NCI Study Research Articles

In silico analyses of solvent effects, toxicity, NBO, homo-lumo and hole-electron transfer of 7-hydroxy-2-nitrofluoranthene

7-Hydroxy-2-nitrofluoranthene (7H2NF) is a fused polynuclear aromatic molecule. A naphthalene molecule is fused with a benzene ring through a five-membered ring. Since it is aromatic, it has conjugated double bonds. In this molecule, an electron-donor and an electron-acceptor are placed in different corners. Hence, electrons can flow from electron-donor to acceptor through π-linkers. DFT/B3LYP/6-311 G method is adopted to perform the calculations. The electronic structure, Frontier energy gap, Mulliken charge analysis, stability, theoretical IR, and UV are investigated with the help of Gaussian 16W software. The NCI study reveals that it has steric and Van der Waals forces. The shaded surface with a projection of LOL indicates that it has electron depleted areas. The hole-electron transfer analysis suggests that it has a CT type excitation at the S6 level. Multiwfn 3.8 is used for these investigations. Toxicity is predicted. Solvent effects are calculated for FMO, MEP, etc.

Theoretical structural analysis (FT-IR, FT-R), solvent effect on electronic parameters NLO, FMO, NBO, MEP, UV (IEFPCM model), Fukui function evaluation with pharmacological analysis on methyl nicotinate

Theoretical investigation on FT-IR and FT-Raman has been done using vibrational spectroscopy with DFT method along with 6-311++G(d,p) as a basis level. The elemental modes of oscillations were allocated and analyzed theoretically. In gas and solvents water, DMSO, ethanol and methanol, NLO prospects were calculated, orbital HOMO-LUMO analysis, MEP studies were performed by DFT method, IEFPCM model. With the help of TD-SCF method, IEFPCM model, UV–Vis spectra have been explored. To understand electron delocalization due to hyper conjugation has been performed by the method NBO. Reactive sites were identified using Fukui functions. Pauli exchange repulsion effect was used to analyze ELF and LOL studies using multiwave function. NCI study was carried out to find bonding and anti-bonding interaction. Mechanism SwissADME was applied to get drug likeness properties.

NCI Study of the Influence of Steric Hindrance on the Conformational Isomers of Propane, Butane, and Ethane Derivatives

AbstractThe role of the steric clash in the rotational energy barrier in CX3CX3 (X=H, CH3, F), propane, and butane compounds was studied using the NCI method and QTAIM approach. We found that the values of the repulsive density integral of NCI agrees with the traditional chemical steric model, as it increases with the size of the substituent. However, not in every case studied here, was the steric clash identified as the origin of the energy barrier. In the ethane case we note the absence of repulsive and attractive NCI across the full spectrum of the dihedral angles studied, whereas only in the propane and butane cases are the results consistent with the classical picture of the steric clash being the origin of the energy barrier. The energy profile for 2,2,3,3‐tetramethylbutane shows two energy barriers of 8.7 kcal/mol and 0.96 kcal/mol, their origin was analysed in terms of the alkyl‐alkyl interactions.

Insights into the origin of selectivity for [2+2] cycloaddition step reaction involved in the mechanism of enantioselective reduction of ketones with borane catalyzed by a B-methoxy oxazaborolidine catalyst derived from (–)-β-pinene: an HMDFT and combined topological ELF, NCI and QTAIM study

Insights into the origin of selectivity for [2+2] cycloaddition step reaction involved in the mechanism of enantioselective reduction of ketones with borane catalyzed by a B-methoxy oxazaborolidine catalyst derived from (–)-β-pinene: an HMDFT and combined topological ELF, NCI and QTAIM study

Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

Risk-Adapted Therapy in Adults with Burkitt Lymphoma: Results of NCI 9177, a Multicenter Prospective Phase II Study of DA-EPOCH-R

Structure and Dynamics in Amino Acid Choline-Based Ionic Liquids: A Combined QTAIM, NCI, DFT, and Molecular Dynamics Study.

Amino acid choline-based ionic liquids (AACBILs) have high biodegradability, low toxicity, availability, low cost, and high thermal stability compared to the traditional ionic liquids (ILs). In this work, the volumetric, structural, and dynamical properties of three AACBILs, that is, choline alanine ([CH][Ala]), choline β-alanine ([CH][β-Ala]), and choline phenylalanine ([CH][Phe]) were investigated using the quantum mechanical calculations and also molecular dynamics simulations in both gas and liquid phases. The density functional theory calculations, noncovalent interactions, and also the quantum theory of atoms in molecules methods have been used to investigate the hydrogen bonds, interaction energies, and also charge transfers between the ions of the studied ILs. Density, isobaric expansion coefficient, mean square displacement (MSD), self-diffusivity, viscosity, electrical conductivity, and transference numbers have been computed for the studied AACBILs in different temperatures and at 0.1 MPa. There is a satisfactory agreement between the calculated data with the corresponding experimental values where they were available. Structural properties including radial distribution functions and spatial distribution functions of cations and anions were investigated. The results showed that because of the presence of an amine group away from the carboxylate group and also the absence of the planar phenyl group in the anion, the interactions between ionic pairs in [CH][β-Ala] are stronger than interactions between ions in [CH][Ala] and [CH][Phe]. The results showed that the order of diffusions and electrical conductivities is [CH][Ala] > [CH][β-Ala] > [CH][Phe], which can be interpreted by different electrostatic, van der Waals, and hydrogen interactions in these ILs. Our study provides considerable molecular insight into the structural features and dynamics of these biodegradable ILs.

Revisiting electronic nature and geometric parameters of cyclophanes and their relation with stability – DFT, QTAIM and NCI study

Abstract Cyclophanes have several geometric restrictions in their structures due to formation of a closed circuit involving benzenoid rings and aliphatic bridges which cause instability. We have chosen a wider variety of ciclophanes for the ωB97XD analysis of geometry and thermodynamic data. More detailed geometric parameters have been used in this work such as the deviation from planarity equations and benzenoid CC bond RMSD. Seventy percent of cyclophanes’ stability is derived from benzenoid geometric parameters. Other twenty percent of cyclophanes’ stability is related to one alkyl bridge geometric parameter and two electronic parameters (global aromaticity according to FLU or D2BIA and number of intramolecular interactions according to QTAIM). In addition, no linear relation between aromaticity and the geometrical parameters was obtained and then aromaticity in cyclophanes cannot be simply evaluated from their benzenoid geometric parameters. Aromaticity of cyclophanes was analyzed locally and globally for each cyclophane using FLU, HOMA, ELF, NICS and D2BIA aromaticity indexes while intramolecular interactions were analyzed by means of QTAIM and NCI.

Unravelling the nature of binding of cubane and substituted cubanes within cucurbiturils: A DFT and NCI study

The nature of interactions between the neutral, charged and substituted cubane, within cucurbituril host were analyzed employing the dispersion corrected density functional theory. The structural comparison between the inclusion complexes of CB7 and CB8 shows a best fit for the CB7. The computed Gibbs free energy for the formation of inclusion complexes by the neutral guests were close to the experimental estimate. The dicationic guest within CB has the highest strain energy with least strain on the host. The conceptual DFT based analysis ECT analysis shows a charge transfer from the host to guest in neutral systems, while for the dicationic guest an electron transfer from guest to host has been noticed, which was further conformed from the quantitative MESP values. The computed NICS values on the cubane, are not affected by the introduction of charge/substituents implying that cubane part act as a spacer group while the functional groups present on the cubane dictates the charge transfer. In AIM analysis, the ρ value is least for the complex cubane@CB7 and highest for the cubane functionalized dicationic complex@CB complexes. The NCI-RDG analysis for the inclusion complex with dicarboxylic guest, the spike at higher density region undergoes a shift, reflecting the increase in repulsive energy. In the inclusion complexes of CB7 the patch escalation in the NCI isosurface occurs evenly in CB7 than on the CB8 inclusion complexes, signifying the fit-induced extra stability of the CB7 inclusion complexes. EDA analysis shows that the Pauli repulsive energy increase with the increase in the size of the guest molecule and among the guest the dicationic has the highest repulsive energy. The presence of higher amount of electrostatic interactions in the dicationic complex has remunerated the dispersion contribution in the dicationic complexes.

Abstract CT135: Updated phase I results from ZUMA-1: a phase I-II multicenter study evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in subjects with refractory aggressive non-Hodgkin lymphoma (NHL)

Abstract Introduction: Anti-CD19 CAR T cells with CD3 zeta and CD28 signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies at the NCI (Kochenderfer, JCO 2014). KTE-C19 utilizes the same CAR construct as investigated in the NCI study in a 6-8 day manufacturing process (Better, ASCO 2014). Updated results from the phase 1 portion of ZUMA-1 are presented here. Methods: Subjects received KTE-C19 at a target dose of 2 × 10⁁6 anti-CD19 CAR T cells/kg after a fixed dose conditioning chemo regimen of cyclophosphamide and fludarabine. The primary objective of phase 1 was to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Key secondary objectives were ORR, duration of response, and biomarkers. Key inclusion criteria were ? 18 years old, ECOG 0-1, and chemo-refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ? 12 months after ASCT. Results: As of 20 Nov 2015, 7 subjects were dosed. All subjects were evaluable for safety and 6 were evaluable for efficacy with a median follow up time of 13 weeks post KTE-C19 infusion. 1 subject experienced a DLT of grade (gr) 4 encephalopathy and gr 4 cytokine release syndrome (CRS) and died due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. CRS and neurotoxicity were managed with supportive care, α-IL6R and steroids. 5 of 7 (71%) subjects responded including 4 CRs (57%). CAR T cells peaked within 2 weeks and were detectable 1-3+ months post infusion. Conclusions: The KTE-C19 regimen evaluated was safe for further study. The predominant toxicities include CRS and neurotoxicity which are generally reversible. CRs and PRs have been observed in subjects with refractory disease. The potentially pivotal phase 2 portion of the study is ongoing (NCT02348216). SubjectSex/Age/ECOGDisease TypeTreatment HistoryGr 3 or Higher KTE-C19-Related Adverse EventsBest Response1M/59/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 encephalopathy (resolved)Partial Response (PR)3M/69/1DLBCLRefractory to 2nd line chemotherapyGr 3 tremor (resolved)Complete Remission* (CR)Gr 3 delirium (resolved)Gr 3 agitation (resolved)Gr 3 restlessness (resolved)Gr 3 somnolence (resolved)4M/69/0DLBCLRefractory to 4th line chemotherapyGr 3 encephalopathy (resolved)Stable DiseaseGr 3 hypophosphataemia (resolved)5M/67/1DLBCLRelapse ≤ 12 mo after ASCTNoneComplete RemissionOngoing 3 mo+6F/34/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 hypoxia (resolved)Complete RemissionOngoing 3 mo+7M/40/0DLBCLRelapse ≤ 12 mo after ASCTNoneComplete RemissionOngoing 3 mo+8F/29/1DLBCLRefractory to 1st, 2nd, 3rd line chemotherapyGr 4 CRSNEGr 4 encephalopathy This study is supported in part by funding from The Leukemia & Lymphoma Society (LLS) Therapy Acceleration Program® Citation Format: Armin Ghobadi, Frederick L. Locke, Sattva S. Neelapu, Tanya Siddiqi, Julio C. Chavez, Chitra M. Hosing, Nancy L. Bartlett, Lihua E. Budde, Adrian Bot, John M. Rossi, Marika Sherman, Lynn Navale, Meg Elias, Jeff Wiezorek, William Y. Go. Updated phase I results from ZUMA-1: a phase I-II multicenter study evaluating the safety and efficacy of KTE-C19 (anti-CD19 CAR T cells) in subjects with refractory aggressive non-Hodgkin lymphoma (NHL). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT135.

745. Updated Phase 1 Results from ZUMA-1: A Phase 1-2 Multi-Center Study Evaluating the Safety and Efficacy of KTE-C19 (Anti-CD19 CAR T Cells) in Subjects with Refractory Aggressive Non-Hodgkin Lymphoma (NHL)

Introduction: Anti-CD19 CAR T cells with CD3-zeta and CD28 signaling domains showed durable remissions in subjects with relapsed/refractory advanced B cell malignancies at the NCI (Kochenderfer et al. Blood 2012, JCO 2014, ASH 2014). KTE-C19 utilizes the same anti-CD19 CAR construct as investigated in the NCI study in a 6-8 day manufacturing process (Better et al. ASCO 2014). ZUMA-1 is a phase 1-2 multicenter, open-label study evaluating the safety and efficacy of KTE-C19 in subjects with refractory aggressive B-cell NHL. Methods: Subjects received KTE-C19 at a target dose of 2 × 106 (minimum 1 × 106) anti-CD19 CAR T cells/kg after a fixed dose conditioning chemotherapy regimen of cyclophosphamide 500 mg/m2/day and fludarabine 30 mg/m2/day for 3 days. The primary objective of phase 1 was to evaluate the safety of KTE-C19 as determined by the incidence of dose-limiting toxicities (DLT). Key secondary objectives were overall response rate, duration of response, levels of CAR T cells in the blood, and levels of serum cytokines. Key inclusion criteria were ≥ 18 years old, ECOG 0-1, and chemotherapy-refractory disease defined as progressive disease or stable disease as best response to last line of therapy, or disease progression ≤ 12 months after autologous stem cell transplant (ASCT). Results: As of 20 Nov 2015, 7 subjects were dosed in the phase 1 portion of the study. All subjects were evaluable for safety and 6 were evaluable for efficacy with a median follow up time of 13 weeks post KTE-C19 infusion. One subject experienced a DLT of grade (gr) 4 encephalopathy and gr 4 cytokine release syndrome (CRS) and died due to an intracranial hemorrhage deemed unrelated to KTE-C19 per the investigator. Key safety and efficacy findings are summarized in the table. CRS and neurotoxicity were managed with supportive care, tocilizumab and systemic steroids. 5 of 7 subjects (71%) had an objective response including 4 complete remissions (57%). Three subjects have ongoing complete remission at 3 months. CAR T cells peaked within two weeks post infusion were detectable 1-3+ months post infusion. Updated clinical and biomarker results will be presented. Conclusions: The KTE-C19 regimen evaluated was safe for further study. The predominant toxicities include CRS and neurotoxicity which are generally reversible. Complete and partial responses have been observed in subjects with refractory disease. KTE-C19 can be centrally manufactured and administered in a multicenter trial. The potentially pivotal phase 2 portion of the study is ongoing. Clinical trial: NCT02348216.SubjectSex/Age/ECOGDisease TypeTreatment HistoryGr 3 or Higher KTE-C19-Related Adverse EventsBest Response1M/59/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 encephalopathy (resolved)Partial Response2M/69/1DLBCLRefractory to 2nd line or later line chemotherapyGr 3 tremor (resolved) Gr 3 delirium (resolved) Gr 3 agitation (resolved) Gr 3 restlessness (resolved) Gr 3 somnolence (resolved)Complete Remission**3M/69/0DLBCLRefractory to 2nd line or later line chemotherapyGr 3 encephalopathy (resolved)Stable Disease4M/67/1DLBCLRelapse ≤ 12 mo after ASCTNoneComplete Remission Ongoing 3 mo+5F/34/0DLBCLRelapse ≤ 12 mo after ASCTGr 3 hypoxia (resolved)Complete Remission Ongoing 3 mo+6M/40/0DLBCLRelapse ≤ 12 mo after ASCTNoneComplete Remission Ongoing 3 mo+7F/29/1DLBCLRefractory to 2nd line or later line chemotherapyGr 4 CRS Gr 4 encephalopathyNE View Table in HTML mo – months, M – male, F – female, NE – not evaluable,*relapsed and retreated with an ongoing PR

An updated re-analysis of the mortality risk from nasopharyngeal cancer in the National Cancer Institute formaldehyde worker cohort study.

BackgroundTo determine whether the National Cancer Institute’s (NCI) suggestion of a persistent increased mortality risk for nasopharyngeal cancer (NPC) in relation to formaldehyde (FA) exposure is robust with respect to alternative methods of data analysis.MethodsNCI provided the cohort data updated through 2004. We computed U.S. and local county rate-based standardized mortality ratios (SMRs) and internal cohort rate-based relative risks (RR) in relation to four formaldehyde exposure metrics (highest peak, average intensity, cumulative, and duration of exposure), using both NCI categories and alternative categorizations. We modeled the plant group-related interaction structure using continuous and categorical forms of each FA exposure metric and evaluated the impact of NCI’s decision to exclude non-exposed workers from the baseline category.ResultsOverall, our results corroborate the findings of our earlier reanalyses of data from the 1994 NCI cohort update. Six of 11 NPC deaths observed in the NCI study occurred in Plant 1, two (including the only additional NPC death) occurred in Plant 3 among workers in the lowest exposure category of highest peak, average intensity and cumulative FA exposure and in the second exposure category of duration of exposure, and the remaining cases occurred individually in three of eight remaining plants. A large, statistically significant, local rate-based NPC SMR of 7.34 (95 % CI = 2.69–15.97) among FA-exposed workers in Plant 1 contrasted with an 18 % deficit in NPC deaths (SMR = 0.82, 95 % CI = .17–2.41) among exposed workers in Plants 2–10. Overall, the new NCI findings led to: (1) reduced SMRs and RRs in the remaining nine study plants in unaffected exposure categories, (2) attenuated exposure-response relations for FA and NPC for all the FA metrics considered and (3) strengthened and expanded evidence that the earlier NCI internal analyses were non-robust and mis-specified as they did not account for a statistically significant interaction structure between plant group (Plant 1 vs. Plants 2–10) and FA exposure.ConclusionsOur updated reanalysis provided little or no evidence to support NCI’s suggestion of a persistent association between FA exposure and mortality from NPC. NCI’s suggestion continues to be driven heavily by anomalous findings in one study plant (Plant 1).Electronic supplementary materialThe online version of this article (doi:10.1186/s12995-016-0097-6) contains supplementary material, which is available to authorized users.

Abstract 4631: Pharmacokinetics and in vivo metabolism of Z-endoxifen: Results from two phase I studies in women with ER+ breast cancer, gynecologic malignancies and desmoids

Abstract Background: Breast cancer recurrence has been shown to differ based upon CYP2D6 genotype and endoxifen (Endx) exposure following treatment with tamoxifen (TAM) in the adjuvant setting. The average Endx Css is 29 nM (range, 2-80 nM) in TAM treated patients at a dose of 20 mg/day. Administration of Endx itself to patients is predicted to provide adequate, consistent, active drug levels in all treated patients, resulting in clinical benefit. As part of two phase 1 trials of oral Endx to determine the safety, tolerability, and MTD, we characterized the pharmacokinetics and in vivo metabolism of Endx. Methods: Patients were given escalating daily oral doses of Endx (28 day cycle) over the dose range of 20 - 160 mg/day in Phase I trials at the Mayo Clinic and NCI. Pharmacokinetics sampling was performed on days 1, 7, 14 and 28, and prior to subsequent cycles. Endx plasma concentrations and metabolite profiles were determined by HPLC and LC/MS/MS. Results: 44 patients with ECOG PS 0-1 have been enrolled to date encompassing 8 dose levels in the Mayo (25 women with AI refractory MBC; median age 58 yrs, range 41-83 yrs) and NCI (19 women with ovary (9), breast (4), desmoid (2), fallopian tube (2), endometrial cancer (2); median age 64 yrs, range 43-75 yrs) studies. Day 1 Endx peak concentrations (Cmax) were reached 4h after the Endx oral dose and mean values of Cmax, C24h, and AUC0-24h increased in proportion to dose. Css was achieved on day 7 and 3.5-fold accumulation (t1/2= 50.5 h) was observed on day 28. At the starting dose ( 20 mg/day) and highest dose level (160 mg/day), Endx Css values of 146 ng/ml (390 nM) and 1950 ng/ml (5200 nM), respectively, were achieved and maintained throughout the 28-day treatment. Endx Css values remained unchanged following continuous dosing for 8-10 months. The mean apparent steady-state clearance was 6.2 L/h. We also characterized the Endx metabolite profile in patient plasma and urine. Metabolites detected in plasma include nor-Endx, N-hydroxy-Endx, Endx-catechol, methoxy-Endx catechol, and Endx-glucuronide, and appear in amounts much lower compared to Endx. Like the parent drug, metabolites accumulated in plasma over the 28-day cycle. Characterization of the pharmacokinetics of Nor-Endx, a putative aromatase inhibitor, is ongoing and will be presented. Conclusion: In these ongoing Phase I studies, daily administration of Endx is well tolerated with Css consistently above those obtained following administration of standard dose tamoxifen. In the Mayo study, expansion at 20 and 100 mg/day has commenced to perform translational studies and further characterize Endx PK. In the NCI study, dose escalation continues to establish the maximum tolerated dose. Supported in part by R01CA 133049, U01 CA69912, P30CA 15083, P50CA 116201 and NCI Contracts CM52206 and HHSN261201100014C. Citation Format: Joel M. Reid, Matthew P. Goetz, Shivaani Kumar, Renee M. McGovern, Sarah A. Buhrow, Stephanie L. Safgren, Vera J. Suman, Travis J. Docktor, Charles Erlichman, Howard Streicher, James H. Doroshow, Jerry Collins, Matthew M. Ames. Pharmacokinetics and in vivo metabolism of Z-endoxifen: Results from two phase I studies in women with ER+ breast cancer, gynecologic malignancies and desmoids. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4631. doi:10.1158/1538-7445.AM2014-4631

Hyperglycemia, hypertriglyceridemia, and hypercholesterolemia in a phase I trial of the combination of an mTOR inhibitor and IGF-1 receptor inhibitor.

2597 Background: Cixutumumab (a fully humanized IgG1 monoclonal antibody directed at IGF-1R) and the mammalian target of rapamycin (mTOR) inhibitor (temsirolimus) were combined in a multicenter phase I study supported in part by 5UO1CA062461-14[RK], 5U01CA062487-17 [PL] and 1R21CA13763301A1 [AN]. Objectives of the NCI study #8109 were to evaluate toxicities and define the MTD of this combination aimed at enhancing anticancer activity via modulation of resistance to mTOR inhibition. The most common adverse events were metabolic in nature, including hyperglycemia, hypercholesterolemia, and hypertriglyceridemia. Methods: This “3+3” phase I trial used a fixed temsirolimus dose of 25 mg IV weekly with escalating doses of cixutumumab to 3, 4 or 6 mg/kg IV weekly. By design, no patients with diabetes or hyperlipidemia at baseline were entered until the expansion cohort. All patients who developed hyperlipidemia or hyperglycemia were monitored or treated by specialists according to a specific treatment algorithm. Results: Of the 32 patients (pts) analyzed, hyperglycemia was seen in 17 (53%) (grade 1-2: 14 [44%], grade 3: 3 [9%]). The average blood sugar across cohorts was 113 mg/dL. No patient developed diabetic ketoacidosis or nonketotic hyperosmolar coma during treatment. Patients were treated primarily with oral hypoglycemic agents (3), insulin (2), combination (2) or lifestyle only (3). Hypertriglyceridemia occurred in 18 pts (56%) (grade 1-2: 17 [53%], grade 4:1 [3%]) and hypercholesterolemia in 18 (56%) pts (grade 1-2). They were treated with triglyceride lowering agents such as fenofibrate or omega 3 fatty acids (12), statins (11), or a combination (3) or lifestyle only (2). No patient developed pancreatitis. Conclusions: The combination of cixutumumab and temsirolimus was well tolerated with adverse metabolic events of hyperglycemia and hyperlipidemia. With appropriate oversight and treatment, these adverse events were treatable and major complications were avoided. No significant financial relationships to disclose.

Systematic Assessment of Potential Cardiac Effects of the Novel Histone Deacetylase (HDAC) Inhibitor Romidepsin.

Abstract 3709Poster Board III-645 BackgroundRomidepsin is an anti-neoplastic agent that has been identified as a novel pan-HDAC inhibitor with single-agent activity in cutaneous T-cell lymphoma (CTCL) in 2 studies (GPI-04-0001 and NCI 1312). In the GPI study the overall response rate (ORR) was 34% including 6 complete clinical responses (CCRs) in 96 pts with CTCL and the median duration of response (DOR) was 14.9 months (mo). In the NCI study, the ORR was 35% including 4 CCR in 71 pts and the median DOR was 11 mo. NCI 1312 has also reported single-agent activity in patients with peripheral T-cell lymphoma with an ORR of 31% including 4 CRs in the 48 pts analyzed. HDAC inhibitors have variably been reported to have cardiovascular effects, in particular, QTc prolongation. To systemically and rigorously evaluate the potential cardiac effects of romidepsin, a cardiac safety monitoring plan was developed after discussions with the FDA Division of Oncology Drug Products. Subsequently, a romidepsin QTc Clinical/Statisitcal Analysis Plan was developed following the ICH E14 Guidelines, to provide a comprehensive evaluation of the cardiac effects of romidepsin. MethodsAn analysis of romidepsin cardiac safety, including review and analysis of ECG findings, was performed. The primary objective of these analyses was to evaluate the effect of romidepsin on the change from baseline on the corrected QT interval of the ECG using the Fridericia QT correction method (QTcF) during Cycle 1 Day 1 exposure to study drug. A total of 4909 ECGs from 110 patients in 3 clinical studies, GPI study, NCI study, and Study GPI-06-0005 (a Phase 1 PK study) were evaluated. The 110 patients comprised 103 patients with T-cell lymphoma and 7 patients with advanced cancer treated with romidepsin at 14 mg/m2 as a 4-hour infusion on Days 1, 8, and 15 of a 28-day cycle. Using a nonlinear mixed effects model the pharmacodynamics of romidepsin was characterized for exposure-QTc effects. ResultsIn an analysis of ECG data, a mean increase of 5.0 msec (90% CI upper bound 7.7 msec) in QTcF interval was measured following infusion of romidepsin; this value includes a contribution to QTc prolongation by pre-dose antiemetics. Data from the NCI study showed that the QTcF change persisted to 24 hours, with a return to baseline by 48 hours, whereas in the smaller GPI-06-0005 study, QTcF peaked 2 hours post infusion and there was no QTcF effect seen at 24 hours. Categorical analyses showed no patients with a change from baseline >60 msec or an absolute QTcF >480 msec. No cardiac events of Torsade de Pointes were reported. Per the ICH E14 guidance,56 a threshold for regulatory concern for mean QTc prolongation is 5 msec with an upper bound of the 95% CI of 10 msec. Prolongations of >60 msec over baseline or a value >500 msec are also considered cautionary. Treatment-emergent morphological changes on ECG (minor ST-segment depression, T-wave flattening, biphasic T-waves, and T-wave inversion) have been observed during treatment with romidepsin; however the overall frequency of these minor, asymptomatic changes was similar to the frequency of pre-exposure abnormalities on each dosing day, suggesting a high degree of background noise in these data. Furthermore, there was no association between these ECG findings and any clinical, functional, or laboratory findings of cardiac abnormalities.Categorical Analysis of QTc Change on Cycle 1, Day 1CategoryStudyGPI Study N=87 n (%)NCI Study N=41 n (%)GPI-06-0005 N=7 n (%)Total N=135 n (%)QTcF change from baseline1No increase31 (36)10 (24)2 (29)43 (32)1-29 msec increase46 (53)27 (66)4 (57)77 (57)30-60 msec increase2 (2)4 (10)1 (14)7 (5)>60 msec increase0000QTcF not available8 (9)008 (6)QTcF absolute value:>450 msec2 (2)2 (5)04 (3)>480 msec0000>500 msec00001For GPI studies, baseline values are those post co-med, or if missing post co-med, then pre-comed baseline is used. ConclusionsThe findings from the romidepsin studies show that the observed QTc changes were below the threshold levels of concern outlined in ICH E14. Pharmacodynamic modeling showed no evidence of a relationship between the plasma concentration of romidepsin and changes in the QTc interval. Since hypokalemia and hypomagnesemia are associated with ECG abnormalities, supplementation with potassium and magnesium to achieve normal levels prior to romidepsin administration is recommended. Disclosures:Cabell:Gloucester Pharmaceuticals: Consultancy. Whittaker:Gloucester Pharmaceuticals: Research Funding. Nichols:Gloucester Pharmaceuticals: Employment, Equity Ownership. Nix:Gloucester Pharmaceuticals: Employment. Burris:Gloucester Pharmaceutcals: Research Funding.

Phase II study of intraperitoneal recombinant interleukin-12 (rhIL-12) in patients with peritoneal carcinomatosis (residual disease < 1 cm) associated with ovarian cancer or primary peritoneal carcinoma

BackgroundPharmacokinetic advantages of intraperitoneal (IP) rhIL-12, tumor response to IP delivery of other cytokines as well as its potential anti-angiogenic effect provided the rationale for further evaluation of IPrhIL-12 in patients with persistent ovarian or peritoneal carcinoma.MethodsA phase 2 multi-institutional trial (NCI Study #2251) of IP rIL-12 (300 nanogram/Kg weekly) was conducted in patients with ovarian carcinoma or primary peritoneal carcinoma.Patients treated with primary therapy for ovarian cancer who had no extraabdominal/parenchymal disease or bulky peritoneal disease were eligible. Four to 8 weeks from last chemotherapy, eligible patients underwent a laparotomy/laparoscopy. Patients with residual disease ≤ 1 cm were registered for the treatment phase 2–5 weeks post surgery. The effect of IP rIL-12 on the expression of TNFα , INFα , IL-10, IP-10, IL-8, FGF, VEGF was also studied.ResultsThirty-four patients were registered for the first screening phase of the study. Median age was 56.6 years (range: 31–71); 12 completed the second phase and were evaluable for response/toxicity. Performance scores of IL-12 treated patients were 0 (11 pts) and 1 (1 pt). There were no treatment related deaths, peritonitis or significant catheter related complications. Toxicities included grade 4 neutropenia (1), grade 3 fatigue (4), headache (2), myalgia (2), non-neutropenic fever (1), drug fever (1), back pain (1), and dizziness (1). The best response observed was SD. Two patients had SD and 9 had PD, and 1 was evaluable for toxicity only.Peritoneal fluid cytokine measurements demonstrated a ≥ 3 fold relative increase post-rhIL-12: IFN-γ, 5/5 pts; TNF-α , 1/5; IL-10, 4/5; IL-8, 5/5; and VEGF, 3/5. IP10 levels were increased in 5/5 patients. Cytokine response profiles suggest either NK or T-cell mediated effects of IP rhIL-12. Cytokine/chemokine results also suggest a pleiotropic response since proteins with potential for either anti-tumor (IFN-γ , IP-10) or pro-tumor growth effects (VEGF, IL-8) were detected.ConclusionIP IL-12 can safely be administered at this dose and schedule to patients after first line chemotherapy for ovarian/peritoneal carcinoma. The maximum response was stable disease. Future IP therapies with rhIL-12 will require better understanding and control of pleiotropic effects of IL-12.

Whole Prostate to 75.6 With Concurrent IMRT Boost to 95 Gray for Biopsy Proven, MRI Defined Dominant Intraprostatic Lesions: Early Results of a Phase I NCI Study

Whole Prostate to 75.6 With Concurrent IMRT Boost to 95 Gray for Biopsy Proven, MRI Defined Dominant Intraprostatic Lesions: Early Results of a Phase I NCI Study

Work in the metal industry and nasopharyngeal cancer mortality among formaldehyde-exposed workers

Objective To investigate further the possibility that the large nasopharyngeal cancer (NPC) mortality excess among a cohort of formaldehyde-exposed workers may be related to occupational factors external to the study plant. Methods Subjects were 7345 workers employed at a plastics-producing plant (1941–1984) in Wallingford, Connecticut evaluated independently as part of a National Cancer Institute cohort study. Vital status for 98% of the cohort and cause of death for 95% of 2872 deaths were determined through 2003. Reconstructed worker exposures to formaldehyde were used to compute unlagged and lagged exposure measures. We computed standardized mortality ratios (SMRs) based on US and local county rates. In a nested case–control study we evaluated mortality risks from NPC and from all other pharyngeal cancers combined (AOPC) in relation to formaldehyde exposure while accounting for potential confounding or effect modification by smoking or external (non-Wallingford) employment. Job applications, Connecticut commercial city directories and a previous survey were used to assign subjects to three external job groups. Results We observed no new deaths from NPC and one additional AOPC death (pharynx unspecified) yielding, respectively, SMRs of 4.43 (7 deaths, 95% CI = 1.78–9.13) and 1.71 (16 deaths, 95% CI = 1.01–2.72). Five of seven NPC cases worked in silver smithing (including brass plating and other jobs related to silver or brass) or other metal work (including steel working and welding), and this type of work was relatively rare in the remaining study population (OR = 14.41, 95% CI = 1.08–82.1). For AOPC, we found a moderate increase in risk for other metal work (OR = 1.40, 95% CI = .31–5.1). Interaction models suggested that NPC and AOPC risks were not elevated in subjects exposed only to formaldehyde. Conclusions The results of our nested case–control study suggest that the large nasopharyngeal cancer mortality excess in the Wallingford cohort may not be due to formaldehyde exposure, but rather reflects the influence of external employment in the ferrous and non-ferrous metal industries of the local area that entailed possible exposures to several suspected risk factors for upper respiratory system cancer (e.g., sulfuric acid mists, mineral acid, metal dusts and heat). Our findings may also help to explain why the associations with formaldehyde and nasopharyngeal cancer reported in the 1994 update of the 10-plant NCI formaldehyde cohort study were unique to the Wallingford plant (Plant 1 in NCI study). Further updates of the NCI formaldehyde cohort study should include co-exposure data on silver smithing and other metal work for all study plants to help explain the unique findings for nasopharyngeal cancer in Plant 1 compared with the other nine plants.

Carcinogenicity and Chronic Toxicity in Rats and Mice Exposed by Inhalation to 1,2‐Dichloroethane for Two Years

Carcinogenicity and chronic toxicity of 1,2-dichloroethane (DCE) were examined by inhalation exposure of groups of 50 F344 rats and 50 BDF1 mice of both sexes to DCE vapor or clean air as control for 6 h/d, 5 d/wk and 104 wk. The rats were exposed to 10, 40 or 160 ppm (v/v) DCE, while the mice were exposed to 10, 30 or 90 ppm. The 2-yr exposure to DCE produced a dose-dependent increase in incidences of benign and malignant tumors, including subcutaneous fibroma, mammary gland fibroadenoma and peritoneal mesothelioma in male rats; subcutaneous fibroma and mammary gland adenoma, fibroadenoma and adenocarcinoma in female rats; and bronchiolo-alveolar adenoma and carcinoma, endometrial stromal polyp, mammary gland adenocarcinoma and hepatocellular adenoma in female mice. No exposure-related change in the incidence of non-neoplastic lesions or in any hematological, blood biochemical or urinary parameter occurred in any DCE-exposed rat or mouse group. The types of tumors and their target organs found in this study were consistent with those observed in rats and mice administered DCE by gavage in a NCI study. Selection of the exposure concentrations was considered appropriate with reference to the maximum tolerated dose for the highest doses and an occupational exposure limit of DCE for the lowest dose. The present findings suggest that those carcinogenic responses be primarily considered for standard setting of occupational and environmental exposure to DCE.

A phase 2 trial of all‐trans‐retinoic acid in combination with interferon‐α2a in children with recurrent neuroblastoma or Wilms tumor: A Pediatric Oncology Branch, NCI and Children's Oncology Group Study

The combination of the antiproliferative and differentiation-inducing effects of retinoids together with the antiproliferative, immunostimulatory, and differentiation-potentiating effects of interferon-alpha (IFN-alpha) were the basis for the development of this combination in pediatric patients with refractory neuroblastoma or Wilms tumor. A phase 2 trial of all-trans-retinoic acid (ATRA), administered orally at a dose of 90 mg/m(2)/day in three divided doses for 3 consecutive days per week, and IFN-alpha2a, administered subcutaneously daily at a dose of 3 x 10(6) U/m(2)/day for 5 consecutive days per week, in 4 week cycles was performed. A two-stage design was used for each disease stratum. Seventeen patients (16 evaluable) with neuroblastoma, median age 9 years, and 15 patients (14 evaluable) with Wilms tumor, median age 6 years, were enrolled. Overall, the combination was well tolerated, with headache being the most common toxicity observed. There were no complete or partial responses. The median number of cycles administered was 1 (range 1-9). Four patients with neuroblastoma had stable disease for 12 or more weeks. The combination of ATRA and IFN-alpha2a was inactive in children with relapsed or refractory neuroblastoma and Wilms tumor. The lack of activity with this combination in children with refractory neuroblastoma is similar to the disappointing phase 2 results of single agent 13-cis-retinoic-acid (13cRA) and does not support further development of ATRA for children with relapsed neuroblastoma.

Reevaluation of mortality risks from nasopharyngeal cancer in the formaldehyde cohort study of the National Cancer Institute

Objective To determine whether the National Cancer Institute’s (NCI) recent suggestion of a causal association between formaldehyde exposure and mortality from nasopharyngeal cancer (NPC) is robust with respect to alternative methods of data analysis and alternative categorizations of formaldehyde exposure. Methods The original authors provided the cohort data. We computed U.S. and local county (regional) rate-based standardized mortality ratios (SMRs) and internal cohort rate-based relative risks (RR) by categories of four formaldehyde exposure metrics (highest peak, average intensity, cumulative, and duration of exposure), using both NCI categories and an alternative categorization based on tertiles of all NPC deaths among exposed subjects. We computed SMRs and RRs for each of 10 study plants and by plant group (Plant 1 (n = 4261) vs. Plants 2–10 ( n = 21,358)). Results Six of 10 NPC deaths observed in the NCI study occurred in only one plant (Plant 1) and the remaining four cases occurred individually in four of the other nine plants studied. A large, statistically significant, regional rate-based NPC SMR of 10.32 (95% CI = 3.79–22.47) among formaldehyde-exposed workers in Plant 1 contrasted sharply with a 35% deficit in NPC deaths (SMR = .65, 95% CI = .08–2.33) among exposed workers in Plants 2–10 combined. The statistically significant exposure–response relationship with formaldehyde and NPC reported in the NCI study for highest peak exposure was driven entirely by a large, statistically significant excess NPC risk in Plant 1 for the highest peak exposure category (4+ ppm). For the remaining nine plants, RRs for all non-baseline highest peak exposure categories were less than 1.0, and we observed no evidence of an exposure–response relationship. Most of the observed NPC excesses for the non-baseline categories of the other exposure metrics (average intensity, cumulative, and duration of formaldehyde exposure) were concentrated in Plant 1, and by contrast to the NCI findings, none of the corresponding exposure–response relationships was statistically significant. Conclusions Overall, our reanalysis provided little evidence to support NCI’s suggestion of a causal association between formaldehyde exposure and mortality from NPC. NCI’s conclusion of a possible causal association was driven heavily by anomalous findings in one study plant (Plant 1). An independent and larger study of Plant 1 by the current authors concluded the NPC excess was not associated with formaldehyde exposure. Our findings cast considerable additional uncertainty regarding the validity of NCI’s suggested causal association.