and optimal target tissue for safe research tumor biopsy in the era of antiangiogenic and targeted agents is needed.

Adenocarcinoma cells in effusion cytology as a diagnostic pitfall with potential impact on clinical management: A case report with brief review of immunomarkers

Distinguishing metastatic carcinoma cells from reactive mesothelial cells in effusion samples is often challenging based on morphology alone. Metastatic carcinoma cells in fluid samples may mimic reactive mesothelial cells due to overlapping cytological features. We report a case of a pleural effusion in a 51‐year‐old female patient with a medical history significant for bilateral ovarian tumors and peritoneal implants diagnosed as serous tumor of borderline malignant potential. The effusion was composed almost entirely of adenocarcinoma cells that morphologically mimicked reactive mesothelial cells. The diagnosis of metastatic adenocarcinoma was made after a wide immunostaining panel of antibodies. Recognizing metastatic adenocarcinoma cells in effusion samples can be challenging and an accurate diagnosis may have significant impact on clinical management as demonstrated by this case. Diagn. Cytopathol. 2012;42:253–258.

Abstract 1754: A pharmacokinetics/pharmacodynamics study of sequence specificity of the PARP inhibitor, olaparib (O) with carboplatin (C) in recurrent women's cancers NCT01237067

Background: C, O, and C+O have documented activity in BRCA1/2 mut+ or BRCA-like breast and ovarian cancers (Br/OvCa). The effect of drug sequence on DNA damage and cell death is unknown. Our in vitro modeling suggests that exposure to O prior to C (O>C) reduced double stranded DNA damage and cell loss. Our trial tests the hypothesis that C>O causes more cellular injury. Methods: Eligible pts have recurrent women9s cancers, good end organ function, and evaluable disease. A 3+3 dose escalation run-in defined the O tablet dose in combination with C (AUC 4). The study will now randomize pts to schedule A or B (below), allowing intra-pt and inter-cohort analysis of PK/PD endpoints. PBMCs will be collected C1/2 for measurement of platination and DNA damage/repair; DNA repair protein integrity will be assessed on archival tissues. Clinical benefit, response frequency and duration, and toxicity will be ascertained. Mutation carriers will undergo progression biopsy for analysis of BRCA1/2 re-expression mutations. Results: The phase I portion is complete. 12 women (8Ov/3Br/1Endometrial[En]) have been accrued on 3 dose levels (DLs). Median prior number of regimens was 5. No DLT have been seen in 5 evaluable pts on DL3 (O tablet 200mg q12h/C AUC4 [1 pt pending]). Gr3 AEs included neutropenia (44%), and gr2 were anemia (56%), fatigue (22 %), C hypersensitivity (22%), thrombocytopenia (11%), and nausea (11%). 1 pt (DL2; stable disease) died of unrelated bleeding during C4. Clinical benefit has been observed in 8 evaluable pts with PR in 2 BRCA1 mut+ OvCa (9 + , 11 + mo), stabilization > 4mo in 6 pts (4OvCa,1BrCa, 1EnCa), and 3 are TETE. Conclusions: O in tablet formulation at 200mg q12h x 7d with C AUC4 q21d is active and tolerable, with observed interactive marrow suppression. Subsequent women will be randomized to examine schedule dependence of activity and toxicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1754. doi:1538-7445.AM2012-1754