Colleen Lewis

Phase 1 and pharmacokinetic study of everolimus in combination with cetuximab and carboplatin for recurrent/metastatic squamous cell carcinoma of the head and neck.

Platinum‐based therapy combined with cetuximab is standard first‐line therapy for recurrent or metastatic squamous cell carcinoma of the head and neck (RMSCCHN). Preclinical studies have suggested that mammalian target of rapamycin inhibitors may overcome resistance to epidermal growth factor receptor blockers and may augment cetuximab antitumor activity. We conducted a phase 1b trial of carboplatin, cetuximab, and everolimus for untreated RMSCCHN.

A phase 1 Bayesian dose selection study of bortezomib and sunitinib in patients with refractory solid tumor malignancies

Background:This phase 1 trial utilising a Bayesian continual reassessment method evaluated bortezomib and sunitinib to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), and recommended doses of the combination.Methods:Patients with advanced solid organ malignancies were enrolled and received bortezomib weekly with sunitinib daily for 4 weeks, every 6 weeks. Initial doses were sunitinib 25 mg and bortezomib 1 mg m−2. Cohort size and dose level estimation was performed utilising the Escalation with Overdose Control (EWOC) adaptive method. Seven dose levels were evaluated; initially, sunitinib was increased to a goal dose of 50 mg with fixed bortezomib, then bortezomib was increased. Efficacy assessment occurred after each cycle using RECIST criteria.Results:Thirty patients were evaluable. During sunitinib escalation, DLTs of grade 4 thrombocytopenia (14%) and neutropenia (6%) at sunitinib 50 mg and bortezomib 1.3 mg m−2 were seen. Subsequent experience showed tolerability and activity for sunitinib 37.5 mg and bortezomib 1.9 mg m−2. Common grade 3/4 toxicities were neutropenia, thrombocytopenia, hypertension, and diarrhoea. The recommended doses for further study are bortezomib 1.9 mg m−2 and sunitinib 37.5 mg. Four partial responses were seen. Stable disease >6 months was noted in an additional six patients.Conclusion:Bortezomib and sunitinib are well tolerated and have anticancer activity, particularly in thyroid cancer. A phase 2 study of this combination in thyroid cancer patients is planned.

Development and Testing of a Tool to Assess Patient Preferences for Phase I Clinical Trial Participation

Rebecca D. Pentz*, Kristopher A. Hendershot, Louisa Wall, Taylor E. White, Susan K. Peterson, Cheryl B. Thomas, Jennifer McCormick, Michael J. Green, Colleen Lewis, Zachary Luke Farmer, Fay J. Hlubocky, Tehseen Dossul, Margie D. Dixon, Yuan Liu, Jeffrey M. Switchenko, Carolina Salvador, Taofeek K. Owonikoko, R. Donald Harvey and Fadlo R. Khuri Emory University School of Medicine, Atlanta, GA, USA Winship Cancer Institute, Atlanta, GA, USA The University of Texas M.D. Anderson Cancer Center, USA Mayo Clinic, Rochester, MN, USA Penn State College of Medicine, Hershey, PA, USA Emory Healthcare, Atlanta, GA, USA The University of Alabama School of Medicine, Birmingham, AL, USA The University of Chicago Medical Center, USA Interactive Research and Development, Main Shahrah-e-Faisal, Karachi, Pakistan

The prognostic and predictive impact of inflammatory biomarkers in patients who have advanced-stage cancer treated with immunotherapy: Inflammatory Biomarkers in Immunotherapy

Optimal prognostic and predictive biomarkers for patients with advanced‐stage cancer patients who received immunotherapy (IO) are lacking. Inflammatory markers, such as the neutrophil‐to‐lymphocyte ratio (NLR), the monocyte‐to‐lymphocyte ratio (MLR), and the platelet‐to‐lymphocyte ratio (PLR), are readily available. The authors investigated the association between these markers and clinical outcomes of patients with advanced‐stage cancer who received IO.

Abstract CT303: A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Background: Preclinical work showed improved anticancer efficacy with the combination of an mTOR and a PI3K inhibitor over either agent alone. We conducted a phase I study to determine the recommended phase II dose (RP2D) of the combination of everolimus (E), an mTOR inhibitor and buparlisib or BKM120 (B), a pan-PI3K inhibitor. Methods: Patients with advanced solid malignancies who have exhausted standard treatment options were enrolled. Main eligibility criteria include ECOG performance status 0-2, adequate end organ function and absence of glucose intolerance, uncontrolled hepatitis, anxiety or depression. Dose escalation was performed using a Bayesian Escalation with Overdose Control (EWOC) design to evaluate different doses of E (5mg or 10mg) and B (20, 40, 60 and 80 mg,) once daily continuously. Eligible patients were enrolled in cohorts of 3 patients. Pharmacokinetic (PK) assessment was conducted in cycle 1 on day 8 using peripheral blood samples collected at time 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours and prior to dosing on cycle 1 D day 15. Pharmacodynamic (PD) impact on mTOR/PI3K pathway modulation was evaluated in skin punch biopsies collected at baseline and at end of cycle 1. Results: We enrolled 35 patients: Median age 63yrs (range:40-79), 21 females (58%); 2 Latinos (6%), 7 Blacks (20%) and 26 Caucasians (74%); with cancers of the lung (8), colorectal (7), sarcomas (3), salivary gland (3), breast (3), thyroid (3), thymic (2), bladder (2), ovarian (2), head and neck (1) and PNET (1). The safety of 6 different dose combinations of E and B (5/20; 10/20; 5/40; 5/60; 10/60; 5/80) was assessed. The most frequent toxicities were: hyperglycemia, diarrhea, nausea, fatigue and AST elevation. The dose limiting toxicities observed in 6 patients were: fatigue (3), hyperglycemia (1), mucositis (1), acute renal failure (1) and urinary tract infection (1). The 5/60 combination was defined as the RP2D. The median number of cycles completed was 2 (range: 0-20). Of the 25 patients evaluable for efficacy, 8 (32%) had disease progression while 17 (68%) achieved stable disease (SD). Median duration of SD was 18 weeks (range: 2-83) and 7 patients had SD lasting ≥6 months. Steady-state PK data for both agents in 24 evaluable patients showed no evidence of drug-drug interaction, with dose-normalized maximum concentrations (Cmax) and area-under-the-curve (AUC0-∞) values for E and B in combination being comparable to single agent data. Preliminary signal of efficacy for the combination was observed in patients with thymic, breast and lung cancer. PD analysis is ongoing and will be presented at the meeting. Conclusion: The safety profile of the combination of everolimus plus buparlisib is well tolerated and the RP2D is 5mg/day and 60mg/day respectively on a continuous daily schedule. The efficacy data are encouraging and warrant further evaluation in phase II studies. Citation Format: Taofeek Kunle Owonikoko, R.Donald Harvey, Colleen Lewis, Zhengjia Chen, John S. Kauh, Meredith Renfroe, Rijalda Deovic, Gabriel L. Sica, Bradley C. Carthon, Wayne Bernard Harris, Bassel F. El-Rayes, Suresh S. Ramalingam, Fadlo R. Khuri. A phase I pharmacokinetic and pharmacodynamic evaluation of the combination of everolimus and buparlisib for concurrent mTOR and PI3K pathway blockade in patients with advanced solid tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT303. doi:10.1158/1538-7445.AM2015-CT303

Abstract C26: Ethnic, gender, and age disparities and outcome of phase I clinical trials of biologically targeted anticancer agents

Background: Age, gender and ethnic-based differences in drug metabolism have been previously reported from large population-based studies. The potential impact of these factors on safety and efficacy outcomes in early phase clinical trials has not been well studied. Methods: We analyzed data from five investigator-initiated phase I clinical trials of targeted biologic agents in solid malignancies conducted at a single academic cancer center. Ethnic distribution of enrolled patients was compared to the referral population demographics at the city, metro and state level. We also analyzed all toxicity experience, dose limiting toxicity (DLT) and clinical benefit to determine any significant differences based on ethnicity i.e. African American, (AA) vs. Caucasian, age or gender. A multivariate logistic regression model was performed to identify significant predictors of DLT. Results: Data from 117 eligible patients was employed for this analysis: AA/Caucasians (27/85); male/female (66/51); median duration on study was 88 days. AA patients were younger in age than Caucasian patients (56 vs. 62 years, p=0.004), otherwise were comparable in terms of weight, Body Mass Index, frequency or grade of toxicity, DLT experience and gender distribution. GI toxicity of nausea/vomiting was more frequent in female patients (43% vs. 24%, p=0.03) but no disparity by age, gender or ethnicity with other types of toxicities or DLT experience. Using median duration of time on study as surrogate for treatment efficacy, there was no difference by gender (M/F 89 vs. 88 days, p=0.822) or ethnicity (AA/Caucasian: 113 vs. 91 days, p=0.840) but significant correlation with age (-0.194, p=0.038) and body weight (0.234, p=0.012) was observed. AA patients had worse overall survival 7.4 (95%CI: 5.3-16.1) vs. 11.4 (95%CI: 9.2-26.3) months with a higher risk of death on univariate [1.812 (95%CI: 1.079-3.045), p=0.025] and multivariate [HR: 2.037 (95%CI: 1.182-3.512), p=0.010] analyses. There was a modest increase in the risk of death in older patients [HR: 1.028, (95%CI: 1.000-1.056), p=0.046] a non-significant trend in improved survival for female patients [HR: 0.687 (0.357-1.321), p=0.260]. Conclusions: Age-, gender- and ethnic-based disparities were observed with specific toxicity and survival of phase I clinical trials of anticancer agents. An enrichment strategy for age and ethnic subgroups in phase I trials is warranted to ensure reliable generalization of study findings. Citation Format: Taofeek K. Owonikoko, Colleen Lewis, Adeniyi K. Busari, Sungjin Kim, Zhengjia Chen, David H. Lawson, Bradley C. Carthon, Bassel F. El-Rayes, Fadlo R. Khuri, John Kauh, R. Donald Harvey, Suresh S. Ramalingam. Ethnic, gender, and age disparities and outcome of phase I clinical trials of biologically targeted anticancer agents. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr C26. doi:10.1158/1538-7755.DISP13-C26

Phase IB dose escalation study of bortezomib and sunitinib in patients with refractory solid tumors.

2538 Background: Sunitinib (S) inhibits several receptor tyrosine kinases (RTKs) involved in tumor proliferation and angiogenesis, specifically PDGFR, VEGFR, KIT, FLT-3, and RET. Bortezomib (B), a ...