Faculty Bibliography

Background: PARP1 inhibition enhances the effects of DNA-damaging agents such as doxorubicin. We sought to investigate PK of PLD in a phase I study of veliparib (ABT-888, V) and PLD in patients (pts) with recurrent ovarian, fallopian tube, and primary peritoneal, and triple negative breast cancers. No prior PK interactions have been described in V clinical trials. Methods: Complete blood samples on day (D) 1 (pre-PLD and 1 hr post PLD), D 8, D 22 on cycle 1 and 2 of treatment in pts receiving PLD 40 mg/m2, day (D) 1 and V D1-14 at varying dose levels of 50,100,150, 200, 300, 350 mg twice daily, were collected in 25 of 31 pts enrolled to a previously reported dose finding phase I study of V and PLD (SGO2012). Plasma PLD levels were measured by HPLC methodology detailed by Gabizon et al Cancer Chemo Pharmacol 2008, 61:695. PK parameter estimates were obtained using non-linear modeling programs available in Winnonlin Ver 5.3. Affect of V dose on PK parameters was estimated with linear regression analysis. Due to a higher degree of GI toxicity with V dosages > 200 mg, we utilized a cut-off of 200 mg for V. PK parameters in the group with dosages greater than or equal to 200 mg (high V, n=18) and those less than 200 mg (low V, n=7) were compared, utilizing an unpaired, 2 sided t-test. Results: PLD clearance (CL) was reduced, half-life (hL) was increased, and AUC/mg was increased with higher dosages of V when compared to historical published data. We noted a positive correlation of the auc/mg dose, p=0.001 and a negative correlation with the CL, p=0.001 and increasing V dose. When analyzed as low and high V groups, the mean +/- SEM hL (hrs) was significantly lower in the low V when compared to the high V group, 83.2 +/- 11.7 vs 108.6 +/- 6.0(p =0.042) , and the mean PLD clearance (ml/h)was greater in the low V versus the high V group 35.9 +/- 5.6 vs 14.2 + 1.0, P<.0001. Similarly the AUC/mg dose (mg x h/L) was significantly lower in the low vs high V groups, 35.0 +/-5.2 vs 74.9 +/- 4.4, P<0.0001. Con!

Objective: To evaluate molecular and clinical markers previously linked to overall survival for their ability to predict residual disease status following primary surgical cytoreduction in advanced-stage epithelial ovarian cancer (EOC) patients enrolled in GOG trials. Methods: Archival specimens of 106 subjects from GOG0114 and GOG0132 were analyzed with immunohistochemistry and immunoblot techniques for markers of angiogenesis, cell cycle, and protein kinase receptor pathways. A retrospective chart review scrutinized each operative report, pathology report, and protocol data form for residual disease status, the initial extent of disease, and surgical effort. Over 300 clinical and molecular markers were analyzed for association with residual disease status using Fischer's exact test and the Kruskal Wallis test. Multivariate analysis was used to determine which clinical and molecular characteristics independently influenced residual disease status. Results: Of 106 patients, 17 had no gross residual disease (NGRD), 36 had minimal (b1 cm) gross residual disease (MGRD), and 53 had bulky (N1 cm) gross residual disease (BGRD). Patients with BGRD had lower expression of MASPIN (P =0.01), bFGF (P =0.009), CD105 (P= 0.008), Cyclin D (P= 0.013), Cyclin E (P =0.006), and p16 (P < 0.001) compared to all patients who were optimally debulked. When analysis separated NGRD patients into their own category, lower expressions of CD105 (P= 0.014), MASPIN (P= 0.046), and p16 (P < 0.001) continued to be associated with BGRD. Below-average CD105 expression was significantly associated with upper abdominal disease (P =0.026), the presence of which most influenced the inability to achieve NGRD on multivariate analysis (P < 0.01). Conclusions: Although clinical absence of upper abdominal disease was most predictive of achieving NGRD, tumor levels of MASPIN, bFGF, CD105, Cyclin D, Cyclin E, and p16 are significantly associated with residual disease status. These molecular predictors are of interest for prospective vali!

Objective: Irinotecan and bevacizumab have single-agent activity in both platinum- sensitive and -resistant recurrent ovarian cancer. We sought to evaluate the efficacy and safety of irinotecan in combination with bevacizumab in these patients. The primary end point of the study was to estimate the progression-free survival (PFS) rate at 6 months. Secondary objectives included overall survival, observed response rate, duration of response, and toxicity. Methods: Patients with recurrent ovarian cancerwho had received any number of prior regimens were eligible. Irinotecan 250 mg/m2 (amended to 175 mg/m2 after treatment-related toxicities in the first 6 patients) and bevacizumab 15 mg/kg every 3 weeks were administered until disease progression or toxicity. Response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) every 2 cycles and by CA-125 criteria for those patients without measurable disease. Results: Thus far, 25 of the planned 35 patients have been enrolled in the study. Themedian age was 61 years (range, 45-78 years). Seven patients were platinum-sensitive and 18 patients were platinum-resistant. The median number of prior regimens was 5 (range, 1-12), with 10 patients having received prior bevacizumab-containing therapies and 9 patients prior topotecan-containing therapies. The median number of study treatments received was 6 cycles (range, 1-25 cycles); 4 patients withdrew after only 1 cycle (3 due to toxicity and 1 due to physician discretion). Of the 19 patients assessable for response at this time, 5 patients experienced partial response (PR), 11 patientsmaintained stable disease (SD), and 3 patients had progressive disease. Eleven of the patients with PR/SD were platinum-resistant. The observed clinical benefit rate (PR+SD) was 68% (95% CI: 50%, 86%) for the 25 enrolled patients (intention to treat). Durable responses were observed, with 9 patients having longer than 24 weeks of sustained response. Themedian PFS was 8.1 months, and the median overall survival was!

Introduction: Topotecan was initially approved for the treatment of recurrent ovarian cancer. In cervical cancer, it has been investigated for its potential as part of systemic therapy for advanced and/or recurrent disease and in combination with cisplatin and radiation as a first-line treatment for advanced disease. As a topoisomerase I (topo I) inhibitor, its activity is predicted to be schedule-dependent and potentiated in a schedule-dependent manner by its interaction with DNA damaging agents. Areas covered: The cytotoxicity of topotecan is believed to be due to double-stranded DNA damage produced when the DNA replication 'fork' on the opposing DNA strand is interrupted by the ternary complex formed by topotecan, topoisomerase I and DNA. This review focuses on: i) combination studies of cisplatin + topotecan both as neoadjuvant and with concomitant radiation; ii) adding this drug as a radiosensitizer in pilot studies for locally advanced disease and iii) topotecan as part of non-cisplatin combinations in metastatic disease. Expert opinion: Cervical cancer continues to claim many victims among parts of the world where early detection and/or vaccination programs are not systemically applied. Topotecan is an attractive building block for improving therapy against advanced disease.

BACKGROUND:Hypercalcemia has been reported in association with a number of malignancies, but it is an unusual manifestation of ovarian cancer. This finding at presentation (possibly aggravated by oral calcium intake) led to discovery of a clear cell carcinoma of the ovary. The implications and pathophysiology of this association are reviewed. CASE REPORT/METHODS:Following presentation with abdominal symptoms, this premenopausal woman was found to have bilateral adnexal masses and hypercalcemia. Her parathormone-related polypeptide was found to be elevated. After surgery and staging, she received adjuvant carboplatin and paclitaxel (later substituted by docetaxel). She has done well on her long-term follow-up. CONCLUSIONS:This rare paraneoplastic manifestation of ovarian cancer may be associated with long-term survival if discovered at an early stage. In this instance, further benefit may have been obtained from adjuvant platinum-based chemotherapy.

This second article in our two-part series on targeted therapies in solid tumors covers the emergence of targeted therapies for the treatment of two common malignancies: lung cancer and breast cancer. In these two tumors, the identification of a promising target has led to successful preliminary applications, and eventually to further advances through drug development and the fine tuning of patient selection. As a result, the percentage of patients with breast or lung cancer who are benefiting from targeted agents has steadily increased, even if the majority are still treated with conventional cytotoxic regimens. We also review the latest therapeutic strategies for colorectal and gynecologic cancers--because these offer an instructive contrast. The curative regimens that have been developed for these two tumors--even those in more advanced stages--have included combinations of surgery and/or radiation with chemotherapy. The Cancer Genome Atlas has revealed complexities in the biology of these tumors that underscore the fact that reliance on selective DNA-damaging agents such as platinums, antimetabolites, and antimitotic agents will continue for some time. We conclude that the therapeutic progress that may arise from the study of molecular pathways will be due not only to the development of new targeted therapies, but also to a better understanding of older drugs developed empirically in the past. Taken together, these two types of advance illustrate the remarkable overall effect of modern cancer therapeutics' focus on tumor biology and tumor immunology.