Showing papers by "David R. Gandara published in 2012"
University of Chicago1, University of California, Davis2, Memorial Sloan Kettering Cancer Center3, University of Pennsylvania4, Harvard University5, University of Southern California6, City of Hope National Medical Center7, Johns Hopkins University8, Loyola University Chicago9, National Institutes of Health10
TL;DR: The addition of bevacizumab to gemcitabine/cisplatin in this trial did not significantly improve PFS or OS in patients with advanced MM, and there were no statistically significant differences in toxicity of grade 3 or greater.
Abstract: Purpose Gemcitabine plus cisplatin is active in malignant mesothelioma (MM), although single-arm phase II trials have reported variable outcomes. Vascular endothelial growth factor (VEGF) inhibitors have activity against MM in preclinical models. We added the anti-VEGF antibody bevacizumab to gemcitabine/cisplatin in a multicenter, double-blind, placebo-controlled randomized phase II trial in patients with previously untreated, unresectable MM. Patients and Methods Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1 and no thrombosis, bleeding, or major blood vessel invasion. The primary end point was progression-free survival (PFS). Patients were stratified by ECOG performance status (0 v 1) and histologic subtype (epithelial v other). Patients received gemcitabine 1,250 mg/m2 on days 1 and 8 every 21 days, cisplatin 75 mg/m2 every 21 days, and bevacizumab 15 mg/kg or placebo every 21 days for six cycles, and then bevacizumab or placebo every 21 days until prog...
220 citations
TL;DR: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations.
Abstract: Purpose: Oral administration of the alkylating agent cyclophosphamide at low doses, metronomic dosing, is well tolerated, with efficacy in multiple tumor types. PARP inhibition potentiates effects of cyclophosphamide in preclinical models. We conducted a phase I trial of the PARP inhibitor veliparib and metronomic cyclophosphamide in patients with refractory solid tumors and lymphoid malignancies. Experimental Design: Objectives were to establish the safety and maximum tolerated dose (MTD) of the combination; characterize veliparib pharmacokinetics (PK); measure poly(ADP-ribose) (PAR), a product of PARP, in tumor biopsies and peripheral blood mononuclear cells (PBMC); and measure the DNA-damage marker γH2AX in PBMCs and circulating tumor cells (CTC). Cyclophosphamide was administered once daily in 21-day cycles in combination with veliparib administered once daily for 7, 14, or 21 days. Results: Thirty-five patients were enrolled. The study treatment was well tolerated, and the MTD was established as veliparib 60 mg with cyclophosphamide 50 mg given once daily. Seven patients had partial responses; an additional six patients had disease stabilization for at least six cycles. PAR was significantly decreased in PBMCs (by at least 50%) and tumor biopsies (by at least 80%) across dose levels (DL); γH2AX levels were increased in CTCs from seven of nine patients evaluated after drug administration. Conclusions: The combination of veliparib with metronomic cyclophosphamide is well tolerated and shows promising activity in a subset of patients with BRCA mutations. A phase II trial of the combination compared with single-agent cyclophosphamide is ongoing in BRCA -positive ovarian cancer, triple-negative breast cancer, and low-grade lymphoma. Clin Cancer Res; 18(6); 1726–34. ©2012 AACR .
194 citations
TL;DR: Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.
Abstract: Background Genetic abnormalities in cell cycle control are common in malignant melanoma. UCN-01 (7-hydroxystaurosporine) is an investigational agent that exhibits antitumor activity by perturbing the cancer cell cycle. A patient with advanced melanoma experienced a partial response in a phase I trial of single agent UCN-01. We sought to determine the activity of UCN-01 against refractory metastatic melanoma in a phase II study. Patients and methods Patients with advanced melanoma received UCN-01 at 90 mg/m2 over 3 h on cycle 1, reduced to 45 mg/m2 over 3 h for subsequent cycles, every 21 days. Primary endpoint was tumor response. Secondary endpoints included progression-free survival (PFS) and overall survival (OS). A two-stage (17 + 16), single arm phase II design was employed. A true response rate of ≥20% (i.e., at least one responder in the first stage, or at least four responders overall) was to be considered promising for further development of UCN-01 in this setting. Results Seventeen patients were accrued in the first stage. One patient was inevaluable for response. Four (24%) patients had stable disease, and 12 (71%) had disease progression. As there were no responders in the first stage, the study was closed to further accrual. Median PFS was 1.3 months (95% CI, 1.2–3.0) while median OS was 7.3 months (95% CI, 3.4–18.4). One-year and two year OS rates were 41% and 12%, respectively. A median of two cycles were delivered (range, 1–18). Grade 3 treatment-related toxicities include hyperglycemia (N = 2), fatigue (N = 1), and diarrhea (N = 1). One patient experienced grade 4 creatinine elevation and grade 4 anemia possibly due to UCN-01. No dose modification was required as these patients had disease progression. Conclusion Although well tolerated, UCN-01 as a single agent did not have sufficient clinical activity to warrant further study in refractory melanoma.
61 citations
TL;DR: A higher cediranib dose level was associated with improved disease control, but this dose was poorly tolerated and did not meet its pre-specified response endpoint.
51 citations
TL;DR: A subgroup-focused, multiple-hypothesis design was selected for S0819 that incorporates coprimary endpoints to assess cetuximab in both the overall study population and among EGFR FISH-positive (FISH+) patients, with the sample size determined based on evaluation in the EG FR FISH+ group.
Abstract: The role of cetuximab for the treatment of advanced non-small-cell lung cancer (NSCLC) is currently unclear. The molecular target of cetuximab, epidermal growth factor receptor (EGFR), as measured by fluorescent in situ hybridization (FISH), has shown potential to be a predictive biomarker for cetuximab efficacy in NSCLC. SWOG S0819 is a Phase III trial evaluating both the value of cetuximab in this setting as well as EGFR FISH as a predictive biomarker. This paper describes the decision process for determining the design and interim monitoring plan for S0819. Six possible designs were evaluated in terms of their properties and the hypotheses that can be addressed within the design constraints. A subgroup-focused multiple-hypothesis design was selected for S0819 incorporating co-primary endpoints to assess cetuximab in both the overall study population and among EGFR FISH positive patients with the sample size determined based on evaluation in the EGFR FISH positive group. The interim monitoring plan chosen specifies interim evaluations of both efficacy and futility in the EGFR FISH positive group alone. The futility monitoring plan to determine early stopping in the EGFR FISH non-positive group is based on evaluation within the positive group, the entire study population, and the non-positive group. SWOG S0819 employs a design which addresses both the biomarker-driven and general efficacy objectives of this study.
48 citations
TL;DR: Neither sorafenib alone or sorafinib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.
Abstract: Purpose Patients with metastatic pancreatic cancer have limited therapeutic options. The role of the Ras-Raf-MAPK pathway and of vascular endothelial growth factor in pancreatic carcinogenesis provided the rational to evaluate the efficacy of sorafenib with or without gemcitabine in a randomized phase II study. Methods Patients with metastatic pancreatic cancer were randomized to sorafenib alone (arm A) or sorafenib with gemcitabine (arm B). Results Arm A was closed to accrual at interim analysis due to the lack of objective response. Median PFS and OS were 2.3 and 4.3 months respectively. There was one partial response among the 37 patients in arm B. Median PFS and OS were 2.9 and 6.5 months respectively. There were more grade 3 and 4 toxicities in arm B with the most common being neutropenia (17%), thrombocytopenia (8%), alkaline phosphatase elevation (14%), venous thromboembolism (8%), diarrhea, hypokalemia and ALT elevation (5%) each. Several associations were noted between single nucleotide polymorphisms in ribonucleotide reductase, Cox-2, vascular endothelial growth factor and survival in patients treated with gemcitabine and sorafenib. Conclusions Neither sorafenib alone or sorafenib in combination with gemcitabine manifested promising activity in metastatic pancreatic cancer.
43 citations
TL;DR: A modest response rate is observed in patients with recurrent or persistent ovarian cancer treated with the combination of bryostatin and cisplatin, and the toxicity profile, however, observed in this pt population, precludes tolerability and prevents this combination from further investigation at this dose and schedule.
Abstract: Background The California Cancer Consortium has performed a Phase II trial of infusional bryostatin, a protein kinase C inhibitor isolated from the marine invertebrate bryozoan, Bugula Neritina, a member of the phylum Ectoprocta, in combination with cisplatin, in patients (pts) with recurrent platinum-sensitive or resistant ovarian cancer (OC). Methods Pts received bryostatin 45 mcg/m2 as a 72 h continuous infusion followed by cisplatin 50 mg/m2. Cycles were repeated every 3 weeks. Dosages were chosen based on phase I data obtained by the CCC in a population of pts with mixed tumor types. Results Eight pts with recurrent or persistent epithelial OC received 23 cycles of treatment. All pts had received previous platinum-based chemotherapy; two pts had received one prior course, five had received two prior courses, and one had received three prior courses of chemotherapy. The median age was 64 (range 32–72), and Karnofsky performance status 90 (range 80–100). A median of 3 cycles of chemotherapy were delivered (range: 1–5). The median progression-free and overall survivals were 3 and 8.2 months respectively. Best responses included two partial responses (one in a platinum-resistant pt), three pts with stable disease, and three progressions. All pts experienced Grade 3 or 4 toxicities including severe myalgias/pain/fatigue/asthenia in six pts, and severe nausea/vomiting/constipation in two other pts. One pt experienced a seizure and liver function tests were elevated in one other. Conclusions A modest response rate is observed in pts with recurrent or persistent ovarian cancer treated with the combination of bryostatin and cisplatin. The toxicity profile, however, observed in this pt population (primarily severe myalgias), precludes tolerability and prevents this combination from further investigation at this dose and schedule. It is possible that platinum pre-exposure in OC patients exacerbates observed toxicity. Phase II dosages of investigational agents in OC pts that are determined by phase I trials in pts with other tumor types should be chosen cautiously.
37 citations
TL;DR: Eribulin mesylate is well tolerated and demonstrates activity in pretreated, TS NSCLC, and is an analog of halichondrin B with a unique mechanism of microtubule binding.
37 citations
TL;DR: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability, and is associated with a modest clinical benefit rate of 25% in the treated patient population with advanced solid tumors.
Abstract: 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavailability of 3-AP in patients with advanced-stage solid tumors. Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 + 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1–3, days 8–10, and days 15–17 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated. Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 ± 29% and was consistent with the finding that the MTD by the oral route was 33% higher than by the intravenous route. Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.
36 citations
TL;DR: Evidence for targeting CD22, a cell adhesion protein known to influence B-cell survival that is also widely expressed in lung cancer cells, is provided and suggests that anti-CD22 mAbs may be useful for targeted therapy of lung cancer, a malignancy that has few tumor-specific targets.
Abstract: Most patients with lung cancer still die from their disease, necessitating additional options to improve treatment. Here, we provide evidence for targeting CD22, a cell adhesion protein known to influence B-cell survival that we found is also widely expressed in lung cancer cells. In characterizing the antitumor activity of an established anti-CD22 monoclonal antibody (mAb), HB22.7, we showed CD22 expression by multiple approaches in various lung cancer subtypes, including 7 of 8 cell lines and a panel of primary patient specimens. HB22.7 displayed in vitro and in vivo cytotoxicity against CD22-positive human lung cancer cells and tumor xenografts. In a model of metastatic lung cancer, HB22.7 inhibited the development of pulmonary metastasis and extended overall survival. The finding that CD22 is expressed on lung cancer cells is significant in revealing a heretofore unknown mechanism of tumorigenesis and metastasis. Our work suggests that anti-CD22 mAbs may be useful for targeted therapy of lung cancer, a malignancy that has few tumor-specific targets.
31 citations
TL;DR: In the emerging era of new anticancer agents directed against molecular targets present in only a small subset of patients within a general population, such as non‐small-cell lung cancer (NSCLC), it is increasingly important to consider simultaneous and early codevelopment of an associated predictive biomarker.
TL;DR: Perifosine is active in select RCC lines, abrogating the induction of AKT phosphorylation mediated by mTOR inhibition and modulation of pro-angiogenesis pathways, providing a basis for future investigations.
Abstract: Inhibition of the mammalian target of rapamycin (mTOR), a regulator of hypoxia inducible factor (HIF), is an established therapy for advanced renal cell cancer (RCC). Inhibition of mTOR results in compensatory AKT activation, a likely resistance mechanism. We evaluated whether addition of the Akt inhibitor perifosine to the mTOR inhibitor rapamycin would synergistically inhibit RCC. Select RCC cell lines were studied [786-O, A498 (VHL mutant), CAKI-1 (VHL wild type), and 769-P (VHL methylated)] with single agent and combination therapy. Growth inhibition was assessed by MTT and cell cycling by flow cytometry. Phospho-AKT (S473) and HIF-2α were assessed by Western blot. Total RNA was isolated from 786-O cells subjected to single agent and combination treatments. In these cells, genome-wide expression profiles were assessed, and real-time PCR was used to confirm a limited set of expression results. Three out of four cell lines (CAKI-1, 769-P, and 786-O) were sensitive to single-agent perifosine with 50% inhibitory concentrations ranging from 5 to 10 μM. Perifosine blocked phosphorylation of AKT induced by rapamycin and inhibited HIF-2α expression in 786-O and CAKI-1. Combined treatment resulted in sub-additive growth inhibition. GeneChip analysis and pathway modeling revealed inhibition of the IL-8 pathway by these agents, concomitant with up-regulation of the KLF2 gene, a known suppressor of HIF1α. Perifosine is active in select RCC lines, abrogating the induction of AKT phosphorylation mediated by mTOR inhibition. Combined mTOR and AKT inhibition resulted in the modulation of pro-angiogenesis pathways, providing a basis for future investigations.
TL;DR: Analysis of the Response Genetics Inc. (RGI) database for this association and implications for therapy suggest increased sensitivity of ALK+ NSCLC to the chemotherapeutic agent pemetrexed.
Abstract: 7582 Background: ALK+ NSCLC represents a molecular target-defined patient population highly responsive to the ALK inhibitor crizotinib. Previous reports have also suggested increased sensitivity of...
TL;DR: Direct involvement between the transcription factor Nrf2 and the MRP3 promoter, which leads to the up-regulation of the MRp3 gene is demonstrated.
TL;DR: The authors evaluated the impact of the progression date (PD) determination approach on PFS estimates and found that it had an uncertain impact on overall survival estimates.
Abstract: BACKGROUND:
In patients with advanced lung cancer, overall survival is largely influenced by progression status. Because progression-free survival (PFS)-based endpoints are controversial, the authors evaluated the impact of the progression date (PD) determination approach on PFS estimates.
METHODS:
Individual patient data from 21 trials (14 North Central Cancer Treatment Group trials and 7 Southwest Oncology Group trials) were used. The reported PD (RPD) was defined as either the radiographic scan date or the clinical deterioration date. PD was determined using Method 1 (M1), the RPD; M2, 1 day after the last progression-free scan; M3, midpoint between the last progression-free scan and the RPD; and M4, an interval-censoring approach. PFS was estimated using Kaplan-Meier (M1-M3), and maximum-likelihood (M4) methods. Simulation studies were performed to understand the impact of the length of time elapsed between the last progression-free scan and the PD on time-to-progression estimates.
RESULTS:
PFS estimates using the RPD were the highest, and M2 was the most conservative. M3 and M4 were similar because the majority of progressions occurred during treatment (ie, frequent disease assessments). M3 was influenced less by the length of the assessment schedules (percentage difference from the true time-to-progression, <1.5%) compared with M1 (11% to 30%) and M2 (−8% to −29%). The overall study conclusion was unaffected by the method used for randomized trials.
CONCLUSIONS:
The magnitude of difference in the PFS estimates was large enough to alter trial conclusions in patients with advanced lung cancer. The results indicate that standards for PD determination, the use of sensitivity analyses, and randomized trials are critical when designing trials and reporting efficacy using PFS-based endpoints. Cancer 2012. © 2012 American Cancer Society.
TL;DR: A phase I trial of carboplatin (Carb) and velapirib [V], a PARP inhibitor, to define dose limiting toxicities [(DLT) during cycle (C) 1] and the maximum tolerated dose (MTD).
Abstract: 1010 Background: Platinum and PARP inhibitors have both shown activity in BRCA-associated breast cancer (BC) patients (pts). We have conducted a phase I trial of carboplatin (Carb) and velapirib [V...
TL;DR: MPM preclinical studies demonstrate activation of AKT pathway proteins, including mTOR, and provide the rationale to test everolimus, an mTOR inhibitor, in MPM.
Abstract: 7083 Background: MPM preclinical studies demonstrate activation of AKT pathway proteins, including mTOR, and provide the rationale to test everolimus, an mTOR inhibitor, in MPM. Methods: Unresectab...
TL;DR: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pEM+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165).
Abstract: 3023 Background: Trametinib, an oral MEK1/MEK2 inhibitor, has demonstrated single-agent clinical activity. In vitro studies of trametinib plus docetaxel (doc), pemetrexed (pem) and erlotinib (erl) showed enhanced growth inhibition of lung cancer cell lines with and without RAS/RAF mutations. Trametinib+doc significantly increased apoptosis compared with either agent alone. Methods: This is a two-part, five-arm, phase I/Ib, open-label study to evaluate the safety and tolerability of trametinib plus doc, erl, pem, pem+carboplatin (pem+carbo), or nab-paclitaxel (nab-pac) (NCT01192165). Part I is dose escalation in patients (pts) with advanced solid tumors; part II is dose expansion in pts with lung and pancreatic cancers. A 3+3 dose-escalation design was used to determine the maximum tolerated dose (MTD) and the recommended phase II regimen (RP2R) for each combination. Dose-limiting toxicities (DLTs) were determined during the first treatment cycle (21 days). Trametinib was started at 0.5 mg/day; chemotherap...
TL;DR: This data indicates that weekly IV T is associated with less toxicity than the daily x 5 regimen, and AVE0005 (aflibercept) (A) is a novel recombinant human fusion protein which binds to circulating VEGF, thereby inhibiting its interaction with cell surface receptors.
Abstract: 7005 Background: Topotecan (T) (oral and IV) is the only FDA-approved second-line chemotherapy for patients with SCLC. Weekly T is associated with less toxicity than the daily x 5 regimen. AVE0005 ...
TL;DR: A randomized multicenter trial comparing the response rate (RR) of V and C to the RR of C alone in patients with deleterious BRCA mutations and recurrent ovarian, or primary peritoneal, fallopian tube or high-grade serous ovarian cancer.
Abstract: 5020 Background: V+C was well tolerated in a phase I trial and responses and prolonged disease stabilization were observed in BRCA + patients (pts).To assess the relative contribution of the PARP i...
TL;DR: This retrospectively assessed objective response rate (ORR) and time to progression (TTP) in pts who received PEM prior to CRIZ in previously treated ALK+ NSCLC and ORR with CriZ post-PEM was assessed.
Abstract: 7599 Background: Retrospective small cohort studies suggest ALK+ NSCLC may be particularly sensitive to PEM. Methods: PROFILE 1005 (NCT00932451; Pfizer) is a large phase 2 multi-center, single-arm study of CRIZ in previously treated ALK+ NSCLC. Eligibility criteria included pts with progressive disease from the PEM arm of companion trial PROFILE 1007. We retrospectively assessed objective response rate (ORR) and time to progression (TTP; 1st dose to objective progression) in pts who received PEM prior to CRIZ. ORR with CRIZ post-PEM was assessed. Results: Of the 439 ALK+ pts enrolled as of June 2011, 369 (84.1%) received prior PEM (single agent or combination; any line advanced/metastatic) with a cumulative ORR of 18.7%. In pts who received PEM combinations 1st-line (1L; n=120) or 2nd-line (2L; n=60), ORR was 24.2% and 16.7%; and median TTP was 6.9 months (mo; 95% CI: 6.0–7.4) and 6.9 mo (95% CI: 4.8–8.8), respectively. In pts who received 2L single-agent PEM (n=80), ORR was 12.5% and median TTP was 5.3 m...
TL;DR: The common arm methodology provides a template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization.
Abstract: Historically, notable variability has been observed in clinical trial outcomes between different regions and populations worldwide, even when employing the same cytotoxic regimen in lung cancer These divergent results underscore the inherent challenges in interpreting trials conducted abroad and raise questions regarding the general applicability of transnational clinical trials Various reasons have been postulated to account for these differences in efficacy and toxicity, including trial design, eligibility criteria, patient demographics and, perhaps most intriguingly, population-related pharmacogenomics However, without methodology to control for such variables, these hypotheses remain largely untested The authors previously developed the 'common arm' approach in order to directly compare efficacy and toxicity results of trials simultaneously performed in different countries By standardizing clinical trial-associated variables such as treatment regimens (dose, schedule, and so on), eligibility, staging, response and toxicity criteria, this approach has the potential to determine the underlying reasons for divergences in trial outcomes across countries, and whether population-associated polymorphisms contribute to these differences In the past decade, Japanese and US investigators have applied the common arm analytic method to trials in both extensive-stage small-cell lung cancer (SCLC) and advanced nonSCLC In the SCLC analysis, a comparison of the cisplatin/irinotecan arms from both trials revealed significant differences in response rates and overall survival Significant differences were also observed in the distribution of gender and performance status The common arm analysis in nonSCLC included two trials from Japan and one from the USA, each containing a 'common' carboplatin/paclitaxel arm Clinical results were similar in the two Japanese trials, but were significantly different from the US trial with regard to survival, neutropenia, febrile neutropenia and anemia The underlying basis for these divergent outcomes is discussed The common arm methodology provides a template for identifying and interpreting patient outcome differences across populations, and is an instructive lesson in the burgeoning era of clinical trials globalization
TL;DR: A pilot trial was conducted to determine if bevacizumab could be incorporated in chemotherapy regimens for advanced NSCLC patients.
Abstract: 7018 Background: Bevacizumab combined with chemotherapy has improved survival in the treatment of advanced NSCLC. This pilot trial was conducted to determine if bevacizumab could be incorporated in...
TL;DR: The detection of EML4-ALK fusion transcripts in the RGI database is updated to reflect a 4.0% frequency and there are 152 NSCLC cases with E ML4-alk fusion positivity.
Abstract: 7594 Background: The ALK inhibitor crizotinib offers a new standard of care for advanced NSCLC patients with EML4-ALK fusion oncogenes. We previously reported a 4.0% frequency of EML4-ALK fusion on...
TL;DR: Despite recent changes to lung adenoCa pathologic classification, adv stage BAC remains a definable and clinically applicable entity, according to the World Health Organization.
Abstract: 7517 Background: Despite recent changes to lung adenoCa pathologic classification, adv stage BAC remains a definable and clinically applicable entity. Patients (pts) with BAC, as well as never-smok...
TL;DR: Intra-patient dose escalation and/or re-escalation of sorafenib were not feasible in pretreated solid tumor patients and the multi-targeted kinase inhibitor remains an investigational approach.
Abstract: Purpose To determine if intra-patient dose escalation of the multi-targeted kinase inhibitor sorafenib is feasible in patients with advanced pretreated solid malignancies. Methods An intra-patient dose escalation scheme starting at 400 mg BID was employed in this prospective trial. Doses were escalated to 600 mg BID for the second cycle and to 800 mg BID for the third cycle in the absence of grade 3+ adverse events. In the event of grade 3+ adverse events during cycle 1, doses were reduced to 400 mg daily through cycle 2. Dose re-escalation for cycle 3 was allowed in the absence of grade 3+ adverse events during cycle 2. Further dose escalation was prohibited. The primary endpoint was the overall percentage of patients tolerating dose escalation to 600 mg BID through cycle 2 or tolerating re-escalation to 400 mg BID through cycle 3. Results Fifty eligible patients with various solid tumors and a median of 3 prior therapies were enrolled. Eleven patients (22%) tolerated primary dose escalation or re-escalation. Only 14 patients (28%) completed cycle 1 without dose modification or discontinuing treatment. Seven of 13 patients tolerated primary dose escalation through cycle 2. Four of 5 patients tolerated dose re-escalation through cycle 3. Reasons for escalation failure included tumor progression (42%) and adverse events (26%). Common grade 3+ adverse events included hand-foot skin reaction, hypertension, and hypophosphatemia. Conclusions Intra-patient dose escalation and/or re-escalation of sorafenib were not feasible in pretreated solid tumor patients. Sorafenib dose escalation remains an investigational approach.
TL;DR: A phase I study to determine maximum tolerated dose (MTD) and pharmacokinetics (PK) of D in patients (pts) with liver dysfunction (LD) and to collect data for NCI ODWG Organ Dysfunction Working GroupCriteria.
Abstract: 3078 Background: Dasatinib (D) is a first in class Src kinase inhibitor, and inhibits BCR-Abl, c-Kit, PDGFR-beta, EPHA2 and Src family kinases including Src, Lck, Yes, Fyn at nanomolar concentrations. Initially FDA approved for use in imatinib resistant CML. It is a small molecule targeted therapy hepatically metabolized primarily by CYP3A4. We conducted a phase I study to determine maximum tolerated dose (MTD) and pharmacokinetics (PK) of D in patients (pts) with liver dysfunction (LD). Methods: Pts with advanced solid tumors or lymphoma, Zubrod ≤2, no baseline ascites or pleural effusions, adequate renal and bone marrow function, received PO D daily. Cycles q28 days. Pts stratified into 4 LD groups: normal, mild, moderate, severe, using Child-Pugh classification (CPC). Data also collected for NCI ODWG Organ Dysfunction Working GroupCriteria. D dose was escalated in sequential cohorts of pts within each LD category. Blood analysis for D concentrations were determined during cycle 1 using a validated LC-M...
TL;DR: This phase II study randomly selects pts with squamous NSCLC to receive either placebo or onartuzumab as maintenance therapy until disease progression, unacceptable toxicity, or death, and aims to achieve 55 pts with Met-positive squamousNSCLC.
TL;DR: Acute changes in exhaled NO and CO concentrations following SABR were found to predict development of RP, a promising method for identifying individuals at highest risk for developing RP.
Abstract: Purpose/Objective(s): Radiation pneumonitis (RP) is the most common toxicity following stereotactic ablative radiation therapy (SABR) for lung tumors, but methods to predict which patients will develop this side effect remain lacking. We performed a prospective clinical trial to assess the feasibility and potential of measuring levels of exhaled nitric oxide (NO), carbon monoxide (CO), nitrous oxide (N2O), and carbon dioxide (CO2) as predicative biomarkers of RP in patients receiving SABR to the lung. Materials/Methods: Twenty patients with lung tumors receiving SABR were enrolled in this pilot study. Exhaled concentrations of NO, CO, N2O, and CO2 were simultaneously measured with a real time laser based instrument immediately prior to and following each fraction. Patients were followed for development of symptomatic RP (Grade 2 or higher, CTCAE v4.0). RP incidence was evaluated for correlation with acute changes in exhaled gas concentrations, baseline concentrations, and dosimetric and demographic factors. Results: Five of twenty patients developed RP at an average of 5.4 months following SABR. Average acute changes in NO were 4.10 6.66% (mean standard error) for symptomatic and 33.5 9.31% for asymptomatic patients. Average acute changes in CO were -0.77% 1.53% for symptomatic and -7.32% 1.81% for asymptomatic patients. Average acute change in NO 12.5% and CO -5.5% correlated with RP incidence (p Z 0.036 and p Z 0.035, respectively). Bivariate analysis showed acute change in NO 12.5% combined with acute change in CO -5.5% strongly correlated with RP incidence (p Z 0.003). Baseline NO 24 parts per billion also correlated with RP incidence (p Z 0.036). N2O and CO2 concentrations were not predicative of symptomatic RP. Dosimetric parameters did not predict for the development of RP. Conclusions: Acute changes in exhaled NO and CO concentrations following SABR were found to predict development of RP. Evaluating changes in exhaled NO and CO concentrations immediately following radiation therapy represents a promising method for identifying individuals at highest risk for developing RP. Author Disclosure: J.M. More: None. N.C. Eclov: None. M. Chung: None. J.H. Shorter: A. Employee; JHS is affiliated with Aerodyne Research Inc., which designed the breath analysis instrument used in this study. R. Burmeister: Q. Leadership; RB is affiliated with Kos Systems, which seeks to develop applications for breath analysis. P. Banos: Q. Leadership; PB is affiliated with Kos Systems, which seeks to develop applications for breath analysis. P. Maxim: None. B.W. Loo: None. M. Diehn: None.
TL;DR: This proposal will attempt to demonstrate optimization of therapy in good performance EGFR mutation negative elderly patients by taking in to consideration the histology of the tumor, the ERCC1 (marker of platinum resistance), RRM1 (for gemcitabine resistance) and TS (for pemetrexed resistance) status.
Abstract: TPS7619 Background: Personalizing therapy based on an individual patient’s molecular profile is a potentially promising approach to optimize efficacy with the available agents. Optimizing efficacy ...