Wing Cheung

A phase I study of single-agent nilotinib or in combination with imatinib in patients with imatinib-resistant gastrointestinal stromal tumors.

Purpose: To study the safety, tolerability, and pharmacokinetics of the selective tyrosine kinase inhibitor nilotinib as a single agent or in combination with imatinib in patients with advanced imatinib-resistant gastrointestinal stromal tumors. Experimental Design: A phase I intercohort dose-escalation trial was done in patients who received either (a) single agent nilotinib 400 mg twice daily or (b) escalating doses of nilotinib (200 mg once daily, 400 mg qd, or 400 mg bid) plus imatinib 400 mg bid (10- and 14-hour interval daily), or (c) nilotinib 400 mg bid plus imatinib 400 mg qd. Safety, pharmacokinetics, and tumor assessments were done. Results: Oral clearance (CL/F) of nilotinib was similar across the combination groups (mean CL/F, 19.1-25.6 L/h), and lower than in the single-agent cohort (mean CL/F, 35.6 L/h). A linear relationship between nilotinib daily dose and peak concentration was observed in the combination cohorts. Observed adverse events (AE) were mostly nonhematologic. Frequently reported AEs were rash (40%), fatigue (38%), abdominal pain (36%), and nausea (36%). Severe AEs (grade 3 or 4) included abdominal pain (13%) and rash (9%), the latter mainly with the combination. Thirty-eight patients had stable disease and two patients achieved partial response with a median progression-free survival of 134 days for the entire group. Conclusions: Nilotinib alone or in combination with imatinib was well tolerated overall and showed clinical activity in imatinib-resistant gastrointestinal stromal tumor patients. This phase I trial identified single-agent nilotinib 400 mg bid or combined with imatinib 400 mg qd as possible phase II doses for further evaluation. (Clin Cancer Res 2009;15(18):5910–6)

Relationship between everolimus exposure and safety and efficacy: meta-analysis of clinical trials in oncology.

BACKGROUND In patients with solid tumours, daily everolimus dosing demonstrated dose proportionality and linear pharmacokinetics. A meta-analysis was conducted to characterise the relationship between everolimus Cmin and efficacy and safety and the effect of CYP3A4 and P-glycoprotein (PgP) substrate/inhibitor/inducer coadministration on everolimus trough concentration (Cmin). METHODS Individual patient data from five phase 2/3 studies, in which steady state, predose pharmacokinetic samples were taken from patients with solid tumours administered everolimus 10mg/day, were pooled. FINDINGS Efficacy and safety were evaluable for 945 and 938 patients, respectively. A 2-fold increase in everolimus Cmin increased the likelihood of tumour size reduction (odds ratio 1.40, 95% confidence interval (CI) 1.23-1.60), was associated with a trend for reduced risk of progression-free survival events (risk ratio [RR] 0.90, 95% CI 0.69-1.18) and increased the risk of grade ⩾3 pulmonary (RR 1.93, 95% CI 1.12-3.34), stomatitis (RR 1.49, 95% CI 1.05-2.10) and metabolic (RR 1.30, 95% CI 1.02-1.65) events. Coadministering everolimus with strong CYP3A4 and PgP inhibitors increased everolimus Cmin by 10% and 20%, respectively; coadministration with CYP3A4 inducers reduced Cmin by 7%. INTERPRETATION A 2-fold increase in everolimus Cmin was associated with improved tumour size reduction and increased risk of high-grade pulmonary, metabolic and stomatitis events. FUNDING Novartis Pharmaceuticals Corporation.

A Phase Ib and Pharmacokinetic Trial of Patupilone Combined with Carboplatin in Patients with Advanced Cancer

Purpose: Patupilone is a microtubule-targeting chemotherapeutic agent with clinical activity in a broad range of taxane-sensitive/resistant tumor types. The present phase Ib study examined the safety/tolerability and pharmacokinetics of patupilone in combination with carboplatin in patients with advanced solid tumors. Experimental Design: Patients with advanced cancer received patupilone via a 5- to 10-min i.v. infusion at doses of 3.6 to 6.0 mg/m2 q3w, immediately followed by carboplatin area under the curve (AUC) 5 or 6 mg/mL/min. Results: Of the 37 patients enrolled, the majority previously received taxanes (81%) and/or platinum-containing drugs (97.3%). The maximum tolerated dose (MTD) of patupilone with carboplatin AUC 6 was 4.8 mg/m2; additional patients were enrolled to consolidate experience at this dose. Of the 22 patients who received the MTD, the most common nonhematologic adverse events were fatigue in six (27.3%) and diarrhea, nausea, vomiting, abdominal pain, and neuropathy in one each (4.5%; all grade 3); hematologic toxicities included two patients (9.1%) with grade 3 neutropenia. The pharmacokinetics of patupilone were similar to those in a previous study of patupilone monotherapy. Of the 26 patients with recurrent platinum-sensitive ovarian cancer, tumor response was assessable by response evaluation criteria in solid tumors in 17; 1 patient (6%) achieved a complete response, and 10 (59%) achieved a partial response. Conclusions: The combination of patupilone 4.8 mg/m2/carboplatin AUC 6 was well tolerated and showed antitumor activity similar to established regimens in patients with recurrent platinum-sensitive ovarian cancer. The optimal dose for this regimen is currently being further refined in phase II trials.

Everolimus for patients with mantle cell lymphoma refractory to or intolerant of bortezomib: multicentre, single‐arm, phase 2 study

The multicentre, open‐label, two‐stage, single‐arm, phase 2, PILLAR (PIvotaL Lymphoma triAls of RAD001)‐1 study (NCT00702052) assessed the efficacy and safety of everolimus 10 mg/d in adults with confirmed mantle cell lymphoma (MCL) refractory to or intolerant of bortezomib who received ≥1 other antineoplastic agent, either separately or in combination with bortezomib. Primary endpoint was overall response rate (ORR) per investigator review according to the response criteria for malignant lymphoma. Secondary endpoints included progression‐free survival (PFS), overall survival (OS) and safety. Fifty‐eight patients were enrolled from August 2008–January 2011. Five partial responses were observed (ORR 8·6%; 90% confidence interval [CI] 3·5–17·3%); the study did not meet the prespecified objective of ≥8 objective responses among 57 patients. Median PFS and OS were 4·4 months (95% CI 3·5–6·1) and 16·9 months (95% CI 14·4–29·9), respectively. Grade 3/4 non‐haematological toxicities occurred in 70·7% of patients. Based on laboratory values, grade 3/4 thrombocytopenia, neutropenia and anaemia occurred in 13·8%, 13·8% and 8·6% of patients, respectively. Everolimus demonstrated modest activity and acceptable tolerability in heavily pretreated patients with MCL refractory to or intolerant of bortezomib. Future studies evaluating everolimus in a less refractory population or in combination with other targeted therapies in refractory MCL are warranted.

Molecular analysis of a male breast cancer patient with prolonged stable disease under mTOR/PI3K inhibitors BEZ235/everolimus

The mTORC1 inhibitor everolimus (Afinitor/RAD001) has been approved for multiple cancer indications, including ER+/HER2− metastatic breast cancer. However, the combination of everolimus with the dual PI3K/mTOR inhibitor BEZ235 was shown to be more efficacious than either everolimus or BEZ235 alone in preclinical models. Herein, we describe a male breast cancer (MBC) patient who was diagnosed with hormone receptor-positive (HR+)/HER2− stage IIIA invasive ductal carcinoma and sequentially treated with chemoradiotherapy and hormonal therapy. Upon the development of metastases, the patient began a 200 mg twice-daily BEZ235 and 2.5 mg weekly everolimus combination regimen. The patient sustained a prolonged stable disease of 18 mo while undergoing the therapy, before his tumor progressed again. Therefore, we sought to both better understand MBC and investigate the underlying molecular mechanisms of the patients sensitivity and subsequent resistance to the BEZ235/everolimus combination therapy. Genomic and immunohistochemical analyses were performed on samples collected from the initial invasive ductal carcinoma pretreatment and a metastasis postprogression on the BEZ235/everolimus combination treatment. Both tumors were relatively quiet genomically with no overlap to recurrent MBC alterations in the literature. Markers of PI3K/mTOR pathway hyperactivation were not identified in the pretreatment sample, which complements previous reports of HR+ female breast cancers being responsive to mTOR inhibition without this activation. The postprogression sample, however, demonstrated greater than fivefold increased estrogen receptor and pathogenesis-related protein expression, which could have constrained the PI3K/mTOR pathway inhibition by BEZ235/everolimus. Overall, these analyses have augmented the limited episteme on MBC genetics and treatment.

A Phase I Study Evaluating the Effect of Everolimus on the Pharmacokinetics of Midazolam in Healthy Subjects

The selective mammalian target of rapamycin (mTOR) inhibitor everolimus has demonstrated competitive inhibition of cytochrome P450 enzyme (CYP) 3A4 in vitro; however, its influence on CYP3A4 activity in humans is unknown. This study examined the influence of everolimus on the pharmacokinetics of midazolam, a sensitive CYP3A4/5 substrate, and its 1‐hydroxy metabolite in 25 healthy male subjects. Compared with administration of oral midazolam 4 mg/day alone, coadministration with everolimus 10 mg/day increased the midazolam maximum plasma concentration (Cmax) by 25% and the area under the plasma concentration–time curve (AUC) by 30%. The Cmax and AUC of 1‐hydroxymidazolam increased by 20% and 25%, respectively. Concomitant administration of everolimus with midazolam did not change the midazolam metabolic ratio (i.e., the ratio of 1‐hydroxymidazolam AUC to midazolam AUC) or the midazolam or 1‐hydroxymidazolam terminal half‐lives (geometric mean ratios for midazolam + everolimus vs. midazolam alone of 0.96, 1.03, and 1.06, respectively). These results suggest everolimus may affect the bioavailability, but not the systemic clearance, of orally coadministered CYP3A4 substrate drugs.

Everolimus dosing recommendations for tuberous sclerosis complex-associated refractory seizures

The present analysis examined the exposure‐response relationship by means of the predose everolimus concentration (Cmin) and the seizure response in patients with tuberous sclerosis complex–associated seizures in the EXIST‐3 study. Recommendations have been made for the target Cmin range of everolimus for therapeutic drug monitoring (TDM) and the doses necessary to achieve this target Cmin.

Abstract 26: Biomarker analysis of a male breast cancer patient with prolonged stable disease under mTOR/PI3K inhibitors BEZ235/RAD001

The mTORC1 inhibitor RAD001 (everolimus) has been approved for multiple cancer indications, including ER+/HER2- metastatic breast cancer. The combination of RAD001 with a dual PI3K/mTOR inhibitor BEZ235 was shown to be even more efficacious than RAD001 alone in preclinical models and was evaluated in clinical trials. We identified a male breast cancer patient who experienced a prolonged stable disease with the RAD001/BEZ235 combination as 3rd line treatment for his metastatic disease and investigated molecular mechanisms to explain the extraordinary benefit and subsequent drug resistance. The 66-year old Caucasian male had stage IIIA invasive ductal carcinoma at initial surgery. He then received two sequential adjuvant therapies: a chemo-radiotherapy and letrozole. When the patient developed multiple metastases, he was treated with chemotherapy and then fulvestrant, before received a 200 mg twice daily BEZ235 and 2.5 mg weekly RAD001 combination regimen, when a left axillary nodal metastasis was developed on fulvestrant. The patient sustained a prolonged stable disease of 18 months while under the therapy before his tumor progressed again. Tumor biopsy samples (formalin fixed, paraffin embedded) were taken from the patient at diagnosis and after progression and analyzed by immunohistochemistry (IHC) and whole exome sequencing. Blood samples were collected for germline DNA pharmacokinetic (PK) analysis. PK profile of BEZ235 was collected with Cmax, AUC, and T1/2 of 766 ng/mL, 6308 ng.h/mL, and 5.53 h, respectively. The observed BEZ235 Cmin values ranged from 75.5 to 504 ng/mL over the study. The 2.5 mg weekly RAD001 dose is substantially lower than the standard 10 mg daily dose and the Cmin could not be reliably determined. IHC assays showed low ER/PR expression (ER 30% 1+; PR 20% 1+, 10% 3+) in the diagnosis sample, but an increase of their expression (60% 1+) in the post progression sample. HER2 expression was negative in both samples. Analysis the same tumor samples using more quantitative AQUA platform demonstrated a drastic 10-fold score increase of ER from 31 to 312 and a 5-fold increase of PR from 271 to 1305. All other examined signaling pathway biomarkers (e.g. pS6, pAKT, pMAPK, pMEK and pEGFR) were expressed in both tumor samples but showed minimal expression changes between the time points. Whole exome sequencing of the diagnosis and post-progression specimens provided average coverage at 142X and 179X, respectively . No functional somatic alterations resulting in hyperactive PI3K/mTOR pathway was detected in genes such as PIK3CA, PTEN, MTOR, TSC1/2 in either tumor samples. In both specimens, a somatic deletion of 16 bp was detected in SPEN, which encodes a potential negative regulator of the estrogen signaling pathway1 . In conclusion, no PI3K/mTOR pathway hyperactivity marker was identified in the diagnostic samples. However, the increased ER/PR expression in the post-progression sample suggests that the effect of PI3K/mTOR pathway blockade by RAD001/BEZ235 might have diminished when the tumor gained further dependence on the hormonal receptor signaling. This hypothesis was supported by the observation that the patient9s tumor achieved another prolonged disease control of about 13 months by exemestane, after progression from BEZ235/RAD001 treatment. 1Legare S, et al. SPEN is a novel candidate tumor suppressor gene that regulates response to tamoxifen in estrogen receptor positive breast cancers. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013. Citation Format: A. Rose Brannron, Davide Melisi, Jennifer Hummel, Carmine Carbone, Melissa Frizziero, Wing Cheung, Parul Patel, Jorge Gallo, Giampaolo Tortora, Michael Morrissey, David Chen. Biomarker analysis of a male breast cancer patient with prolonged stable disease under mTOR/PI3K inhibitors BEZ235/RAD001. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Integrating Clinical Genomics and Cancer Therapy; Jun 13-16, 2015; Salt Lake City, UT. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(1_Suppl):Abstract nr 26.

Bioavailability of everolimus administered as a single 5 mg tablet versus five 1 mg tablets: a randomized, open-label, two-way crossover study of healthy volunteers

Background The mammalian target of rapamycin (mTOR) inhibitor everolimus has a well-established pharmacokinetics profile. We conducted a randomized, single-center, open-label, two-sequence, two-period crossover study of healthy volunteers to assess the relative bioavailability of everolimus administered as one 5 mg tablet or five 1 mg tablets. Methods Subjects were randomized 1:1 to receive everolimus dosed as one 5 mg tablet or as five 1 mg tablets on day 1, followed by a washout period on days 8–14 and then the opposite formulation on day 15. Blood sampling for pharmacokinetic evaluation was performed at prespecified time points, with 17 samples taken for each treatment period. Primary variables for evaluation of relative bioavailability were area under the concentration–time curve from time zero to infinity (AUCinf) and maximum blood concentration (Cmax). Safety was assessed by reporting the incidence of adverse events (AEs). Results Twenty-two participants received everolimus as one 5 mg tablet followed by five 1 mg tablets (n=11) or the opposite sequence (n=11). The Cmax of five 1 mg tablets was 48% higher than that of one 5 mg tablet (geometric mean ratio, 1.48; 90% confidence interval [CI], 1.35–1.62). AUCinf was similar (geometric mean ratio, 1.08; 90% CI, 1.02–1.16), as were the extent of absorption and the distribution and elimination kinetics. AEs, all grade 1 or 2, were observed in 54.5% of subjects. Conclusion Although the extent of absorption was similar, the Cmax of five 1 mg tablets was higher than that of one 5 mg tablet, suggesting these formulations lead to different peak blood concentrations and are not interchangeable at the dose tested.