Maryann Redlinger

Phase II Trial of Sorafenib in Advanced Thyroid Cancer

PURPOSE Given the molecular pathophysiology of thyroid cancer and the spectrum of kinases inhibited by sorafenib, including Raf kinase, vascular endothelial growth factor receptors, platelet-derived growth factor receptor, and RET tyrosine kinases, we conducted an open-label phase II trial to determine the efficacy of sorafenib in patients with advanced thyroid carcinoma. PATIENTS AND METHODS Eligible patients with metastatic, iodine-refractory thyroid carcinoma received sorafenib 400 mg orally twice daily. Responses were measured radiographically every 2 to 3 months. The study end points included response rate, progression-free survival (PFS), and best response by Response Evaluation Criteria in Solid Tumors. RESULTS Thirty patients were entered onto the study and treated for a minimum of 16 weeks. Seven patients (23%; 95% CI, 0.10 to 0.42) had a partial response lasting 18+ to 84 weeks. Sixteen patients (53%; 95% CI, 0.34 to 0.72) had stable disease lasting 14 to 89+ weeks. Seventeen (95%) of 19 patients for whom serial thyroglobulin levels were available showed a marked and rapid response in thyroglobulin levels with a mean decrease of 70%. The median PFS was 79 weeks. Toxicity was consistent with other sorafenib trials, although a single patient died of liver failure that was likely treatment related. CONCLUSION Sorafenib has clinically relevant antitumor activity in patients with metastatic, iodine-refractory thyroid carcinoma, with an overall clinical benefit rate (partial response + stable disease) of 77%, median PFS of 79 weeks, and an overall acceptable safety profile. These results represent a significant advance over chemotherapy in both response rate and PFS and support further investigation of this agent in these patients.

Combined MTOR and autophagy inhibition: Phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

A Phase I Trial of the Oral, Multikinase Inhibitor Sorafenib in Combination with Carboplatin and Paclitaxel

Purpose: This study evaluated the safety, maximum tolerated dose, pharmacokinetics, and antitumor activity of sorafenib, a multikinase inhibitor, combined with paclitaxel and carboplatin in patients with solid tumors. Patients and Methods: Thirty-nine patients with advanced cancer (24 with melanoma) received oral sorafenib 100, 200, or 400 mg twice daily on days 2 to 19 of a 21-day cycle. All patients received carboplatin corresponding to AUC6 and 225 mg/m2 paclitaxel on day 1. Pharmacokinetic analyses were done for sorafenib on days 2 and 19 of cycle 1 and for paclitaxel on day 1 of cycles 1 and 2. Pretreatment tumor samples from 17 melanoma patients were analyzed for BRAF mutations. Results: Sorafenib was well tolerated at the doses evaluated. The most frequent severe adverse events were hematologic toxicities (grade 3 or 4 in 33 patients, 85%). Twenty-seven (69%) patients had sorafenib-related adverse events, the most frequent of which were dermatologic events (26 patients, 67%). Exposure to paclitaxel was not altered by intervening treatment with sorafenib. Treatment with sorafenib, paclitaxel, and carboplatin resulted in one complete response and nine partial responses, all among patients with melanoma. There was no correlation between BRAF mutational status and treatment responses in patients with melanoma. Conclusions: The recommended phase II doses are oral 400 mg twice daily sorafenib, carboplatin at an AUC6 dose, and 225 mg/m2 paclitaxel. The tumor responses observed with this combined regimen in patients with melanoma warrant further investigation.

Phase I Clinical and Pharmacogenetic Trial of Irinotecan and Raltitrexed Administered Every 21 Days to Patients With Cancer

PURPOSE Irinotecan and raltitrexed display schedule-dependent synergy in vitro, which supports the clinical investigation of the combination. Functional polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene result in intracellular redistribution of folate derivatives, which may affect raltitrexed-associated cytotoxicity. PATIENTS AND METHODS Patients with a range of solid cancers and good performance status received irinotecan as a 90-minute infusion on day 1 and raltitrexed as a 15-minute infusion on day 2, repeated every 21 days. Samples were collected for MTHFR C677T genotyping and fasting plasma homocysteine during the first cycle. RESULTS Thirty-nine assessable patients received 127 cycles of therapy. Irinotecan doses ranged from 100 to 350 mg/m(2), and raltitrexed, 1.0 to 4.0 mg/m(2). Raltitrexed doses of more than 3.0 mg/m(2) were not tolerated and were associated with dose-limiting asthenia, diarrhea, and AST/ALT elevation. Irinotecan/raltitrexed doses of 350/3.0 mg/m(2) were well-tolerated; principal toxicities included neutropenia, diarrhea, and fatigue. Two partial responses were observed in patients with pretreated gastroesophageal cancers. Homozygotes with the MTHFR 677 TT polymorphism incurred significantly less raltitrexed-associated toxicity than those with either wild-type or heterozygous genotypes (P = .05). No significant differences were noted in plasma homocysteine values between the genotypic subtypes, and plasma homocysteine levels did not predict the risk of toxicity. CONCLUSION Irinotecan and raltitrexed doses of 350 and 3.0 mg/m(2) are recommended for further study on a day 1, 2 schedule every 21 days. Efficacy results suggest that trials in upper and lower gastrointestinal malignancies are warranted. MTHFR C677T genotypes may be predictive of clinical raltitrexed toxicity.

Pharmacokinetic analysis of irinotecan plus bevacizumab in patients with advanced solid tumors

PurposeThe purpose of this study was to evaluate the effect of bevacizumab on the pharmacokinetics (PK) of irinotecan and its active metabolite. Exploratory analyses of the impact of variability in uridine diphosphate glucuronosyltransferase 1A (UGT1A) genes on irinotecan metabolism and toxicity were conducted.MethodsThis was an open-labeled, fixed-sequence study of bevacizumab with FOLFIRI (irinotecan, leucovorin, and infusional 5-fluorouracil). Pharmacokinetic assessments were conducted in cycles 1 and 3.ResultsForty-five subjects were enrolled. No difference in dose-normalized AUC0–last for irinotecan and SN-38 between irinotecan administered alone or in combination with bevacizumab was identified. Leukopenia was associated with higher exposure to both irinotecan and SN-38. UGT1A1 polymorphisms were associated with variability in irinotecan PK. Gastrointestinal toxicity was associated with UGT1A6 genotype. No other associations between UGT1A genotypes and toxicity were detected.ConclusionBevacizumab does not affect irinotecan PK when administered concurrently. A variety of pharmacogenetic relationships may influence the pharmacokinetics of irinotecan and its toxicity.

Phase 1 and pharmacodynamic trial of everolimus in combination with cetuximab in patients with advanced cancer

Preclinical and clinical studies suggest mTOR (mammalian target of rapamycin) inhibitors may have metabolic and antiangiogenic effects, and synergize with epidermal growth factor pathway inhibitors. Therefore, a phase 1/pharmacodynamic trial of everolimus with cetuximab was performed.

Imaging with [18f]-fluorodeoxyglucose positron emission tomography (FDG-PET) and dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) as markers of drug effect in a phase I dose-escalation study of combined RAD 001 and cetuximab.

3048 Background: Preclinical studies suggest that mTOR inhibitors may have both metabolic and anti-angiogenic effects. We employed FDG-PET as a pharmacodynamic marker of mTOR inhibition, and DCE-MRI as an indicator of changes in tumor blood flow in a phase 1 combination study of RAD001 and cetuximab. METHODS 29 patients with EGFR-expressing solid tumors were randomized to a 3-week run-in of single agent RAD001 (30-70 mg PO) or cetuximab (400 mg/m2 IV loading, 250 mg/m2 IV maintenance) weekly, followed by the combination weekly. The primary endpoints were phase II dose finding and toxicity characterization. FDG-PET and DCE-MRI were performed at three time points (baseline, run-in, and combination), to assess for changes in tumor metabolic activity and perfusion, and for subsequent correlation to treatment response (CT or MRI after every two cycles of combination therapy). RESULTS RAD 001 was tolerated at the highest dose level. Grade 3 or worse toxicity included thrombocytopenia, hypokalemia, elevation in AST and alkaline phosphatase, and skin toxicity. 10 patients were evaluable for response. 5 patients had stable disease lasting 4-19 months (colon, parotid, anal and 2 ovarian). Mean % change in SUVmax from baseline for those treated with RAD001 during run-in (n=12) was -23.4 (range +1.4 to -52.9%), and a dose relationship was evident. The SUV change in pts treated first with cetuximab (n=13) was -9.6% (-53 to +35%). In 10 pts in whom RAD001 was added after cetuximab, there was an additional 11% decrease in SUV, while in patients treated first with RAD001, the SUV change was +12.4%, suggesting that an initial inhibitory effect was being circumvented by the tumor. Mean % change in SUVmax from baseline for the group with SD was lower than in the group with PD. The Ktrans measured by DCE-MRI did not change (-0.9%, n=7), irrespective of run-in drug. CONCLUSIONS Metabolic responses by FDG-PET compared to DCE-MRI changes reveal that the metabolic effects of RAD001 alone and in combination with cetuximab predominate, while antiangiogenic effects appear to be minimal in this patient population.

Abstract 4500: Combined mTOR inhibition and autophagy inhibition: Phase I trial of temsirolimus and hydroxchloroquine in patients with advanced solid tumors

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Therapy-induced autophagy may be a key resistance mechanism that explains the low rates of clinical benefit observed in trials of mTOR inhibitors in multiple cancers. For example, the mTOR inhibitor temsirolimus produced a 0% stable disease rate in a prior phase II trial in patients with metastatic melanoma. Hydroxychloroquine (HCQ) is an autophagy inhibitor that augments the antitumor efficacy of a number of anticancer therapies including mTOR inhibitors in preclinical models. To determine the safety and pharmacodynamic (PD) effects of combining an mTOR inhibitor with an autophagy inhibitor, we report the results of a phase I clinical trial of temsirolimus and HCQ in patients with advanced solid tumors. Methods: We conducted a traditional 3+3 phase I dose escalation clinical trial in which patients were treated with 1 week single agent temsirolimus 25 mg IV weekly followed by combined weekly temsirolimus with increasing doses of daily continuous HCQ. Patients with advanced solid tumors with any number of prior therapies were eligible. The primary objective was to determine the maximal tolerated dose (MTD) of HCQ in this combination. Secondary objectives included toxicity rate, response rate, measurement of therapy-induced accumulation of autophagic vesicles (AV) in serial peripheral blood mononuclear cells (PBMC) and tumor tissue, and pharmacokinetic (PK) analysis of temsirolimus, sirolimus and HCQ to explore drug interactions and establish a PK-PD relationship. A 12 patient expansion at the MTD or HCQ 600 mg bid (final planned dose level) in patients with metastatic melanoma with serial FDG-PET scans is planned. Results: 23 patients were enrolled with 14 evaluable for response and toxicity. The median number of prior treatments was 4. HCQ was successfully dose escalated from 200 mg daily to 600 mg bid in 4 cohorts. There was one dose limiting toxicity (DLT) at 200 mg HCQ, grade 4 thrombocytopenia with bleeding, that lead to dose expansion. The 800 mg dose cohort was also expanded due to a death from streptococcal pneumonia in month 3 of treatment. No additional bleeding, infections, or other DLTs were observed. Anorexia, nausea, and fatigue were common grade 2 toxicities. Stable disease was achieved in 10/14 evaluable patients, including 4/5 patients with metastatic melanoma. After 6 weeks of treatment, a significant accumulation of AV was observed in PBMC of patients treated with this combination compared to pretreatment samples providing PD evidence of consistent autophagy inhibition. Conclusions: The combination of temsirolimus and HCQ demonstrated significant clinical activity, and a manageable safety profile in a highly treatment-refractory patient population. PD evidence of autophagy inhibition was observed. The recommended phase II dose, PK-PD analysis, response rate, and FDG-PET results in the melanoma expansion will be presented. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4500. doi:10.1158/1538-7445.AM2011-4500