A Phase Ib Dose-Escalation Study of LCL161 Plus Oral Topotecan for Patients With Relapsed/Refractory Small Cell Lung Cancer and Select Gynecologic Malignancies.

BACKGROUND: This was an open-label, multicenter, single-arm phase Ib dose-escalation study of oral LCL161 administered in combination with oral topotecan in patients with relapsed/refractory small cell lung cancer (SCLC) and select gynecological cancers. METHODS: Cohorts of 3-6 patients initiated treatment with LCL161 and topotecan in escalating doses. LCL161 was administered orally on days 1, 8, and 15 of each 21-day cycle; topotecan was administered orally for the first 5 days of each 21-day cycle. RESULTS: A total of 35 patients were enrolled in 6 cohorts; 30 patients were female; 4 patients had SCLC and 19 patients had ovarian cancer. Median prior lines of therapy were 3 (1-10). Median duration of treatment was 7.1 weeks (0.1-174). The most frequent grade 3/4 treatment-related adverse events were thrombocytopenia (51.43%) and anemia (31.43%). ORR was 9.7%; 58% of patients had SD. The study was stopped early before the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) were determined. CONCLUSION: The addition of LCL161 to oral topotecan caused more myelosuppression when dosed together than what was associated with either drug alone. Moreover, the drug combination did not improve outcomes. The study was terminated early (ClinicalTrials.gov Identifier: NCT02649673).

Discordance in Tumor Mutation Burden from Blood and Tissue Affects Association with Response to Immune Checkpoint Inhibition in Real-World Settings.

BACKGROUND: Tumor mutation burden (TMB), a biomarker for immune checkpoint inhibitor (CPI) response, is reported by both blood- and tissue-based next-generation sequencing (NGS) vendors. However, the agreement between TMB from blood (bTMB) and tissue (tTMB) in real-world settings, both in absolute value and association with CPI response, is not known. MATERIALS AND METHODS: This study utilizes Sarah Cannon's precision medicine platform, Genospace, to harmonize clinico-genomic data from 17 206 patients with cancer with NGS results from September 2015 to August 2021. A subset of patients have both bTMB and tTMB results. Statistical analyses are performed in R and include (1) correlation (r) and concordance (ρ) between patient-matched bTMB-tTMB pairs, (2) distribution of total bTMB and tTMB values, and (3) association of bTMB and tTMB with time to CPI therapy failure. RESULTS: In 410 patient-matched bTMB-tTMB pairs, the median bTMB (m = 10.5 mut/Mb) was significantly higher than the median tTMB (m = 6.0 mut/Mb, P < .001) leading to conflicting "high" and "low" statuses in over one-third of cases at a threshold of 10 mut/Mb (n = 410). Significant differences were observed in the distribution of bTMB values from blood-NGS vendors, with guardant health (GH) reporting higher (m = 10.5 mut/Mb, n = 2183) than Foundation Medicine (FMI, m = 3.8 mut/Mb, n = 462, P < .001). bTMB from GH required a higher threshold (≥40 mut/Mb) than bTMB from FMI (≥12 mut/Mb) in order to be associated with CPI response. CONCLUSIONS: This study uncovers variability in bTMB reporting among commercial NGS platforms, thereby evidencing a need for assay-specific thresholds in identifying patients who may respond to CPI therapy.

Adavosertib with Chemotherapy in Patients with Primary Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer: An Open-Label, Four-Arm, Phase II Study.

PURPOSE: This study assessed the efficacy, safety, and pharmacokinetics of adavosertib in combination with four chemotherapy agents commonly used in patients with primary platinum-resistant ovarian cancer. PATIENTS AND METHODS: Women with histologically or cytologically confirmed epithelial ovarian, fallopian tube, or peritoneal cancer with measurable disease were enrolled between January 2015 and January 2018 in this open-label, four-arm, multicenter, phase II study. Patients received adavosertib (oral capsules, 2 days on/5 days off or 3 days on/4 days off) in six cohorts from 175 mg once daily to 225 mg twice daily combined with gemcitabine, paclitaxel, carboplatin, or pegylated liposomal doxorubicin. The primary outcome measurement was overall response rate. RESULTS: Three percent of patients (3/94) had confirmed complete response and 29% (27/94) had confirmed partial response. The response rate was highest with carboplatin plus weekly adavosertib, at 66.7%, with 100% disease control rate, and median progression-free survival of 12.0 months. The longest median duration of response was in the paclitaxel cohort (12.0 months). The most common grade ≥3 adverse events across all cohorts were neutropenia [45/94 (47.9%) patients], anemia [31/94 (33.0%)], thrombocytopenia [30/94 (31.9%)], and diarrhea and vomiting [10/94 (10.6%) each]. CONCLUSIONS: Adavosertib showed preliminary efficacy when combined with chemotherapy. The most promising treatment combination was adavosertib 225 mg twice daily on days 1-3, 8-10, and 15-17 plus carboplatin every 21 days. However, hematologic toxicity was more frequent than would be expected for carboplatin monotherapy, and the combination requires further study to optimize the dose, schedule, and supportive medications.

Next-Generation Sequencing of Patients With Breast Cancer in Community Oncology Clinics.

PURPOSE: Molecular biomarkers informing disease diagnosis, prognosis, and treatment decisions in patients with breast cancer are being uncovered by next-generation sequencing (NGS) technologies. In this study, we survey how NGS is used for patients with breast cancer in real-world settings with a focus on physician behaviors and sequencing results. METHODS: We conducted a retrospective analysis of patients with breast cancer who received NGS testing from commercial vendors as part of standard of care from 2014 to 2019. A total of 2,635 NGS reports from 2,316 unique breast cancer patients were assessed. Hormone receptor and human epidermal growth factor receptor 2 statuses were abstracted from patient medical records. Comparative gene amplification and mutation frequencies were analyzed using Pearson's correlation and Lin's concordance statistics. RESULTS: The number of physicians ordering NGS tests for patients with breast cancer increased more than six-fold from 2014 to 2019. Tissue- and plasma-based tests were ordered roughly equally by 2019, with plasma-based testing ordered most frequently in hormone receptor-positive subtypes. Patients with triple-negative breast cancer were most likely to receive NGS testing. Gene amplifications including ERBB2 were detected less frequently in our real-world data set as compared to previous genomic landscape studies, whereas the opposite was true for gene mutations including ESR1. Pathogenic mutations in the PI3K pathway (38.6%) and DNA damage repair pathway (11.0%) were frequently reported. Alterations were also reported across other cellular pathways. CONCLUSION: Overall, we found that an increasing number of physicians in community settings are adopting NGS in the care of patients with breast cancer. Discrepancies between our real-world NGS data and previous genomic landscape studies are likely owed to the prevalence of plasma-based testing in community oncology clinics, as the reference data were from tissue-based NGS alone.

Tumor-Specific and Tumor-Agnostic Molecular Signatures Associated With Response to Immune Checkpoint Inhibitors.

PURPOSE: Next-generation sequencing (NGS) testing is being incorporated into routine standard of care for patients with cancer. Immune checkpoint inhibitors (CPIs) are approved for use in both tumor-specific and tumor-agnostic indications. We sought to determine tumor type-specific or tumor-agnostic correlations between mutations detected by NGS and response to CPIs. MATERIALS AND METHODS: A retrospective analysis of 26,004 patient records with NGS data available was conducted. Time to treatment failure and overall survival analyses were performed. Hazard ratios and associated statistics were computed in the R programming language. The study was considered exempt from internal review board review and data were considered nonhuman subjects. RESULTS: Response to CPIs varied between tumor types with melanoma and lung cancer performing relatively better on CPIs than other tumor types. Within tumor types, response to CPIs was stratified by mutations in specific genes. Tumor-agnostic markers including high tumor mutation burden and microsatellite instability-high were also associated with longer time to treatment failure on CPIs. Importantly, within the high tumor mutation burden and microsatellite instability-high groups, mutations in individual genes correlate with response to CPIs. CONCLUSION: The results from commercial NGS panels may be used to stratify patients for response to CPIs. In tumors where CPIs show relatively low efficacy, there may be distinct patient populations-based on gene mutation status-that are predicted to have better response to CPIs. Likewise, there may be distinct patient populations who do relatively worse on CPIs within tumor types known to respond well to CPIs.

Molecular Profiling in Drug Development: Paving a Way Forward.

As researchers learn more about tumor biology and the molecular mechanisms involved in tumorigenesis, metastasis, and tumor evolution, clinical trials are growing more complex and patient selection for clinical trials is becoming more specific. Rather than exploit certain phenotypic characteristics of tumor cells (e.g., rapid cell division and uncontrolled cell growth), pharmaceuticals targeting the genotypic causes of tumorigenesis are emerging. The sequencing of the human genome, advances in chemical techniques, and increased efficiency in drug target identification have changed the way drugs are developed. Now, more precise drugs targeting specific mutations within individual genes are being used to treat narrow patient populations harboring these specific driver mutations, often with greater efficacy and lower toxicity than traditional chemotherapeutic agents. This precision in drug development relies not only on the ability to design exquisitely specific pharmaceuticals but also to identify (with the same level of precision) the patients who are most likely to respond to those therapies. Robust screening techniques and adequate molecular oncology education are required to match the appropriate patient to precision therapies, and these same screening techniques provide the data necessary to advance to the next generation of drug development.

A Randomized, Double-Blinded, Phase II Trial of Carboplatin and Pemetrexed with or without Apatorsen (OGX-427) in Patients with Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer: The SPRUCE Trial.

BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). METHODS: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity. RESULTS: The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months. CONCLUSION: The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting. IMPLICATIONS FOR PRACTICE: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.

A phase I dose escalation study of NK012, an SN-38 incorporating macromolecular polymeric micelle.

PURPOSE: This study evaluated the safety, tolerability, pharmacokinetics, and maximum tolerated dose (MTD) and recommended phase II dose (RD) of NK012, a macromolecular polymeric micelle formulation of SN-38 (the active metabolite of irinotecan). PATIENTS AND METHODS: Patients with previously treated advanced solid tumors and acceptable organ function were administered NK012 as a 30-min infusion every 21 or 28 days without premedications. Patients were screened for UGT1A1 *28 polymorphism prior to enrollment. Patients homozygous for UGT1A1*28 allele (*28/*28 genotype patients) were treated at a reduced dose level with the potential for dose escalation based on toxicities. Pharmacokinetic samples were obtained during cycles 1 and 2. RESULTS: Thirty-nine patients were enrolled, and thirty-eight patients were treated with NK012. NK012 was escalated from 9 to 37 mg/m(2) in patients with UGT1A1*28 allele genotype of wt/wt and wt/*28. The MTD/RD of a Q21D regimen was determined to be 28 mg/m(2) where the dose-limiting toxicity is myelosuppression, which appears to be cumulative and limits timely subsequent dosing. Based on delayed neutrophil recovery, the NK012 dose of 28 mg/m(2) administered on an every 28 days schedule was confirmed as the RD. Gastrointestinal toxicities were mild, with no grade 3 diarrhea reported. The T1/2z value of polymer-unbound SN-38 was significantly prolonged compared to that of SN-38 metabolized from CPT-11, indicating a sustained high systemic SN-38 concentration. Six patients had confirmed partial responses. Eighteen additional patients had stable disease as their best response to treatment. CONCLUSIONS: The recommended phase II dose of NK012 for UGT1A1 wt/wt and wt/*28 genotype patients is 28 mg/m(2) every 28 days. Additional clinical development as a single agent in specific patient populations or in combination with other chemotherapy agents is warranted.

A first-in-human phase I study of the oral Notch inhibitor, LY900009, in patients with advanced cancer.

BACKGROUND: Notch signalling regulates stem cell development and survival and is deregulated in multiple malignancies. LY900009 is a small molecule inhibitor of Notch signalling via selective inhibition of the γ-secretase protein. We report the first-in-human phase I trial of LY900009. METHODS: Dose escalation (Part A) was performed in cohorts of three advanced cancer patients using a modified continual reassessment method and dose confirmation (Part B) was performed in ovarian cancer patients. LY900009 was taken orally thrice weekly (every Monday, Wednesday, and Friday) during a 28-d cycle. The primary objective determined the maximum tolerated dose (MTD); secondary end-points included toxicity, pharmacokinetics, pharmacodynamics, and antitumour activity. RESULTS: Thirty-five patients received LY900009 at dose levels ranging from 2-60 mg. Study drug-related adverse events were diarrhoea (46%), vomiting (34%), anorexia (31%), nausea (31%), and fatigue (23%). At 30 mg, a dose-limiting toxicity (grade III mucosal inflammation) was observed. LY900009 absorption was rapid, with median tmax at 1-4 h post-dose. LY900009 inhibited plasma levels of amyloid-ß peptide in a dose-dependent manner with 80-90% inhibition observed in the 30- to 60-mg cohorts. No responses were seen, but five patients had stable disease. Two patients (5.7%) with leiomyosarcoma and ovarian cancer received four cycles of therapy. One patient (15 mg) showed markedly increased glandular mucin consistent with pharmacologic inhibition of the Notch pathway. CONCLUSIONS: The recommended MTD schedule for future studies was 30 mg thrice weekly, which exceeds the target inhibition level observed in preclinical models to promote tumour regression in humans.

Safety and activity of IT-139, a ruthenium-based compound, in patients with advanced solid tumours: a first-in-human, open-label, dose-escalation phase I study with expansion cohort.

OBJECTIVE: This phase I clinical study (NCT01415297) evaluated the safety, tolerability, maximum-tolerated dose (MTD), pharmacokinetics and pharmacodynamics of IT-139 (formerly NKP-1339) monotherapy in patients with advanced solid tumours. IT-139, sodium trans-(tetrachlorobis(1H-indazole)ruthenate(III)), is a novel small molecule that suppresses the stress induction of GRP78 in tumour cells. GRP78 is a key regulator of misfolded protein processing, and its upregulation in tumours is associated with intrinsic and drug-induced resistance. METHODS: Forty-six patients with advanced solid tumours refractory to treatment received intravenous infusions of IT-139 on days 1, 8 and 15 for every 28 days, and doses were evaluated across nine cohorts at 20, 40, 80, 160, 320, 420, 500, 625 and 780 mg/m2. RESULTS: Overall, IT-139 was well tolerated. The treatment-emergent adverse events (AEs) occurring in ≥20% of patients were nausea, fatigue, vomiting, anaemia and dehydration. The majority of patients had AEs that were ≤grade 2, regardless of relationship with the study drug. Of the total 38 efficacy-evaluable patients, one patient with a carcinoid tumour achieved a durable partial response. Nine additional patients achieved stable disease . The MTD was determined to be 625 mg/m2. IT-139 exhibited first-order linear pharmacokinetics. CONCLUSIONS: IT-139 demonstrated a manageable safety profile at the MTD and modest anti-tumour activity in this study of patients with solid tumours refractory to treatment. The lack of dose-limiting haematological toxicity and the absence of neurotoxicity position IT-139 well for use in combination with a broad spectrum of anticancer drugs. TRIAL REGISTRATION NUMBER: NCT01415297.

Molecular Pathways: Fatty Acid Synthase.

Therapies that target tumor metabolism represent a new horizon in anticancer therapies. In particular, cancer cells are dependent on the generation of lipids, which are essential for cell membrane synthesis, modification of proteins, and localization of many oncogenic signal transduction enzymes. Because fatty acids are the building blocks of these important lipids, fatty acid synthase (FASN) emerges as a unique oncologic target. FASN inhibitors are being studied preclinically and beginning to transition to first-in-human trials. Early generation FASN inhibitors have been studied preclinically but were limited by their pharmacologic properties and side-effect profiles. A new generation of molecules, including GSK2194069, JNJ-54302833, IPI-9119, and TVB-2640, are in development, but only TVB-2640 has moved into the clinic. FASN inhibition, either alone or in combination, holds promise as a novel therapeutic approach for patients with cancer.

A Phase I Study of the Hsp90 Inhibitor AUY922 plus Capecitabine for the Treatment of Patients with Advanced Solid Tumors.

BACKGROUND: This phase I study determined the maximum tolerated dose (MTD) of AUY922 with capecitabine in advanced solid tumors. METHODS: Capecitabine 1000 mg/m(2) PO BID was administered with escalating doses of AUY922 IV; the MTD of AUY922 was combined with capecitabine 1250 mg/m(2) (DL6). RESULTS: 23 patients were treated at 5 dose levels (22 mg/m(2)-70 mg/m(2)). No DLTs were observed until DL6 (grade 3 diarrhea). Reversible vision darkening was seen in 26%. Four patients had partial response; 2 previously progressed on fluorouracil. Eight patients had stable disease (median 25.5 weeks). CONCLUSION: AUY922 plus capecitabine was well-tolerated up to 70 mg/m(2) with encouraging preliminary efficacy.

A phase I study of VS-6063, a second-generation focal adhesion kinase inhibitor, in patients with advanced solid tumors.

OBJECTIVE: VS-6063 (also known as defactinib or PF-04554878) is a second-generation inhibitor of focal adhesion kinase (FAK) and proline-rich tyrosine kinase-2 (Pyk2). This phase I dose-escalation study was conducted in patients with advanced solid malignancies. METHODS: Using a traditional 3 + 3 design, VS-6063 was administered orally twice daily (b.i.d.) in 21-day cycles to cohorts of three to six patients. In cycle 1, a lead-in dose was administered to assess single-dose pharmacokinetics; steady-state pharmacokinetics was assessed after 15 days of continuous dosing. Dose escalation was performed in the fasted state, and repeated in two additional cohorts in the fed state. RESULTS: Forty-six patients were treated across nine dose levels (12.5-750 mg b.i.d.). Dose-limiting toxicities, comprising headache (n = 1), fatigue (n = 1) and unconjugated hyperbilirubinemia (n = 3), occurred at the 300- or 425-mg b.i.d. dose level and were reversible. Frequent adverse events included nausea (37 %), fatigue (33 %), vomiting (28 %), diarrhea (22 %) and headache (22 %). A maximum-tolerated dose was not defined. Dose escalation was stopped at the 750-mg b.i.d. dose due to decreased serum exposure in the 500- and 750-mg versus 300- and 425-mg groups. Food delayed the time to peak serum concentration without affecting serum drug exposure. No radiographic responses were reported. Disease stabilization at ~12 weeks occurred in six of 37 (16 %) patients receiving doses ≥100 mg b.i.d. CONCLUSIONS: VS-6063 has an acceptable safety profile. Treatment-related adverse events were mild to moderate, and reversible. The recommended phase II fasting dose of VS-6063 is 425 mg b.i.d.

A first-in-human phase I dose-escalation, pharmacokinetic, and pharmacodynamic evaluation of intravenous LY2090314, a glycogen synthase kinase 3 inhibitor, administered in combination with pemetrexed and carboplatin.

PURPOSE: LY2090314 (LY) is a glycogen synthase kinase 3 inhibitor with preclinical efficacy in xenograft models when combined with platinum regimens. A first-in-human phase 1 dose-escalation study evaluated the combination of LY with pemetrexed/carboplatin. PATIENTS AND METHODS: Forty-one patients with advanced solid tumors received single-dose LY monotherapy lead-in and 37 patients received LY (10-120 mg) plus pemetrexed/carboplatin (500 mg/m(2) and 5-6 AUC, respectively) across 8 dose levels every 21 days. Primary objective was maximum tolerated dose (MTD) determination; secondary endpoints included safety, antitumor activity, pharmacokinetics, and beta-catenin pharmacodynamics. RESULTS: MTD of LY with pemetrexed/carboplatin was 40 mg. Eleven dose-limiting toxicities (DLTs) occurred in ten patients. DLTs during LY monotherapy occurred at ≥ 40 mg: grade 2 visual disturbance (n = 1) and grade 3/4 peri-infusional thoracic pain during or shortly post infusion (n = 4; chest, upper abdominal, and back pain). Ranitidine was added after de-escalation to 80 mg LY to minimize peri-infusional thoracic pain. Following LY with pemetrexed/carboplatin therapy, DLTs included grade 3/4 thrombocytopenia (n = 4) and grade 4 neutropenia (n = 1). Best overall response by RECIST included 5 confirmed partial responses (non-small cell lung cancer [n = 3], mesothelioma, and breast cancer) and 19 patients having stable disease. Systemic LY exposure was approximately linear over dose range studied. Transient upregulation of beta-catenin measured in peripheral blood mononuclear cells (PBMCs) occurred at 40 mg LY. CONCLUSIONS: The initial safety profile of LY2090314 was established. MTD LY dose with pemetrexed/carboplatin is 40 mg IV every 3 weeks plus ranitidine. Efficacy of LY plus pemetrexed/carboplatin requires confirmation in randomized trials.

Evaluation of CYP3A-mediated drug-drug interactions with romidepsin in patients with advanced cancer.

Two multicenter, single-arm, single-infusion, open-label studies were conducted to evaluate the effect of ketoconazole (a strong CYP3A inhibitor) or rifampin (a strong CYP3A inducer) daily for 5 days on the pharmacokinetics (PK) and safety of romidepsin (8 mg/m(2) intravenous 4-hour infusion for the ketoconazole study or a 14 mg/m(2) intravenous 4-hour infusion for the rifampin study) in patients with advanced cancer. Romidepsin coadministered with ketoconazole (400 mg) or rifampin (600 mg) was not bioequivalent to romidepsin alone. With ketoconazole, the mean romidepsin AUC and Cmax were increased by approximately 25% and 10%, respectively. With rifampin, the mean romidepsin AUC and Cmax were unexpectedly increased by approximately 80% and 60%, respectively; this is likely because of inhibition of active liver uptake. For both studies, romidepsin clearance and volume of distribution were decreased, terminal half-life was comparable, and median Tmax was similar. Overall, the safety profile of romidepsin was not altered by coadministration with ketoconazole or rifampin, except that a higher incidence and greater severity of thrombocytopenia was observed when romidepsin was given with rifampin. The use of romidepsin with rifampin and strong CYP3A inducers should be avoided. Toxicity related to romidepsin exposure should be monitored when romidepsin is given with strong CYP3A inhibitors.

Factors affecting the pharmacokinetics and pharmacodynamics of PEGylated liposomal irinotecan (IHL-305) in patients with advanced solid tumors.

IHL-305 is a PEGylated liposomal formulation of irinotecan (CPT-11). The objective of this study was to evaluate the factors associated with interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 in patients with advanced solid tumors. IHL-305 was administered intravenously once every 4 weeks as part of a Phase I study. Pharmacokinetic studies of the liposomal sum total CPT-11, released CPT-11, SN-38, SN-38G, 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin, and 7-ethyl-10-[4-amino-1-piperidino]-carbonyloxycamptothecin in plasma were performed. Noncompartmental and compartmental pharmacokinetic analyses were conducted using pharmacokinetic data for sum total CPT-11. The pharmacokinetic variability of IHL-305 is associated with linear and nonlinear clearance. Patients whose age and body composition (ratio of total body weight to ideal body weight [TBW/IBW]) were greater than the median age and TBW/IBW of the study had a 1.7-fold to 2.6-fold higher ratio of released CPT-11 area under the concentration versus time curve (AUC) to sum total CPT-11 AUC. Patients aged <60 years had a 1.3-fold higher ratio of percent decrease in monocytes at nadir to percent decrease in absolute neutrophil count at nadir as compared with patients aged ≥60 years. There was an inverse relationship between patient age and percent decrease in monocytes at nadir, ie, younger patients have a higher percent decrease in monocytes. Patients with a higher percent decrease in monocytes at nadir have a decreased plasma exposure of sum total CPT-11. The pharmacokinetics and pharmacodynamics of IHL-305 are consistent with those of other PEGylated liposomal carriers. Interpatient variability in the pharmacokinetics and pharmacodynamics of IHL-305 was associated with age, body composition, and monocytes.

A phase 1 study of the sachet formulation of the oral dual PI3K/mTOR inhibitor BEZ235 given twice daily (BID) in patients with advanced solid tumors.

Introduction The PI3 kinase (PI3K) pathway is a commonly dysregulated pathway in cancers and is an attractive target for antitumor therapy. BEZ235 is a potent, highly specific and selective dual PI3K/mTOR inhibitor. Methods Patients were enrolled in a 3 + 3 dose escalation design to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetics (PK) of BEZ235 when administered twice-daily as an oral sachet. For intrapatient PK comparison, patients were to receive a lead in of the total daily dose in a QD schedule for the first 8 days of the initial 28 day cycle. Patients continued treatment until unacceptable toxicity or disease progression occurred. Results Thirty-three patients received BEZ235. Initial dose levels of 200 and 400 mg BID had no DLTs. At the 600 mg BID dose level with 1200 mg QD lead in dose two DLTs of grade 3 mucositis occurred early in the first treatment cycle, the lead-in QD dosing was eliminated. Fatigue and mucositis limited dosing at 600 mg BID in subsequent patients. The 400 mg BID dose level was re-explored, with DLTs of grade 3 hyperglycemia, dehydration, fatigue, and grade 3 thrombocytopenia. Twelve patients were enrolled at an intermediate dose of 300 mg BID; a grade 3 mucositis DLT was reported in 1 patient, and this dose was declared the MTD. Preliminary PK data demonstrate a consistent increase in PK parameters (Cmax and AUC) with dose level compared to QD dosing. Fifteen patients experienced stable disease as their best response, including 10 (colorectal [4 patients], endometrial [3 patients], carcinoid NOS, pancreas, and melanoma) who had disease control for ≥16 weeks. Conclusions The recommended dose of BEZ235 administered BID as an oral sachet formulation is 300 mg BID. Toxicities seen have been reported for other dual PI3K/mTOR inhibitors.

Phase 1, open-label, dose escalation, safety, and pharmacokinetics study of ME-344 as a single agent in patients with refractory solid tumors.

BACKGROUND: The current phase 1, open-label, dose escalation study was conducted to establish the safety, tolerability, pharmacokinetic profile, and preliminary antitumor activity of the novel mitochondrial inhibitor ME-344 in patients with refractory solid tumors. METHODS: Patients with refractory solid tumors were treated in a 3 + 3 dose escalation design. ME-344 was administered via intravenous infusion on days 1, 8, and 15 of the first 28-day cycle and weekly thereafter. Pharmacokinetics was assessed on days 1 and 15 of the first cycle. RESULTS: A total of 30 patients (median age, 65 years; 67% of whom were female) received ME-344. There were 5 dose-limiting toxicities reported. Four patients developed grade 3 neuropathy (2 patients each at doses of 15 mg/kg and 20 mg/kg) and 1 patient treated at a dose of 10 mg/kg developed a grade 3 acute myocardial infarction (toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.03]). The maximum tolerated dose (MTD) was defined as 10 mg/kg weekly. The most common adverse events were nausea, dizziness, and fatigue. At the MTD of 10 mg/kg, the maximal plasma concentration (Cmax) was 25.8 µg/mL and the area under the concentration curve from time zero to infinity was 25.9 hour*µg/mL. One patient with small cell lung cancer achieved a partial response for ≥ 52 weeks. Four patients had prolonged stable disease (1 patient each with urothelial carcinoma [47 weeks], carcinoid tumor [≥ 40 weeks], cervical leiomyosarcoma [39 weeks], and cervical cancer [≥ 31 weeks]). CONCLUSIONS: The once-weekly administration of ME-344 was generally well tolerated in the current study, a first-in-human study; dose-limiting neuropathy was noted, but not at the MTD. Exposures at the 10-mg/kg dose level suggest a sufficient therapeutic index. The preliminary clinical activity as a monotherapy supports the further clinical development of ME-344 in combination with chemotherapy.

A phase Ib study of linsitinib (OSI-906), a dual inhibitor of IGF-1R and IR tyrosine kinase, in combination with everolimus as treatment for patients with refractory metastatic colorectal cancer.

PURPOSE: To determine the maximum tolerated dose (MTD) of the combination of linsitinib (OSI-906), a dual inhibitor of IGFR and IR tyrosine kinase activity, and everolimus as treatment for patients with refractory metastatic colorectal cancer (mCRC). METHODS: Eligible adult patients with refractory mCRC, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate end-organ function received escalating doses of OSI-906 and everolimus in a 3 + 3 design. Treatment continued until disease progression or unacceptable toxicity, with response evaluations every 8 weeks. RESULTS: Eighteen patients with metastatic CRC were treated. There were no dose-limiting toxicities (DLTs) in the first dose level (DL, OSI-906 50 mg BID; everolimus 5 mg QD). At DL2 (OSI-906 100 mg BID; everolimus 10 mg QD, n =6), three patients had DLTs considered related to everolimus (grade 3 mucositis, 2; grade 3 thrombocytopenia, 1). An amendment introduced DL2a (OSI-906 100 mg BID; everolimus 5 mg QD, n =5); DLTs were seen in two patients (one patient each: grade 3 thrombocytopenia with bleeding; inability to receive 75 % of doses due to neutropenia/thrombocytopenia). DL1 was the MTD; a total of 7 patients were treated at this dose. Common adverse events across all DLs included grade 1/2 fatigue (50 %) and anorexia (50 %). There were no objective responses to treatment; median time of study treatment was 7.6 weeks (range: 3.9-53 weeks). CONCLUSIONS: The MTD of OSI-906 and everolimus was 50 mg BID and 5 mg QD, respectively. No indications of clinical activity were observed in refractory mCRC patients.