A phase I study of AT-101, a BH3 mimetic, in combination with paclitaxel and carboplatin in solid tumors.

Background AT-101 is a BH3 mimetic that inhibits the heterodimerization of Bcl-2, Bcl-xL, Bcl-W, and Mcl-1 with pro-apoptotic proteins, thereby lowering the threshold for apoptosis. This phase I trial investigated the MTD of AT-101 in combination with paclitaxel and carboplatin in patients with advanced solid tumors. Methods Patients were treated with AT-101 (40 mg) every 12 h on days 1, 2 and 3 of each cycle combined with varying dose levels (DL) of paclitaxel and carboplatin [DL1: paclitaxel (150 mg/m2) and carboplatin (AUC 5) on day 1 of each cycle; DL2: paclitaxel (175 mg/m2) and carboplatin (AUC 6) on day 1 of each cycle]. Secondary objectives included characterizing toxicity, efficacy, pharmacokinetics, and pharmacodynamics of the combination. Results Twenty-four patients were treated across two DLs with a planned expansion cohort. The most common tumor type was prostate (N = 11). Two patients experienced DLTs: grade 3 abdominal pain at DL1 and grade 3 ALT increase at DL2; however, the MTD was not determined. Moderate hematologic toxicity was observed. One CR was seen in a patient with esophageal cancer and 4 patients achieved PRs (1 NSCLC, 3 prostate). PD studies did not yield statistically significant decreases in Bcl-2 and caspase 3 protein levels, or increased apoptotic activity induced by AT-101. Conclusion The combination of AT-101 at 40 mg every 12 h on days 1, 2 and 3 combined with paclitaxel and carboplatin was safe and tolerable. Based on the modest clinical efficacy seen in this trial, this combination will not be further investigated. Clinical Trial Registration: NCT00891072, CTEP#: 8016.

A phase I trial of MK-2206 and hydroxychloroquine in patients with advanced solid tumors.

PURPOSE: Given the evidence that coordinate inhibition of AKT induces autophagy, we studied the combination of the AKT inhibitor, MK-2206 with hydroxychloroquine (HCQ) in patients with advanced solid tumors. METHODS: Patients were treated with weekly MK-2206 (135 mg or 200 mg) plus HCQ (200 mg, 400 mg or 600 mg BID). RESULTS: Thirty-five patients were enrolled across 5 dose levels. Two DLTs of grade 3 maculo-papular rash were observed at dose level 2 (MK-2206 200 mg weekly plus HCQ at 400 mg BID) and 1 DLT of grade 3 fatigue at dose level 2B (MK-2206 135 mg weekly plus HCQ 600 mg BID). The maximum tolerated dose (MTD) was declared as dose level 2B. The most common adverse events attributed to MK-2206 were hyperglycemia (N = 18; 51%), fatigue (N = 17; 49%), maculo-papular rash (N = 16; 46%), diarrhea (N = 12; 34%), anorexia (N = 11; 31%), and nausea (N = 11; 31%). Patients experiencing adverse events attributed to HCQ were small in number (N = 13) and primarily included fatigue (N = 5; 14%) and maculo-papular rashes (N = 3; 9%). Statistically significant effects on the pharmacokinetic properties of MK-2206 were observed in combination with HCQ. In addition, the plasma concentrations of HCQ in the combination with MK-2206 were significantly higher than the plasma levels of HCQ as monotherapy in prior studies. The best overall response of stable disease was observed in 5/34 (15%) patients. CONCLUSION: The combination of MK-2206 and hydroxychloroquine was tolerable, but with substantial number of drug-related AEs and minimal evidence of antitumor activity.

Leptomeningeal spread of gestational trophoblastic neoplasia in a 19-year old woman.

Gestational trophoblastic neoplasia (GTN) with brain metastasis is usually seen in patients with advanced disease. Ten percent of metastatic gestational trophoblastic disease involves the brain and spinal cord, most often manifesting as an intracerebral mass or subdural hematoma, and are generally known to be a poor prognostic factor (Dadlani et al., 2010). Leptomeningeal metastases are tremendously rare and not well documented in the literature. A standardized treatment regimen for patients with brain metastases has not been established and is controversial due to a number of multimodal treatments that have been published in the literature without a prospective trial having been completed. We report a case of a patient with gestational trophoblastic disease that metastasized to the lung and leptomeninges, who after treatment with induction chemotherapy using etoposide (E) and cisplatin (P) followed by etoposide, methotrexate and dactinomycin (EMA) chemotherapy achieved a complete response without brain radiation (Han et al., 2012).

Phase I trial of selenium plus chemotherapy in gynecologic cancers.

PURPOSE: Preclinical studies performed in our laboratory have shown that high-dose selenium inhibits the development of carboplatin drug resistance in an ovarian cancer mouse xenograft model. Based on these data, as well as the potential serious toxicities of supranutritional doses of selenium, a phase I trial of a combination of selenium/carboplatin/paclitaxel was designed to determine the maximum tolerated dose, safety, and effects of selenium on carboplatin pharmacokinetics in the treatment of chemo-naive women with gynecologic cancers. Correlative studies were performed to identify gene targets of selenium. METHODS: Chemo-naïve patients with gynecologic malignancy received selenious acid IV on day 1 followed by carboplatin IV and paclitaxel IV on day 3. A standard 3 + 3 dose-escalating design was used for addition of selenium to standard dose chemotherapy. Concentrations of selenium in plasma and carboplatin in plasma ultrafiltrate were analyzed. RESULTS: Forty-five patients were enrolled and 291 treatment cycles were administered. Selenium was administered as selenious acid to 9 cohorts of patients with selenium doses ranging from 50 µg to 5000 µg. Grade 3/4 toxicities included neutropenia (66.7%), febrile neutropenia (2.2%), pain (20.0%), infection (13.3%), neurologic (11.1%), and pulmonary adverse effects (11.1%). The maximum tolerated dose of selenium was not reached. Selenium had no effect on carboplatin pharmacokinetics. Correlative studies showed post-treatment downregulation of RAD51AP1, a protein involved in DNA repair, in both cancer cell lines and patient tumors. CONCLUSION: Overall, the addition of selenium to carboplatin/paclitaxel chemotherapy is safe and well tolerated, and does not alter carboplatin pharmacokinetics. A 5000 µg dose of elemental selenium as selenious acid is suggested as the dose to be evaluated in a phase II trial.

Morbidity and Mortality Risk Assessment in Gynecologic Oncology Surgery Using the American College of Surgeons National Surgical Quality Improvement Program Database.

INTRODUCTION: Gynecologic oncology patients represent a distinct patient population with a variety of surgical risks. The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database provides an opportunity to analyze large cohorts of patients over extended periods with high accuracy. Our goal was to develop a postoperative risk assessment calculator capable of providing a standardized, objective means of preoperatively identifying high-risk patients in the gynecologic oncology population. METHODS: We queried the ACS NSQIP database for gynecologic oncology patients from 2005 to 2013. Multivariate logistic regression was performed to generate predictive models specific for 30-day postoperative mortality and major morbidity. RESULTS: There were 12,831 patients with a primary gynecologic malignancy identified: 7847 uterine, 3366 adnexal, 1051 cervical, and 567 perineum cancers. In this cohort, 125 (0.97%) patients died, and 784 (6.11%) major morbidity events were recorded within 30 days of their surgery. For 30-day mortality, the mean calculated predictive probability was 0.128 (SD, 0.219) compared with 0.009 (SD, 0.027) in patients alive 30 days postoperatively (P < 0.0001). The mean predictive probability of major morbidity was 0.097 (SD, 0.095) compared with 0.059 (SD, 0.043) in patients who did not experience major morbidity 30 days postoperatively (P < 0.0001). CONCLUSIONS: Using NSQIP data, these predictive models will help to determine patients at risk for 30-day mortality and major morbidity. Further clinical validation of these models is required.

Ogilvie's Syndrome after Robotic-Assisted Radical Hysterectomy for Cervical Cancer.

Acute colonic pseudo-obstruction (ACPO), also known as Ogilvie's syndrome, is defined by poor peristaltic activity of the colon that mimics mechanical obstruction in the absence of any mechanical occlusive gut lesion. This case report is the first to be published on ACPO occurring after robotic-assisted radical hysterectomy. Given that robotic-assisted laparoscopic surgery has become the next major stage of advancement for a range of operations, especially in gynecologic oncology surgery, this report emphasizes the importance of recognizing precipitating factors associated with this syndrome, including minimally invasive surgery.

Nonbacterial thrombotic endocarditis: A rare manifestation of gynecologic cancer.

•Nonbacterial thrombotic endocarditis (NBTE) is a rare complication of cancer.•NBTE may precede the diagnosis of an occult gynecologic malignancy.•Malignancy-induced NBTE must be considered in patients with unprovoked venous thromboembolism.•The most effective treatment is anticoagulation and treatment of the underlying cancer.

Use of comprehensive genomic profiling to direct point-of-care management of patients with gynecologic cancers.

OBJECTIVE: To determine the feasibility and clinical utility of using comprehensive genomic profiling (CGP) in the course of clinical care to identify clinically relevant tumor genomic alterations for patients with either rare or refractory gynecologic cancers to facilitate point-of-care management. Use of an expert, multidisciplinary, institutional molecular tumor board (MTB) assessment is discussed regarding input on putative targeted options for individualized therapy. METHODS: A prospective clinical trial is ongoing. We report on the initial 69 patients with gynecologic cancers that were either rare or refractory to standard therapy. CGP was performed by Foundation Medicine, Inc. Genomic alterations were reviewed by members of an MTB. Consensus recommendations on genomically targeted, FDA-approved, on- and off-label therapies and clinical trials were sent to the treating physician, and decisions and outcomes were assessed. RESULTS: Study outcomes were available for 64 patients. The mean number of genes altered per tumor was 4.97 (median=4; range, 1-26), and the average turnaround time from testing laboratory report to generation of formal recommendations was approximately three weeks. Evaluation of genomic and clinical data by the MTB led to generation of targeted treatment options in all 64 patients, and the percentage of patients for whom one or more of these recommendations were implemented by the treating physician was 39%. Sixty-four percent of the patients receiving targeted therapy based on a CGP result experienced radiologic response or showed evidence of clinical benefit or stable disease. CONCLUSION: These data suggest that an institutional MTB is a feasible venue for reviewing tumor genomic profiling results and generating clinical recommendations. These data also support the need for further studies and guidelines on clinical decision making with greater availability of broad genomically based diagnostics.

Pilomatrix carcinoma of the vulva.

BACKGROUND: Pilomatrix carcinomas are rare, frequently occurring in older male patients. We report a case of vulvar pilomatrix carcinoma in a 30-year-old woman, the second known reported case occurring on the external genitalia. CASE: A 30-year-old female originally presented at an outside institution for the management of an asymptomatic vulvar mass that was biopsied and read as invasive squamous cell carcinoma. Pathology review at our institution reclassified the vulvar mass as a low-grade pilomatrix carcinoma. The patient underwent radical hemivulvectomy without an inguinal-femoral groin node dissection. She has remained without evidence of disease recurrence for more than 5 years since her diagnosis. CONCLUSION: Pilomatrix carcinoma can be confused for an invasive squamous cell carcinoma. Due to its low risk of metastases, a less radical surgical approach can be taken. Consideration of this unusual malignancy is important in the determination of appropriate management.

Multimodal endovascular palliation for femoral arterial blowout in the setting of metastatic vulvar carcinoma.

BACKGROUND: Vascular blowout syndrome is a well-known, life-threatening condition complicating advanced-stage head and neck malignancies but has rarely been reported in the gynecologic oncology realm in association with the femoral circulation. A 50-year-old woman with metastatic vulvar squamous cell carcinoma presented with left threatened femoral arterial blowout, secondary to an exophytic neoplastic mass originating from the left inguinal lymph nodes. METHODS: Bland embolization of the tumor as well as 3 vessel covered stent revascularization was successfully performed with excellent tumor devascularization and reinstitution of arterial integrity. RESULTS: Successful devascularization of the tumor, with no non-target embolization was achieved, with excellent apposition and deployment of 3 covered stents in the femoral artery bifurcation. CONCLUSION: We present a unique case of threatened femoral artery blowout syndrome in the setting of metastatic vulvar carcinoma requiring various endovascular techniques for palliation. These endovascular techniques can be invaluable in minimally invasive palliation of advanced stage neoplasms abutting the iliofemoral circulation.

Phase 2 trial of paclitaxel, 13-cis retinoic acid, and interferon alfa-2b in the treatment of advanced stage or recurrent cervical cancer.

OBJECTIVE: Overexpression of bcl-2 is a mechanism of drug resistance in cervical cancer. Agents that down-regulate bcl-2 may decrease tumor cell threshold and sensitize tumor cells to chemotherapy. The objective of this multi-institutional phase 2 trial was to evaluate the efficacy and toxicity of paclitaxel and bcl-2 modulators (13-cis retinoic acid and interferon alfa-2b) in patients with advanced-stage or recurrent cervical cancer. MATERIALS AND METHODS: Patients had biopsy-proven metastatic, first relapse, or persistent cervical cancer with no prior chemotherapy except for chemosensitizing agents. The treatment consisted of oral 13-cis retinoic acid, 1 mg/kg, and subcutaneous interferon alfa-2b, 6 mU/m, days 1 to 4, and intravenous paclitaxel, 175 mg/m, day 4 until disease progression or adverse events prohibited treatment. The primary endpoint was overall response rate. RESULTS: Thirty-three patients were enrolled between March 2001 and June 2009. Thirty-one patients were eligible for evaluation of treatment response. Twenty-seven patients (82%) received prior concurrent chemoradiation or radiotherapy alone before study enrollment. The overall response rate was 30% (6 complete responses and 4 partial responses). Furthermore, 7 patients (21%) had stable disease. Grade 3 or 4 adverse events included neutropenia (n =16 [48%]), febrile neutropenia (n = 1 [3%]), and anemia (n = 1 [3%]). There were no treatment-related deaths. The median progression-free survival was 3.4 months (95% confidence interval, 2.0-7.4 months), and overall survival was 11.2 months (95% confidence interval, 7.5-26.2 months). Of 6 patients with complete responses, 5 patients survived more than 2 years. CONCLUSIONS: Combination therapy with paclitaxel, 13-cis retinoic acid, and interferon alfa-2b is feasible and safe in treating patients with advanced and recurrent cervical cancer.

Effects of ketoconazole and esomeprazole on the pharmacokinetics of pazopanib in patients with solid tumors.

PURPOSE: The metabolism of pazopanib is primarily mediated by CYP3A4. The solubility of pazopanib is pH-dependent, and an elevated gastric pH may decrease its bioavailability. This study evaluated the effect of a potent CYP3A4 inhibitor, ketoconazole, and the proton pump inhibitor esomeprazole on the pharmacokinetics and safety of pazopanib and its metabolites. METHODS: In Arm A, patients received pazopanib 400 mg alone once daily for 7 days followed by pazopanib 400 mg plus ketoconazole 400 mg once daily for 5 days. In Arm B, patients received pazopanib 800 mg once daily for 7 days, followed by pazopanib 800 mg plus esomeprazole 40 mg once daily for 5 days, and then pazopanib alone on the last day. RESULTS: Arm A enrolled 21 patients. In the presence of ketoconazole, mean area under the plasma concentration-time curve 24 h post-dose (AUC(0-24)) and mean maximum observed concentration (C max) of pazopanib increased by 66 and 45 %, respectively; mean AUC(0-24) and C max for pazopanib metabolites were lower or remained unchanged. Arm B enrolled 13 patients. In the presence of esomeprazole, mean pazopanib AUC(0-24) and C max decreased by 40 and 42 %, respectively; mean values of those parameters for metabolites of pazopanib also decreased. CONCLUSIONS: Concomitant use of pazopanib with a strong CYP3A4 inhibitor should be avoided. If coadministration is necessary, pazopanib should be reduced to 400 mg. Concomitant use of pazopanib and proton pump inhibitors should also be avoided. Alternative dosing regimens that do not increase gastric pH at the time of pazopanib dosing should be considered.

Phase I study of RO4929097, a gamma secretase inhibitor of Notch signaling, in patients with refractory metastatic or locally advanced solid tumors.

PURPOSE: To determine the maximum-tolerated dose (MTD) and assess safety, pharmacokinetics, pharmacodynamics, and evidence of antitumor activity of RO4929097, a gamma secretase inhibitor of Notch signaling in patients with advanced solid malignancies. PATIENTS AND METHODS: Patients received escalating doses of RO4929097 orally on two schedules: (A) 3 consecutive days per week for 2 weeks every 3 weeks; (B) 7 consecutive days every 3 weeks. To assess reversible CYP3A4 autoinduction, the expanded part of the study tested three dosing schedules: (B) as above; modified A, 3 consecutive d/wk for 3 weeks; and (C) continuous daily dosing. Positron emission tomography scans with [(18)F]fluorodeoxyglucose (FDG-PET) were used to assess tumor metabolic effects. RESULTS: Patients on schedule A (n = 58), B (n = 47), and C (n = 5; expanded cohort) received 302 cycles of RO4929097. Common grade 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. Transient grade 3 hypophosphatemia (dose-limiting toxicity, one patient) and grade 3 pruritus (two patients) were observed at 27 mg and 60 mg, respectively; transient grade 3 asthenia was observed on schedule A at 80 mg (one patient). Tumor responses included one partial response in a patient with colorectal adenocarcinoma with neuroendocrine features, one mixed response (stable disease) in a patient with sarcoma, and one nearly complete FDG-PET response in a patient with melanoma. Effect on CYP3A4 induction was observed. CONCLUSION: RO4929097 was well tolerated at 270 mg on schedule A and at 135 mg on schedule B; the safety of schedule C has not been fully evaluated. Further studies are warranted on the basis of a favorable safety profile and preliminary evidence of clinical antitumor activity.

The unique characteristics of ovarian carcinogenesis in the adolescent and young adult population.

Ovarian cancer in the adolescent and young adult (AYA) population is a disease that is distinctly different with regard to risk factors, genetics, and pathology when compared to ovarian cancers occurring in older women. This article will review the theories behind ovarian carcinogenesis and attempt to elucidate why these tumors exhibit their unique biologic characteristics. Knowledge of these differences will allow us to begin to develop strategies for future research endeavors enabling improved survival in AYA women diagnosed with ovarian cancer.