Bible, Keith C.

Abstract Background: The combination of a microtubule stabilizing agent and an mTOR inhibitor has been identified as a synergistic combination in preclinical models. Additional studies have further evaluated the impact of treatment sequence with paclitaxel and rapamycin where administration of rapamycin after paclitaxel was associated with synergy. In our preclinical studies, apoptosis was greater with the combination of ixabepilone and temsirolimus than with either single agent. Thus, a Phase I study of the combination of Ixabepilone (IXB) and Temsirolimus (TEM) was performed to determine the maximum tolerated dose (MTD), describe the toxicity profile and characterize the pharmacokinetics of each agent in patients with advanced cancer. Methods: Eligible patients included adults with a histologically confirmed solid tumor malignancy that was metastatic or unresectable who have received ≤ 2 chemotherapy regimens and had ECOG PS ≤ 2 with adequate bone marrow, renal and hepatic function. Using a standard 3+3 design, patients were treated with IXB IV over 3 hours on day 1 and TEM IV over 0.5 hours on days 2 and 9 (schedule A) or days 1 and 8 (schedule B) every 21 days. Pharmacokinetics (PK) was performed in patients on schedule B. Results: 22 evaluable patients were enrolled between August 24, 2011 and November 7, 2014. The final 7 patients were treated on schedule B. Patients were treated at 3 dose levels of IXB (mg/m2)/TEM (mg): DL1- 24/15 (A- 6 pts, B- 2 pts); DL2- 32/15 (A- 3 pts, B- 5 pts); DL3- 32/20 (A- 6 pts). One patient had DLT (grade 3 hypophosphatemia) and 1 patient expired due to disease progression in DL1A. No DLTs were seen in DL2A. The dose was escalated to DL3 and 1 patient had DLT (grade 3 hypokalemia). Following a change to schedule B, 5 patients were enrolled to DL2B and 1 experienced DLT (grade 4 neutropenia, grade 4 thrombocytopenia, grade 4 sepsis). The dose was reduced to DL1B and 2 more patients were enrolled, both of whom experienced DLTs (grade 5 bronchopulmonary hemorrhage and grade 4 neutropenia). Grade 4 events considered at least possibly related to treatment occurred in 6 of 22 patients (27%) and included cardiac arrest, dyspnea, hypokalemia, hypoxia, multi-organ failure, decreased platelets, acute renal failure, neutropenia, neutropenic fever, sepsis, and decreased WBCs. Patients received a median of 4 cycles (range, 1-10+). Partial response was noted in 1 patient and stable disease was noted in 11 patients. One patient remains on treatment after 11 cycles. IXB (plasma), TEM (whole blood) and sirolimus (whole blood) concentrations were measured by a sensitive, specific lc/ms/ms assay. A 24 and 32 mg/m2 IXB dose yields Cmax of 159 and 312 ng/ml, respectively. The IXB CLp and t1/2 values were 31 L/h and 76 h, respectively. The Cmax, Cl and t1/2 values after a 15 mg TEM dose were 518 ng/ml, 6.4 L/h and 11 h, respectively. The Cmax and t1/2 values of sirolimus after a 15 mg TEM dose were 37.6 ng/ml and 49 h, respectively. The PK of IXB and TEM in combination were similar to those reported for each drug alone. Conclusions: The reasons for the unpredictable, severe toxicity of the IXB/TEM combination are unclear. The MTD could not be determined, and enrollment was discontinued. This trial exemplifies challenges associated with development of drug combinations with mTOR inhibitors. Supported in part by UM1 CA186686 and P30 CA15083. Clinical trial information: NCT01375829 Citation Format: Joel M. Reid, Michael E. Menefee, Felix Boakye-Agyeman, Chad A. Walden, Charles Erlichman, Keith C. Bible. Phase I and pharmacokinetic study of ixabepilone and temsirolimus in adult patients with advanced solid tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B113.

Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. Results: The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. Conclusions: We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.