Narayana Narasimhan - Academia.edu (original) (raw)

Papers by Narayana Narasimhan

Blood, Nov 13, 2019

Background Duvelisib, an oral dual PI3K-δ and PI3K-γ inhibitor, is approved by the US Food and Dr... more Background Duvelisib, an oral dual PI3K-δ and PI3K-γ inhibitor, is approved by the US Food and Drug Administration for the treatment of adult patients with relapsed or refractory (R/R) follicular lymphoma (FL) after ≥ 2 prior systemic therapies. In multiple phase 1-3 studies that included patients with iNHL, duvelisib was shown to be efficacious, with a favorable risk-benefit profile. This study will evaluate whether duvelisib efficacy at the approved 25 mg twice daily (BID) dose can be achieved and maintained with an acceptable or improved safety profile by the inclusion of prespecified 2-week drug holidays in patients with R/R iNHL. Study Design and Methods TEMPO is a randomized, open-label, multicenter, international, phase 2 study of duvelisib in adult patients with R/R iNHL in whom ≥ 1 line of prior therapy has failed. The primary objective is to evaluate the efficacy of duvelisib administered with prescribed drug holidays, with the primary endpoint of overall response rate (ORR) by the 2007 revised International Working Group criteria. Key secondary endpoints include ORR by the 2014 Lugano criteria, progression-free survival, overall survival, time to treatment failure, duration of response, lymph node response rate, time to the first response, adverse event profile, and determination of pharmacokinetics parameters. Exploratory objectives include assessment of quality of life and biomarkers of treatment response and toxicity. Key inclusion criteria include histologically confirmed FL grades 1 to 3a, marginal zone lymphoma (splenic, nodal, or extranodal) or small lymphocytic lymphoma, radiological evidence of disease progression and ≥ 1 bidimensionally measurable lesion ≥ 1.5 cm, adequate organ function, and Eastern Cooperative Oncology Group performance status ≤ 2. Key exclusion criteria include prior allogeneic hematopoietic stem cell transplant; previous treatment with a PI3K inhibitor; history of drug-induced colitis or drug-induced pneumonitis; ongoing treatment for systemic infection; central nervous system NHL; prolonged QT interval; history of tuberculosis treatment within the 2 past years; history of stroke, unstable angina, myocardial infarction, or ventricular arrhythmia requiring medication or mechanical control within the past 6 months; history of or concurrent interstitial lung disease of any severity and/or severely impaired lung function; ongoing treatment with chronic immunosuppressants; and any unstable or severe uncontrolled medical condition. A total of 102 patients are planned to be enrolled. Patients will be randomized 1:1 to 2 arms and stratified by number of prior therapies (1 or > 1), bulky disease status (longest diameter of baseline lesion < 5 cm or ≥ 5 cm), and time since last recurrence (≥ 24 months or < 24 months). In arm 1, patients will receive duvelisib 25 mg BID for one 10-week (W) cycle followed by 25 mg BID on W3 and W4 of each subsequent 4-week cycle. In arm 2, patients will receive duvelisib 25 mg BID on W1, W2, W5, W6, W9, and W10 of one 10-week cycle and then on W3 and W4 of each subsequent 4-week cycle. Patients will be treated until disease progression, unacceptable toxicity, or withdrawal. This study will test the null hypothesis that the ORR in each arm is ≤ 30% against the alternative that the ORR is ≥ 55%. The study has a 2-stage design. In stage 1, 15 patients will be enrolled in each arm, with response assessment after ≥ 3 cycles. If there are fewer than 6 partial or complete responses, consideration may be given to terminating the arm. Otherwise, in stage 2, 36 additional patients will be enrolled, for a total of 51 per arm. Enrollment is planned to be initiated in August 2019. Approximately 50 sites will be open for enrollment across the United States, Europe, and Asia. Disclosures Karmali: Takeda, BMS: Other: Research Funding to Institution; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Astrazeneca: Speakers Bureau. Youssoufian:Verastem Oncology: Consultancy, Equity Ownership. Sprott:SMOC Therapeutics: Employment, Equity Ownership; Verastem Oncology: Employment, Equity Ownership. Weaver:FemtoDx: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Inventor; Verastem Oncology: Employment, Equity Ownership, Patents & Royalties: Inventor; Hillstream Biopharma: Consultancy, Equity Ownership. Narasimhan:Verastem: Employment, Equity Ownership. Lustgarten:Verastem: Employment. Patrick:Verastem Oncology: Employment. Zalutskaya:Verastem Inc: Employment, Equity Ownership. Gordon:Gilead: Other: Advisory Board; Juno/Celgene: Other: Advisory Board, Research Funding; Zylem LLC: Other: co-founder; research in nanoparticles in cancer; Bayer: Other: Advisory Board. OffLabel Disclosure: Duvelisib (DUV), a dual PI3K-delta,gamma inhibitor, is US FDA approved at 25 mg twice daily (BID) for the treatment of R/R chronic lymphocytic leukemia or small lymphocytic lymphoma after at…

Lancet Oncology, Dec 1, 2016

Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung... more Anaplastic lymphoma kinase (ALK) gene rearrangements are oncogenic drivers of non-small-cell lung cancer (NSCLC). Brigatinib (AP26113) is an investigational ALK inhibitor with potent preclinical activity against ALK mutants resistant to crizotinib and other ALK inhibitors. We aimed to assess brigatinib in patients with advanced malignancies, particularly ALK-rearranged NSCLC. In this ongoing, single-arm, open-label, phase 1/2 trial, we recruited patients from nine academic hospitals or cancer centres in the USA and Spain. Eligible patients were at least 18 years of age and had advanced malignancies, including ALK-rearranged NSCLC, and disease that was refractory to available therapies or for which no curative treatments existed. In the initial dose-escalation phase 1 stage of the trial, patients received oral brigatinib at total daily doses of 30-300 mg (according to a standard 3 + 3 design). The phase 1 primary endpoint was establishment of the recommended phase 2 dose. In the phase 2 expansion stage, we assessed three oral once-daily regimens: 90 mg, 180 mg, and 180 mg with a 7 day lead-in at 90 mg; one patient received 90 mg twice daily. We enrolled patients in phase 2 into five cohorts: ALK inhibitor-naive ALK-rearranged NSCLC (cohort 1), crizotinib-treated ALK-rearranged NSCLC (cohort 2), EGFR(T790M)-positive NSCLC and resistance to one previous EGFR tyrosine kinase inhibitor (cohort 3), other cancers with abnormalities in brigatinib targets (cohort 4), and crizotinib-naive or crizotinib-treated ALK-rearranged NSCLC with active, measurable, intracranial CNS metastases (cohort 5). The phase 2 primary endpoint was the proportion of patients with an objective response. Safety and activity of brigatinib were analysed in all patients in both phases of the trial who had received at least one dose of treatment. This trial is registered with ClinicalTrials.gov, number NCT01449461. Between Sept 20, 2011, and July 8, 2014, we enrolled 137 patients (79 [58%] with ALK-rearranged NSCLC), all of whom were treated. Dose-limiting toxicities observed during dose escalation included grade 3 increased alanine aminotransferase (240 mg daily) and grade 4 dyspnoea (300 mg daily). We initially chose a dose of 180 mg once daily as the recommended phase 2 dose; however, we also assessed two additional regimens (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg) in the phase 2 stage. four (100% [95% CI 40-100]) of four patients in cohort 1 had an objective response, 31 (74% [58-86]) of 42 did in cohort 2, none (of one) did in cohort 3, three (17% [4-41]) of 18 did in cohort 4, and five (83% [36-100]) of six did in cohort 5. 51 (72% [60-82]) of 71 patients with ALK-rearranged NSCLC with previous crizotinib treatment had an objective response (44 [62% (50-73)] had a confirmed objective response). All eight crizotinib-naive patients with ALK-rearranged NSCLC had a confirmed objective response (100% [63-100]). Three (50% [95% CI 12-88]) of six patients in cohort 5 had an intracranial response. The most common grade 3-4 treatment-emergent adverse events across all doses were increased lipase concentration (12 [9%] of 137), dyspnoea (eight [6%]), and hypertension (seven [5%]). Serious treatment-emergent adverse events (excluding neoplasm progression) reported in at least 5% of all patients were dyspnoea (ten [7%]), pneumonia (nine [7%]), and hypoxia (seven [5%]). 16 (12%) patients died during treatment or within 31 days of the last dose of brigatinib, including eight patients who died from neoplasm progression. Brigatinib shows promising clinical activity and has an acceptable safety profile in patients with crizotinib-treated and crizotinib-naive ALK-rearranged NSCLC. These results support its further development as a potential new treatment option for patients with advanced ALK-rearranged NSCLC. A randomised phase 2 trial in patients with crizotinib-resistant ALK-rearranged NSCLC is prospectively assessing the safety and efficacy of two regimens assessed in the phase 2 portion of this trial (90 mg once daily and 180 mg once daily with a 7 day lead-in at 90 mg). ARIAD Pharmaceuticals.

Cancer Research, Jun 15, 2022

Introduction: EGFR activating mutations are observed in 10-50% of NSCLC patients and the common m... more Introduction: EGFR activating mutations are observed in 10-50% of NSCLC patients and the common mutations (L858R [L] and exon 19 deletions [D]) are initially sensitive to first-, second-, and third-generation EGFR inhibitors (eg erlotinib [1G], afatinib [2G], and osimertinib [3G], respectively). However, on-target resistance is observed in a substantial percentage of patients, with T790M (T) and C797S (C) observed most frequently (post-1G/2G and post-3G, respectively). We set out to identify a next-generation inhibitor with 1) potent activity against all 8 major single (L and D), double (LT, DT, LC, DC), and triple (LTC, DTC) mutant variants, 2) selectivity over wild type (WT) EGFR, and 3) ability to penetrate the central nervous system (CNS). Experimental Procedures: Drug activity was determined by assessing effects in kinase assays and on tumor and BaF3 cell lines expressing WT or mutant forms of EGFR. For efficacy studies, mice were dosed orally once daily at doses that did not exceed the maximum tolerated dose. Results: Here we report the identification of a series of compounds with potent and selective in vitro and in vivo activity against all major classes of EGFR activating and resistance mutations and with selectivity over WT EGFR. A representative member from this series (Cmpd A) potently inhibits the kinase activity of EGFR L, LT, and LTC variants with IC50s ≤0.2 nM, compared to IC50s for osimertinib of 0.4, 0.2, and 360 nM respectively. In engineered BaF3 cells, Cmpd A inhibited viability of all 8 EGFR single, double, and triple mutant variants with IC50s <7 nM, while erlotinib was inactive against LT, DT, LTC, and DTC, and osimertinib was inactive against LC, DC, LTC, and DTC. Cmpd A inhibited the activity of all 8 variants with 7- to 46-fold selectivity over WT EGFR, which compared favorably to the 7- to 10-fold selectivity erlotinib exhibited for L and D. In vivo, Cmpd A (30 mg/kg QD) induced tumor regression, or inhibited tumor growth by at least 90%, in models containing EGFR single (L), double (LT), and triple (LTC and DTC) mutant variants. Studies to examine the CNS penetration of compounds are underway. Conclusions: We have identified a series of next-generation EGFR inhibitors with potent in vitro and in vivo activity against single, double, and triple mutant EGFR variants including T790M and C797S. Citation Format: Wei-Sheng Huang, Sara Nadworny, Narayana Narasimhan, Charles J. Eyermann, David C. Dalgarno, Victor M. Rivera, William C. Shakespeare. Discovery of potent and selective next-generation EGFR inhibitors with activity against single, double, and triple mutant EGFR variants including T790M and C797S [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3342.

Clinical Drug Investigation, Aug 22, 2014

Background In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase ... more Background In vitro studies have demonstrated that the aqueous solubility of the tyrosine kinase inhibitor ponatinib decreases as pH increases. Objectives The primary aim of this study was to assess the effects of the gastric proton pump inhibitor lansoprazole on the pharmacokinetics of ponatinib. The single-dose safety profile of ponatinib with and without coadministration of lansoprazole was also characterized. Methods This was a phase I, open-label, non-randomized, two-period crossover study in 20 healthy subjects aged 18-55 years. Subjects received a single oral dose of ponatinib 45 mg alone on day 1, an oral dose of lansoprazole 60 mg on day 14, and ponatinib 45 mg plus lansoprazole 60 mg on day 15. Results Lansoprazole coadministration resulted in a 1-h increase in the time to maximum plasma concentration (t max) of ponatinib (6 vs. 5 h post-dose; P \ 0.001). A corresponding 25 % decrease in the geometric mean maximum plasma concentration (C max) of ponatinib was observed for ponatinib ? lansoprazole versus ponatinib alone (40.67 vs. 53.96 ng/mL). Importantly, lansoprazole did not decrease the overall ponatinib systemic exposure as assessed by the ponatinib area under the plasma concentration-time curve from time zero to infinity (AUC ? 1,153 ngÁh/mL for lansoprazole ? ponatinib vs. 1,222 ngÁh/mL for ponatinib alone). The safety profile was considered acceptable when ponatinib was administered alone or with lansoprazole. Conclusions Although coadministration of lansoprazole led to a modest, albeit statistically significant, reduction in ponatinib C max , overall systemic exposure to ponatinib did not change. The findings suggest that no dose adjustment is necessary when ponatinib is administered with drugs that increase gastric pH.

Investigational New Drugs, Apr 13, 2023

Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-pos... more Brigatinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for the treatment of ALK-positive non-small cell lung cancer. This open-label, parallel-group study investigated the effect of chronic hepatic impairment on the pharmacokinetics (PK) of brigatinib to inform dosing recommendations for these patients. Participants with hepatic impairment classified according to Child-Pugh categories of mild (A), moderate (B), or severe (C) and matched-healthy participants with normal hepatic function received a single oral dose of 90-mg brigatinib. Plasma samples were collected for the determination of brigatinib plasma protein binding and estimation of plasma PK parameters. Twenty-seven participants were enrolled (Child-Pugh A-C, n = 6 each; matched-healthy participants, n = 9). The mean fraction of free plasma brigatinib was comparable for the Child-Pugh A (11.1%), Child-Pugh B (10.8%), and healthy participant groups (8.5%); free brigatinib was higher in the Child-Pugh C group (23.1%). There were no clinically meaningful effects of mild or moderate hepatic impairment on unbound systemic exposures (area under the plasma concentration-time curve [AUC]) of brigatinib (geometric least-squares mean ratios [90% CI] of 89.32% [69.79%-114.31%] and 99.55% [77.78%-127.41%], respectively). In the severe hepatic impairment group, brigatinib unbound AUC was approximately 37% higher (geometric least-squares mean ratio [90% CI] of 137.41% [107.37%-175.86%]) compared with healthy participants with normal hepatic function. Brigatinib was well tolerated in healthy participants and in participants with hepatic impairment. No dose adjustment is required for patients with mild or moderate hepatic impairment. The brigatinib dose should be reduced by approximately 40% for patients with severe hepatic impairment.

The Journal of Clinical Pharmacology, Dec 16, 2021

The BCR‐ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leu... more The BCR‐ABL1 inhibitor ponatinib is approved for the treatment of adults with chronic myeloid leukemia or Philadelphia chromosome–positive acute lymphoblastic leukemia, including those with the T315I mutation. We report a population pharmacokinetic model‐based analysis for ponatinib and its application to inform dose selection for pediatric development. Plasma concentration–time data were collected from 260 participants (86 healthy volunteers; 174 patients with hematologic malignancies) enrolled across 7 clinical trials. Data were analyzed using nonlinear mixed‐effects modeling. Ponatinib pharmacokinetics were described by a 2‐compartment model with first‐order elimination from the central compartment. The final model included body weight and age as covariates on the apparent central volume of distribution; however, exposure variability explained by these covariates was small compared with overall variability in the population. None of the covariates evaluated, including sex, age (19‐85 years), race, body weight (40.7‐152.0 kg), total bilirubin (0.1‐3.16 mg/dL), alanine aminotransferase (6‐188 U/L), albumin (23.0‐52.5 g/L), and creatinine clearance (≥28 mL/min) had clinically meaningful effects on apparent oral clearance. Simulations based on the final model predicted that daily doses of 15 to 45 mg result in steady‐state average concentrations that are in the pharmacological range for BCR‐ABL1 inhibition and approximate or exceed concentrations associated with suppression of T315I mutant clones. The final model was adapted using allometric scaling to inform dose selection for pediatric development. Clinicaltrials.gov identifier: NCT00660920; NCT01667133; NCT01650805

Cancer Research, Aug 1, 2015

Phosphorus, despite its abundance in the human body, is rarely found in drug molecules, with clin... more Phosphorus, despite its abundance in the human body, is rarely found in drug molecules, with clinical utility limited to a few phosphonic or bisphosponic acid-based medicines and several phosphonate or phosphate-containing prodrugs. Concerns about poor cell penetration, low oral bioavailability, or biological instability have limited application of these functional classes in drug design. In our efforts to discover pharmaceuticals with novel functionality, we introduced a neutral, stable phosphine oxide moiety as a unique hydrogen-bond acceptor in the design of anaplastic lymphoma kinase (ALK) inhibitors. ALK is a receptor tyrosine kinase first identified as a chromosomal rearrangement (NPM-ALK fusion gene) in anaplastic large cell lymphoma (ALCL) and subsequently detected as an alternate fusion oncogene (EML4-ALK) in a subset of non-small cell lung cancers (NSCLC). Crizotinib, the first approved ALK inhibitor, has demonstrated impressive clinical benefit in EML4-ALK (ALK+) NSCLC patients. Drug resistance, however, emerges rapidly and point mutations within the kinase domain have been identified as a major resistance mechanism. With the specific objective to identify more potent ALK inhibitors with pan-inhibitory activity against crizotinib-resistant ALK mutants, we designed and tested a series of phosphine oxide-based compounds culminating in the identification of the clinical candidate AP26113. AP26113 exhibited 10-fold greater potency than crizotinib against ALK-positive ALCL and NSCLC cell lines, and effectively inhibited clinically relevant crizotinib-resistant mutants. AP26113 displayed ∼100-fold increased selectivity for ALK-positive cells over ALK-negative cell lines while maintaining selectivity over insulin receptor tyrosine kinase receptors. Consistent with the in vitro profile, AP26113 demonstrated oral efficacy in multiple ALK+ mouse models including Karpas-299 (ALCL), H3122 (NSCLC), and Ba/F3 cells expressing crizotinib resistant mutants including G1269S and L1196M. Finally, AP26113 exhibited excellent drug-like properties including high cell permeability and solubility, moderate cross-species protein binding, and inactivity toward major cytochrome P450 iso-enzymes and hERG ion channels. Medicinal chemistry efforts leading to the discovery of this potent pan-ALK inhibitor, including design strategy, chemical series evolution, and DMPK optimization will be presented. AP26113 is currently in a global phase 2 registration trial (NCT02094573) in patients with locally advanced or metastatic NSCLC who test positive for the ALK oncogene and were previously treated with crizotinib. Citation Format: Wei-Sheng Huang, Feng Li, Lisi Cai, Yongjin Xu, Sen Zhang, Scott D. Wardwell, Yaoyu Ning, Anna Kohlmann, Tianjun Zhou, Emily Y. Ye, Xiaotian Zhu, Narayana I. Narasimhan, Tim Clackson, Victor M. Rivera, David Dalgarno, William C. Shakespeare. Discovery of AP26113, a potent, orally active inhibitor of anaplastic lymphoma kinase and clinically relevant mutants. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2827. doi:10.1158/1538-7445.AM2015-2827

Clinical pharmacology in drug development, May 1, 2015

Ponatinib, an oral tyrosine kinase inhibitor with significant activity in heavily pretreated pati... more Ponatinib, an oral tyrosine kinase inhibitor with significant activity in heavily pretreated patients with chronic myeloid leukemia, is a CYP3A4 substrate. This open‐label, nonrandomized, fixed‐order crossover study evaluated the effect of multiple oral doses of rifampin, a strong CYP3A4 inducer, on the pharmacokinetics of ponatinib (45 mg, single dose). Twenty healthy adults received ponatinib on day 1, rifampin 600 mg alone on days 8–13, 15, and 16, and rifampin 600 mg with ponatinib on day 14. Rifampin decreased maximum plasma concentration (Cmax) and area under the plasma concentration‐time curve (AUC) from time zero to time of last measurable concentration (AUC0‐t) and from time zero to infinity (AUC0‐∞) of ponatinib by 42%, 59%, and 63%, respectively, with no effect on time to Cmax. The limits of the 90% confidence intervals of the estimated geometric mean ratios of ponatinib Cmax, AUC0‐t, and AUC0‐∞ did not fall within the 80–125% margins for equivalence, suggesting a statistically significant interaction. Coadministration of ponatinib with strong CYP3A4 inducers should be avoided unless the benefit outweighs the possible risk of ponatinib underexposure, because the safety of ponatinib dose increases has not been studied in this context.

$Research paper thumbnail of A Phase 1 Trial of Oral AP24534 in Patients with Refractory Chronic Myeloid Leukemia and Other Hematologic Malignancies: First Results of Safety and Clinical Activity against T315I and Resistant Mutations$

Blood, Nov 20, 2009

Abstract 643 AP24534 is an orally available multiple tyrosine kinase inhibitor (TKI) designed usi... more Abstract 643 AP24534 is an orally available multiple tyrosine kinase inhibitor (TKI) designed using a structure-based approach as a pan-BCR-ABL inhibitor. AP24534 potently inhibits the enzymatic activity of BCR-ABL-T315I, the native enzyme and all other tested variants. It also inhibits survival of cell lines expressing these BCR-ABL variants with IC50s of < 40 nM, and inhibits Flt3 and c-Src. We report here preliminary results from our ongoing phase 1 clinical trial. The objectives of this study are to assess the safety of AP24534, establish a maximum tolerated dose and schedule for further investigation, and provide preliminary assessments of clinical activity. The trial employs an open-label dose escalation design. Patients (pts) with hematologic malignancies refractory to treatment, ECOG status ≤ 2, adequate hepatic and renal function, and normal cardiac function are eligible and receive a single daily oral dose of AP24534. Thirty-two pts (16 males) have been enrolled, median age 63 years (range 31-79). Diagnoses include 27 CML (19 chronic [CP], 4 accelerated [AP], 4 blast phase [BP]), 1 Ph+ ALL, 2 myelofibrosis, 1 myeloma, 1 MDS. BCR-ABL mutation status in 28 Ph+ pts included 5 pts with no mutation, 12 T315I (8 at entry, 4 by history), 3 F317L, (2 at entry, 1 by history), 2 M351T, and 1 each L273M/F359V, G250E, E279K, F359C, L387F and E453K. Prior therapies in CML pts included imatinib (100% of pts), dasatinib (94%), nilotinib (53%), interferon (47%), chemotherapy (41%), and investigational (65%); 83% were resistant to 3 or more TKIs. Pts have been treated at the following dose levels: 2 mg (3 pts), 4 mg (6 pts), 8 mg (7 pts), 15 mg (8 pts), 30 mg (7 pts), and 60 mg (1 pt). 21 pts remain on study. Of 23 pts in the 4 highest (8-60 mg) dosing cohorts, 19 remain on study. Median time on study drug is currently 3.4 months (range 5 days to 10 months). At the time of this report, preliminary safety and efficacy data are available for 31 patients. No DLTs have been observed. The most common drug-related adverse events (AE) were nausea (15%), fatigue and dry eye (12% each), anorexia, arthralgia, dizziness, dry mouth, headache, hot flush, myalgia, vomiting (8% each), and QTc prolongation (1 pt in 2 mg, 1 pt in 4 mg cohort). Grade 3 or 4 thrombocytopenia occurred in 36% pts (18% entered with thrombocytopenia), and grade 3 or 4 neutropenia in 41% (18% entered with neutropenia). Both types of hematologic toxicity were more frequent in pts with advanced stages of CML or baseline cytopenia. Pharmacokinetic data demonstrate that the half life of the drug is 19-45 hours. The relationship of Cmax to dose is linear over the dosing range. The Cmax on day 1 at the 30 mg dose is approximately 55 nM. After one 28-day cycle, the AUC is 2.5- to 3-fold higher than single dose AUC. PD data demonstrate inhibition of CrkL phosphorylation at doses of 8 mg and higher. Overall best hematologic response was complete hematologic response (CHR) in 16 of 18 CP pts (88%), 5 of whom had CHR on entry, major hematologic response (MHR) in 2 of 4 AP pts, and no response in 4 BP and 1 ALL pts. Cytogenetic responses were 4 complete cytogenetic responses (CCyR) and 2 PCyR. Of the 12 patients with T315I mutations, 9 remain on study without progression. Best hematologic response in the T315I subset was CHR in 5 of 6 CP pts (83%), 2 of whom had CHR on entry, MHR in 2 of 2 AP pts, resolution of extramedullary symptoms in 1 BP pt, and no response in 2 BP and 1 ALL pts. Nine of 12 T315I pts are evaluable for CyR: 2 (1 CP, 1 AP) achieved CCyR after 2 and 5 months (at 4 mg and 15 mg), and 1 CP achieved PCyR after 3 months at 15 mg. Of 3 pts with dasatinib resistant F317L, 1 discontinued for an unrelated AE (CNS ischemia), and 2 remain on study in CP at 8 and 15 mg. One pt with nilotinib resistant F359C remains on study with CHR, CCyR, and major molecular response after 4 months at 15 mg. Conclusions: No DLTs have been observed at doses up to 30 mg AP24534. PK and PD demonstrate that blood levels at 30 mg exceed those needed for in vitro inhibition of resistant mutant BCR-ABL isoforms, including T315I. Preliminary analysis reveals evidence of clinical antitumor activity in patients with resistance to approved second-line TKIs dasatinib and nilotinib, including pts with the T315I mutation of BCR-ABL. Disclosures: Cortes: ARIAD: Research Funding. Deininger:Novartis : Consultancy; BMS : Consultancy; Celgene: Consultancy; ARIAD : Consultancy; Genzyme: Research Funding. Shah:Novartis : Consultancy; Bristol-Myers Squibb: Consultancy. Spinos:ARIAD: Employment. Hu:ARIAD: Employment. Berk:ARIAD: Employment, Equity Ownership. Narasimhan:ARIAD: Employment, Equity Ownership. Rivera:ARIAD: Employment, Equity Ownership. Clackson:ARIAD: Employment, Equity Ownership. Haluska:ARIAD: Employment, Equity Ownership.

Journal of Clinical Pharmacy and Therapeutics, Jul 25, 2013

What is known and objective: Ponatinib is a potent oral tyrosine kinase inhibitor with activity a... more What is known and objective: Ponatinib is a potent oral tyrosine kinase inhibitor with activity against BCR-ABL, the primary driver of chronic myeloid leukaemia and Philadelphia chromosome-positive acute lymphoblastic leukaemia. This single-centre, single-dose, randomized, open-label, three-period crossover study evaluated the pharmacokinetics and bioavailability of a single oral dose of ponatinib (45-mg tablet) under fasting conditions and following consumption of high-and low-fat meals by healthy subjects. Methods: Subjects were randomly assigned to one of the six possible treatment sequences, each evaluating three ponatinib 45-mg treatments: administered under fasting conditions; administered after a high-fat meal; or administered after a standardized low-fat meal. The high-fat meal derived approximately 50% of its total caloric content from fat, with approximately 150, 250 and 500-600 calories derived from protein, carbohydrates and fat, respectively (total of approximately 900-1000 calories). The standardized low-fat meal derived no more than 20% of total caloric content from fat, with approximately 56, 428 and 63 calories derived from protein, carbohydrates and fat, respectively (total of approximately 547 calories). During each of the three treatment periods, blood samples were collected predose and at 13 time points over the 96-h post-dose interval. Plasma concentrations of ponatinib were measured by liquid chromatography/tandem mass spectrometry. Mixed-model analyses of variance (ANOVA) were performed on natural log-transformed PK parameters C max and AUC 0-∞. Results and discussion: Geometric mean maximum plasma concentration (C max) values for the fasted, low-fat and highfat regimens were 54Á7, 51Á6 and 51Á5 ng/mL, respectively. Geometric mean area under the concentration-time curve from time zero to infinity (AUC 0-∞) values for the fasted, low-fat and high-fat regimens were 1273, 1244 and 1392 h 3 ng/mL, respectively. All limits of the 90% CIs of the estimated geometric mean ratios for C max and all AUC comparisons fell within the 80%-125% margins. These results indicate that consumption of a high-or low-fat meal within 30 min prior to administration of ponatinib had no effect on the single-dose pharmacokinetics of ponatinib. What is new and conclusion: Food does not affect the single-dose pharmacokinetics of ponatinib. These data demonstrate that ponatinib may be administered with or without food.

The Journal of Clinical Pharmacology, Jun 25, 2013

Molecular Cancer Therapeutics, Jun 1, 2011

Ponatinib (AP24534) is a novel multitargeted kinase inhibitor that potently inhibits native and m... more Ponatinib (AP24534) is a novel multitargeted kinase inhibitor that potently inhibits native and mutant BCR-ABL at clinically achievable drug levels. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor a (PDGFRa). Here, using leukemic cell lines containing activated forms of each of these receptors, we show that ponatinib potently inhibits receptor phosphorylation and cellular proliferation with IC 50 values comparable to those required for inhibition of BCR-ABL (0.3 to 20 nmol/L). The activity of ponatinib against the FLT3-ITD mutant, found in up to 30% of acute myeloid leukemia (AML) patients, was particularly notable. In MV4-11 (FLT3-ITD þ/þ) but not RS4;11 (FLT3-ITD À/À) AML cells, ponatinib inhibited FLT3 signaling and induced apoptosis at concentrations of less than 10 nmol/L. In an MV4-11 mouse xenograft model, once daily oral dosing of ponatinib led to a dose-dependent inhibition of signaling and tumor regression. Ponatinib inhibited viability of primary leukemic blasts from a FLT3-ITD positive AML patient (IC 50 4 nmol/L) but not those isolated from 3 patients with AML expressing native FLT3. Overall, these results support the investigation of ponatinib in patients with FLT3-ITD-driven AML and other hematologic malignancies driven by KIT, FGFR1, or PDGFRa.

The mTOR pathway is hyperactivated through oncogenic transformation in many human malignancies. R... more The mTOR pathway is hyperactivated through oncogenic transformation in many human malignancies. Ridaforolimus (AP23573; MK-8669) is a novel rapamycin analogue that selectively targets mTOR and is currently under clinical evaluation. In this study, we investigated the mechanistic basis for the antitumor activity of ridaforolimus in a range of human tumor types, exploring potential markers of response, and determining optimal dosing regimens to guide clinical studies. Administration of ridaforolimus to tumor cells in vitro elicited dose-dependent inhibition of mTOR activity with concomitant effects on cell growth and division. We showed that ridaforolimus exhibits a predominantly cytostatic mode of action, consistent with the findings for other mTOR inhibitors. Potent inhibitory effects on vascular endothelial growth factor secretion, endothelial cell growth, and glucose metabolism were also observed. Although PTEN and/or phosphorylated AKT status have been proposed as potential mTOR pathway biomarkers, neither was predictive for ridaforolimus responsiveness in the heterogeneous panel of cancer cell lines examined. In mouse models, robust antitumor activity was observed in human tumor xenografts using a series of intermittent dosing schedules, consistent with pharmacodynamic observations of mTOR pathway inhibition for at least 72 hours following dosing. Parallel skin-graft rejection studies established that intermittent dosing schedules lack the immunosuppressive effects seen with daily dosing. Overall these findings show the broad inhibitory effects of ridaforolimus on cell growth, division, metabolism, and angiogenesis, and support the use of intermittent dosing as a means to optimize antitumor activity while minimizing systemic effects.

Purpose: Non–small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically ... more Purpose: Non–small cell lung cancers (NSCLCs) harboring ALK gene rearrangements (ALK+) typically become resistant to the first-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) crizotinib through development of secondary resistance mutations in ALK or disease progression in the brain. Mutations that confer resistance to second-generation ALK TKIs ceritinib and alectinib have also been identified. Here, we report the structure and first comprehensive preclinical evaluation of the next-generation ALK TKI brigatinib.Experimental Design: A kinase screen was performed to evaluate the selectivity profile of brigatinib. The cellular and in vivo activities of ALK TKIs were compared using engineered and cancer-derived cell lines. The brigatinib–ALK co-structure was determined.Results: Brigatinib potently inhibits ALK and ROS1, with a high degree of selectivity over more than 250 kinases. Across a panel of ALK+ cell lines, brigatinib inhibited native ALK (IC50, 10 nmol/L) with 12-fold greater potency than crizotinib. Superior efficacy of brigatinib was also observed in mice with ALK+ tumors implanted subcutaneously or intracranially. Brigatinib maintained substantial activity against all 17 secondary ALK mutants tested in cellular assays and exhibited a superior inhibitory profile compared with crizotinib, ceritinib, and alectinib at clinically achievable concentrations. Brigatinib was the only TKI to maintain substantial activity against the most recalcitrant ALK resistance mutation, G1202R. The unique, potent, and pan-ALK mutant activity of brigatinib could be rationalized by structural analyses.Conclusions: Brigatinib is a highly potent and selective ALK inhibitor. These findings provide the molecular basis for the promising activity being observed in ALK+, crizotinib-resistant patients with NSCLC being treated with brigatinib in clinical trials. Clin Cancer Res; 22(22); 5527–38. ©2016 AACR.

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Members of t... more Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Background: Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib is a multi-targeted tyrosine kinase inhibitor (TKI) with potent activity against BCR-ABL being investigated in a pivotal phase 2 trial in patients with chronic myeloid leukemia (CML). Previously, ponatinib has been shown to potently inhibit FGFR1-4 kinase activity. Here the activity of ponatinib is explored against FGFR1-4 activated via multiple discrete mechanisms in a variety of cancer types in vitro and in vivo. Results: The cellular activity of ponatinib was first examined in Ba/F3 cells engineered to express activated FGFRs. Ponatinib selectively inhibited viability of cells expressing FGFR1-4, with IC50s of 8 to 34 nM, while having no effect on viability of parental Ba/F3 cells (IC50 >1000 nM). Likewise, ponatinib inhibited phosphorylation of FGFR1-4 with IC50s of 29 to 39 nM. Four other TKIs in clinical development that have been reported to have anti-FGFR activity were substantially less potent: dovitinib (IC50: 34 to 235 nM), cediranib (54 to >1000 nM), BIBF 1120 (214 to >1000 nM) and brivanib (503 to >1000 nM). Next the activity of ponatinib was examined in a panel of cell lines representing multiple tumor types and containing FGFRs dysregulated by a variety of mechanisms. Ponatinib potently inhibited growth of breast cancer cells containing amplified FGFR1 or FGFR2 (GI50: 14-69 nM) and of gastric cancer cells with amplified FGFR2 (GI50: 10-25 nM). In endometrial cancer cells with an activating mutation in the kinase domain of FGFR2 (N549K), or a mutation that increases ligand binding (S252W), ponatinib inhibited growth with GI50s of 14-61 nM. In bladder cancer cells with a mutation in FGFR3 that causes constitutive dimerization (S249C), ponatinib inhibited growth with GI50s of 103-181 nM. In all cell lines, the effects on cell growth were accompanied by inhibition of FGFR or FRS2α phosphorylation. In comparison, ponatinib was less potent in a panel of cell lines lacking expression of activated FGFRs (GI50: 372 nM to >1 uM). The 4 other TKIs examined were less active compared to ponatinib in all FGFR mutant cell lines examined. Daily oral dosing of ponatinib (30 mg/kg) to mice reduced growth of FGFR2N549K endometrial and FGFR3S249C bladder tumor xenografts by approximately 80% and induced regression of gastric tumors expressing amplified FGFR2 by 50%. In all 3 models, dose-dependent inhibition of FGFR phosphorylation in the tumor was demonstrated. Conclusion: Ponatinib exhibits potent, pan-FGFR inhibitory activity that compares favorably to dovitinib, cediranib, BIBF 1120 and brivanib. These results provide a strong rationale for clinical evaluation of ponatinib in FGFR-driven cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3560. doi:10.1158/1538-7445.AM2011-3560

Cancer Research, Apr 15, 2006

Bone metastases, frequent consequences of common malignancies such as breast, lung, and prostate ... more Bone metastases, frequent consequences of common malignancies such as breast, lung, and prostate cancer, involve complex molecular processes and are extremely difficult to treat. In the bone microenvironment, metastatic cancer cells produce osteoclast activating factors (eg, ...

Journal of Clinical Oncology, May 20, 2013

8031 Background: AP26113 is a novel tyrosine kinase inhibitor (TKI) that potently inhibits mutant... more 8031 Background: AP26113 is a novel tyrosine kinase inhibitor (TKI) that potently inhibits mutant activated forms of anaplastic lymphoma kinase (ALK+) and epidermal growth factor receptor (EGFRm), and TKI-resistant forms including L1196M (ALK) and T790M (EGFR). AP26113 does not inhibit native EGFR. Methods: The dose finding phase (3+3 design) of this phase I/II open-label, multicenter study is ongoing in pts with advanced malignancies (except leukemia) refractory to available therapies or for whom no standard treatment exists. Initial dosing is orally once daily. Results: As of 14 Jan 2013, 44 pts were enrolled: 30 mg n=3, 60 mg n=3, 90 mg n=8, 120 mg n=8, 180 mg n=11, 240 mg n=9, 300 mg n=2; 64% female, median age 60 yrs; diagnoses: non-small cell lung cancer (NSCLC, n=37), other (n=7). 26 pts discontinued: 18 disease progression, 6 adverse event (AE), 2 deaths (sudden death, hypoxia; both possibly related). Most common AEs: nausea (45%), fatigue (39%), diarrhea (27%); most common grade 3/4 treatment-related AE: diarrhea (5%). 2 dose limiting toxicities observed: grade 3 ALT increase, 240 mg; grade 4 dyspnea, 300 mg. Doses <300 mg are being explored further. 21 pts had ALK+ history (18 NSCLC, 3 other). Among 18 evaluable ALK+ pts, 10 responded. 15 ALK+ pts had 0 (n=3) or 1 (n=12) prior ALK TKI (crizotinib); of these, 2/3 and 8/12 pts (67%) responded, including 2 complete responses. The longest response is 40 wks (ongoing). 4 of 5 ALK+ pts with untreated or progressing CNS lesions at baseline and with follow-up scans had evidence of radiographic improvement in CNS, including 1 pt resistant to crizotinib and LDK378 (overall response = stable disease). 16 pts had EGFRm history (15 NSCLC, 1 SCLC); 14 pts had ≥1 prior EGFR TKI. Of 12 EGFRm pts with a follow-up scan, 1 pt (prior erlotinib) responded at 120 mg (duration 21 wks, ongoing), 6 pts had stable disease (2 ongoing, duration 7-31 wks). Conclusions: AP26113 has promising anti-tumor activity in ALK+ pts, with initial evidence of activity in EGFRm pts, and is generally well tolerated. Phase II will begin after the recommended phase II dose is determined, with 4 cohorts: crizotinib-naïve NSCLC; crizotinib-resistant NSCLC; EGFR TKI-resistant NSCLC; other tumors. NCT01449461. Clinical trial information: NCT01449461.

Clinical Pharmacokinectics, Aug 20, 2020

Background and objectives Brigatinib is an oral tyrosine kinase inhibitor approved in multiple co... more Background and objectives Brigatinib is an oral tyrosine kinase inhibitor approved in multiple countries for the treatment of patients with anaplastic lymphoma kinase-positive metastatic non-small cell lung cancer who have progressed on or are intolerant to crizotinib. We report a population pharmacokinetic model-based analysis for brigatinib. Methods Plasma concentration-time data were collected from 442 participants (105 healthy volunteers and 337 patients with cancer) who received single or multiple doses of oral brigatinib in one of five trials. Data were analyzed using non-linear mixed-effects modeling (NONMEM software version 7.3). Results Brigatinib plasma concentrations were best described by a three-compartment model with a transit compartment input (number of transit compartments = 2.35; mean transit time = 0.9 h). The final model included albumin as a covariate on apparent clearance. None of the additional covariates examined, including sex, age, race, body weight, mild or moderate renal impairment, total bilirubin, aspartate aminotransferase, and alanine aminotransferase, were found to meaningfully explain variability in apparent clearance, suggesting that no dose adjustment is required based on these covariates. Conclusions Results from these population pharmacokinetic analyses informed the prescribing guidance for patients with mild or moderate renal impairment in the US Prescribing Information and the European Summary of Product Characteristics for brigatinib.

Clinical pharmacology in drug development, Dec 20, 2018

Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated ap... more Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, received accelerated approval in the United States for the treatment of patients with metastatic ALK + non-small-cell lung cancer who have progressed on or are intolerant to crizotinib. A clinical study was conducted to assess the effect of food on brigatinib pharmacokinetics (PK). Healthy subjects received a single oral dose of brigatinib 180 mg (2 × 90-mg tablets) after a 10-hour fast or after a high-fat meal in a 2-period, 2-sequence crossover study. Plasma samples for PK characterization were collected over 168 hours postdose. Twenty-four subjects were enrolled (mean age 44 years; 58% male), with 21 included in the PK-evaluable population. Brigatinib peak concentration was reduced by 13% under fed (high-fat meal) versus fasted conditions, with no effect on area under the concentration-time curve.The median time to peak concentration of brigatinib was longer under fed conditions (5 hours) than in fasted conditions (2 hours). Treatment-emergent adverse events were similar under fasted (48%) and fed (46%) conditions and were of mild intensity. Consumption of a high-fat meal decreased the rate of brigatinib oral absorption but had no impact on the extent of absorption, thereby supporting brigatinib administration without regard to meals. These recommendations are reflected in the US prescribing information for brigatinib.