Nagdeep Giri

A phase II trial of dacomitinib, an oral pan-human EGF receptor (HER) inhibitor, as first-line treatment in recurrent and/or metastatic squamous-cell carcinoma of the head and neck

BACKGROUND An open-label, multicenter, single-arm phase II trial was conducted to investigate the clinical activity of dacomitinib in recurrent/metastatic squamous-cell carcinoma of the head and neck (RM-SCCHN). PATIENTS AND METHODS Eligible patients were administered dacomitinib at 45 mg orally daily, in 21-day cycles. Primary end point was objective response rate. RESULTS Sixty-nine patients were enrolled with a median age of 62 years. Among response-evaluable patients, 8 [12.7%, 95% confidence interval (CI) 5.6% to 23.5%] achieved a partial response and 36 (57.1%) had stable disease, lasting ≥24 weeks in 9 patients (14.3%). The median progression-free survival (PFS) was 12.1 weeks and the median overall survival (OS) was 34.6 weeks. Most adverse events (AEs) were tolerable. The most common grade 3 or higher treatment-related AEs were diarrhea (15.9%), acneiform dermatitis (8.7%), and fatigue (8.7%). Treatment-related AEs led to at least one dose interruption in 28 (40.6%) patients and dose reductions in 26 (37.7%). Permanent treatment discontinuation occurred in 8 (11.6%) patients due to treatment-related AEs. CONCLUSIONS Dacomitinib demonstrated clinical activity in RM-SCCHN, and the primary end point of this study was met. The toxicity profile of this agent was generally manageable with dose interruptions and adjustments.

A phase II study (ARCHER 1042) to evaluate prophylactic treatment of dacomitinib-induced dermatologic and gastrointestinal adverse events in advanced non-small-cell lung cancer

BACKGROUND ARCHER 1042, a randomized phase II trial, explored the impact of prophylactic treatment on select dermatologic adverse events of interest (SDAEI), diarrhea, and mucositis associated with dacomitinib, an oral irreversible pan-human epidermal growth factor receptor (HER) inhibitor, in development for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Patients with advanced NSCLC treated with dacomitinib were enrolled in two cohorts. Cohort I patients were randomized 1:1 to receive oral doxycycline or placebo (4 weeks). Cohort II patients received oral VSL#3 probiotic plus topical alclometasone. Primary end points for Cohorts I and II were incidence of all grade and grade ≥2 SDAEI in the first 8 weeks of treatment and quality of life (QoL) assessed by the Skindex-16 survey. Additional primary end points for Cohort II were incidence of all grade and grade ≥2 diarrhea and mucositis in the first 8 weeks of treatment; QoL regarding diarrhea and mucositis incidence was assessed by the modified-Oral Mucositis Daily Questionnaire. RESULTS Cohort I randomized 114 evaluable patients: 56 in the doxycycline arm, 58 in the placebo arm. Cohort II enrolled 59 evaluable patients. Doxycycline significantly reduced the incidence of grade ≥2 SDAEI by 50% (P = 0.016) compared with placebo. The incidence of all grade SDAEI was lower with doxycycline than with placebo but did not reach statistical significance. Doxycycline was associated with less deterioration in QoL compared with placebo. Alclometasone was associated with less deterioration in QoL compared with placebo but did not statistically significantly reduce the incidence of all grade or grade ≥2 SDAEI. VSL#3 did not reduce the incidence of all grade or grade ≥2 diarrhea and did not impact mucositis scores. CONCLUSIONS Doxycycline was effective as a prophylactic treatment for dacomitinib-induced grade ≥2 SDAEI. Both doxycycline and alclometasone reduced the negative impact in patient-reported dermatologic AEs. The probiotic was not effective for preventing diarrhea or mucositis.

A phase I open‐label study to investigate the potential drug–drug interaction between single‐dose dacomitinib and steady‐state paroxetine in healthy volunteers

Dacomitinib is currently in development for the treatment of non‐small cell lung cancer. Formation of the major circulating metabolite (PF‐05199265) is mediated by cytochrome P450 (CYP) 2D6 and CYP2C9. This phase I, single fixed‐sequence, two‐period study evaluated the effect of paroxetine, a CYP2D6 inactivator, on dacomitinib pharmacokinetics in healthy volunteers who were extensive CYP2D6 metabolizers. Subjects received a single 45‐mg dacomitinib dose alone and in combination with paroxetine (30 mg/day for 10 consecutive days, with dacomitinib administered on day 4) at steady‐state levels. Blood samples were collected through 240 hours post‐dacomitinib dosing. Dacomitinib exposure (area under the concentration–time curve from 0 to infinity; AUCinf) increased 37%; however a reduction in PF‐05199265 AUCinf of approximately 90% was observed during the paroxetine treatment period. The maximum concentration of dacomitinib changed minimally. Adverse events reported with single‐dose dacomitinib administered alone or in the presence of steady‐state levels of paroxetine were mostly mild, and no serious adverse events were reported. While paroxetine significantly inhibited CYP2D6‐mediated metabolism of a single dose of dacomitinib, the modest effect on dacomitinib exposure is unlikely to be clinically relevant when dacomitinib is given daily. Dose adjustment of dacomitinib may therefore not be required upon coadministration with a CYP2D6 inhibitor.

Safety and Efficacy of Dacomitinib in Korean Patients with KRAS Wild-Type Advanced Non–Small-Cell Lung Cancer Refractory to Chemotherapy and Erlotinib or Gefitinib: A Phase I/II Trial

Introduction: Dacomitinib (PF-00299804), an irreversible pan-human epidermal growth factor receptor ([HER]-1/EGFR, HER-2, and HER-4) tyrosine kinase inhibitor, demonstrated antitumor activity in Western patients with non–small-cell lung cancer (NSCLC) at a dose of 45 mg once daily. We report data from a phase I/II, multicenter, open-label study of Korean patients with refractory KRAS wild-type adenocarcinoma NSCLC (defined as patients with evidence of disease progression during or within 6 months of treatment with chemotherapy and gefitinib or erlotinib). Methods: The phase I dose-finding portion identified the recommended phase II dose (RP2D) in Korean patients, evaluated safety, and characterized the pharmacokinetics of dacomitinib. In the phase II portion, patients received dacomitinib at the RP2D. The primary end point was progression-free survival at 4 months (PFS4m). Results: Twelve patients enrolled in phase I, and 43 patients enrolled in phase II at the RP2D of 45 mg once daily. In phase II, PFS4m was 47.2% (95% confidence interval [CI], 31.6–61.3; one-sided p-value = 0.0007). Median PFS was 15.4 weeks (95% CI, 9.7–17.6); median overall survival was 46.3 weeks (95% CI, 32.7–not reached); and the objective response rate was 17.1% (95% CI, 7.2–32.1). Common treatment-related adverse events were dermatitis acneiform, diarrhea, and paronychia; there were no treatment-related grade 4 or 5 adverse events. Pharmacokinetic parameters of dacomitinib in Korean patients were similar to those reported in Western patients. By patient report, NSCLC symptoms “cough” and “pain” showed improvement within 3 weeks of initiating treatment. Conclusions: Dacomitinib was well tolerated and had antitumor activity in Korean patients with NSCLC who had previously progressed on chemotherapy and an epidermal growth factor receptor tyrosine kinase inhibitor.

A Phase I Clinical Trial and Independent Patient-derived Xenograft Study of Combined Targeted Treatment with Dacomitinib and Figitumumab in Advanced Solid Tumors

Purpose: This phase I, open-label, single-arm trial assessed the safety and tolerability of dacomitinib–figitumumab combination therapy in patients with advanced solid tumors. Experimental Design: A standard 3 + 3 dose escalation/de-escalation design was utilized. Starting doses were figitumumab 20 mg/kg administered intravenously once every 3 weeks and dacomitinib 30 mg administered orally once daily. We also performed an independent study of the combination in patient-derived xenograft (avatar mouse) models of adenoid cystic carcinoma. Results: Of the 74 patients enrolled, the most common malignancies were non–small cell lung cancer (24.3%) and colorectal cancer (14.9%). The most common treatment-related adverse events in the 71 patients who received treatment across five dose levels were diarrhea (59.2%), mucosal inflammation (47.9%), and fatigue and acneiform dermatitis (45.1% each). The most common dose-limiting toxicity was mucosal inflammation. Dosing schedules of dacomitinib 10 or 15 mg daily plus figitumumab 20 mg/kg every 3 weeks after a figitumumab loading dose were tolerated by patients over multiple cycles and considered recommended doses for further evaluation. Objective responses were seen in patients with adenoid cystic carcinoma, ovarian carcinoma, and salivary gland cancer. Pharmacokinetic analysis did not show any significant drug−drug interaction. In the adenoid cystic carcinoma xenograft model, figitumumab exerted significant antitumor activity, whereas dacomitinib did not. Figitumumab-sensitive tumors showed downregulation of genes in the insulin-like growth factor receptor 1 pathway. Conclusions: Dacomitinib−figitumumab combination therapy was tolerable with significant dose reductions of both agents to less than the recommended single-agent phase II dose of each drug. Preliminary clinical activity was demonstrated in the potential target tumor adenoid cystic carcinoma. Clin Cancer Res; 23(5); 1177–85. ©2016 AACR. See related commentary by Sundar et al., p. 1123

Phase 2 study of intermittent pulse dacomitinib in patients with advanced non-small cell lung cancers

BACKGROUND Dacomitinib is a second-generation, irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Pre-clinical data suggest that intermittent pulsatile dosing of dacomitinib may result in inhibition of EGFR T790M. METHODS We evaluated safety, pharmacokinetics and efficacy of intermittent pulsatile dacomitinib in both molecularly unselected patients and patients with lung cancers harboring EGFR T790M (Clinical Trial Registration Number NCT01858389). RESULTS Thirty-eight patients were treated on study with pulse dacomitinib; sixteen with EGFR T790M in Cohort A and 22 who were not molecularly selected in Cohort B. One patient out of 16 patients in Cohort A had a partial response to study therapy (ORR 6.3%, 95% CI 0.2-30.2%). The median progression-free survival (PFS) in Cohort A was 2.3 months and median PFS in Cohort B was 1.6 months. The adverse event profile was similar to standard daily dose dacomitinib with the most frequent treatment-related toxicities occurring in >20% of patients being diarrhea, rash, stomatitis, nausea, dry skin, paronychia, fatigue, and decreased appetite. CONCLUSION Intermittent pulsatile dacomitinib is safe and relatively well tolerated but is not effective in patients that harbor EGFR T790M or in unselected patients with non-small cell lung cancer.

Impact of a planned dose interruption of dacomitinib in the treatment of advanced non-small-cell lung cancer (ARCHER 1042)

OBJECTIVES Dacomitinib is a pan-HER inhibitor for advanced non-small-cell lung cancer (NSCLC). We explored the impact of a planned 4-day dacomitinib dose interruption on plasma exposure of dacomitinib and adverse events (AEs) of interest in Cohort III of the ARCHER 1042 study. MATERIALS AND METHODS Patients, treatment-naïve for advanced NSCLC with EGFR activating mutations, received oral dacomitinib 45mg QD (once daily). A planned dose interruption occurred in Cycle 1 from Days 11 through 14. The primary endpoint was the pharmacokinetic (PK) characteristics of dacomitinib in Cycle 1Day 10 and during dose interruption. Secondary endpoints included safety and concomitant medications used to treat AEs of interest. RESULTS Cohort III enrolled 25 patients. Median plasma Cmax of dacomitinib in Cycle 1 Day 10 was 83.40ng/mL. Average median plasma dacomitinib concentration during the 4-day dose interruption was 42.63ng/mL. In the first 8 weeks of treatment 1) 80% of patients used concomitant medications for dermatologic AEs, 76% for diarrhea, and 44% for stomatitis, and 2) all patients experienced treatment-emergent AEs and 28% had all-causality Grade 3 AEs. CONCLUSION At 45mg QD dosing, PK parameters of plasma dacomitinib in Cycle 1 Day 10 were comparable to that obtained in Cycle 1 Day 14 from other dacomitinib studies. Average median plasma dacomitinib concentration during the 4-day dose interruption was approximately half of the median plasma Cmax of dacomitinib observed prior to dose interruption. The toxicity profile was consistent with that from other studies of dacomitinib.

Abstract CT208: Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Dacomitinib (D) is a highly selective, irreversible small molecule inhibitor of the human epidermal growth factor receptor family of tyrosine kinases in clinical development for the treatment of non-small cell lung cancer (NSCLC). A 45-mg once daily oral dose is currently being evaluated in Phase 3 for NSCLC therapy in multiple settings. D has not previously been administered clinically as an intravenous dose. The absolute bioavailability (F%) of D in rats, dogs and monkeys was found to range from 56% to 100% at doses between 20 and 50 mg/kg. The current study was conducted to estimate the absolute bioavailability of D after oral administration (Test) relative to intravenous (IV, Reference) administration. Methods: A total of 14 healthy volunteers (HV) were enrolled in this Phase 1, open-label, 2-period, 2-treatment, fixed sequence study. Each HV received 2 treatments of D: Reference (20 mg IV infusion over 1 hour) and Test (45 mg oral), with a washout period of at least 16 days between each. Plasma samples to determine concentrations of D and its metabolite, PF-05199265, were collected at intervals up to 216 hours post-dose after IV or oral dose, and safety was assessed. F% was estimated as the ratio of dose-normalized adjusted geometric means of AUCinf for oral D and IV D using a mixed-effect model with treatment as a fixed effect and subject as a random effect. Corresponding 90% confidence intervals (CIs) were to be obtained from the same model. Results: The mean AUCinf, Cmax and CL/F for D after a single 45-mg oral dose were 1487 ng*hr/mL, 19.84 ng/mL and 30.27 L/hr, respectively. The mean AUCinf, Cmax and CL for D after a single 20-mg IV dose were 847 ng*hr/mL, 52 ng/mL and 23.61 L/hr, respectively. Mean pharmacokinetic parameters following a single oral dose in this study were similar to those observed in other single oral dose studies in HV. Conclusions: Assuming that clearance of D is similar via oral or IV administration at the administered doses, the absolute bioavailability of D was estimated to be 80.01% (90% CI: 74.90%, 85.47%). Single oral doses of D in both treatments were generally safe and well tolerated in the HV evaluated in this study. Citation Format: Nagdeep Giri, Robert R. LaBadie, Yali Liang, Tanya Boutros, Zelanna Goldberg, Carlo L. Bello. Absolute bioavailability of dacomitinib (PF-00299804): Comparison of oral and intravenous administration in healthy volunteers. [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 CT208. doi:10.1158/1538-7445.AM2014-CT208

Phase 1 study to investigate the pharmacokinetic properties of dacomitinib in healthy adult Chinese subjects genotyped for CYP2D6

Abstract 1. This study aimed to characterise the pharmacokinetics of dacomitinib, a pan-human epidermal growth factor receptor tyrosine kinase inhibitor, and its metabolite, PF-05199265, in healthy Chinese subjects. 2. In this open-label, single-centre, nonrandomised study (NCT02097433), 14 subjects received a single dacomitinib 45-mg oral dose. Pharmacokinetic samples for dacomitinib and PF-05199265 were collected pre- and postdose. Subjects were genotyped for cytochrome P450 (CYP)2D6 metaboliser status. Safety was assessed throughout the study. 3. The geometric mean (per cent coefficient of variability) area under the concentration–time curve from time zero to infinity (AUCinf) and maximum plasma concentration (Cmax) were 1662 ngċh/mL (26%) and 21.51 ng/mL (27%), respectively, for dacomitinib and 469 ngċh/mL (65%) and 5.54 ng/mL (79%) for PF-05199265. Median times to Cmax were 8 and 4 h postdose for dacomitinib and PF-05199265, respectively; mean terminal half-life of dacomitinib was 62.7 h. Geometric mean apparent clearance and volume of distribution of dacomitinib were 27.06 L/h and 2415 L, respectively. The metabolite PF-05199265-to-dacomitinib ratios were 0.2907 for AUCinf and 0.2656 for Cmax. 4. Dacomitinib total (AUCinf) and peak exposures (Cmax) were similar among subjects with different CYP2D6 genotypes, whereas both parameters for PF-05199265 were higher in extensive metabolisers (n = 5) versus intermediate metabolisers (n = 8).

Abstract 763: A phase 1 open-label study to investigate the potential drug-drug interaction (DDI) between single-dose (SD) dacomitinib (PF-00299804; DC) and steady-state (SS) paroxetine (PX) in healthy volunteers (HVs)

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Introduction: DC, a small molecule, pan-HER inhibitor, is partly metabolized by cytochrome P450 (CYP) 2D6. Concomitant administration with therapeutic agents that are inhibitors of CYP2D6 could potentially cause DDIs. This study evaluated the effect of PX, a potent CYP2D6 inhibitor, on the pharmacokinetics (PK) of DC in HVs who were extensive CYP2D6 metabolizers. The safety and tolerability of SD DC was also assessed when given alone and co-administered with PX. Methods: In this Phase 1, single fixed-sequence, 2-period study, 14 HVs received a 45 mg SD of DC alone (Period 1). After a 21-day washout, 30 mg of PX was given daily for 10 days (Period 2) and on Day 4, a 45 mg SD of DC was co-administered with PX. Blood samples were collected up to 240 h post DC dose in both periods and analyzed for DC, its CYP2D6 metabolite PF-05199265, and PX using validated high performance liquid chromatographic tandem mass spectrometric methods. PK parameters were calculated using noncompartmental methods. Analysis of variance was performed on natural log transformed AUC and Cmax to estimate adjusted mean treatment differences and 90% confidence intervals (CI) which were exponentiated to produce the adjusted geometric mean ratio (GMR) and 90% CI of the ratios. Results: 14 males (median age 41 [23-54] yrs; 9 black, 5 Caucasian) were evaluated for PK and safety. The GMR and 90% CI of AUCinf and Cmax for DC when given as DC + PX vs DC alone was 137.2% (109.1%, 172.6%) and 110% (82.9%, 145.1%), respectively. Median Tmax of DC was 8 and 10 h post dose, and its half-life was 96 and 90 h, in the presence and absence of PX, respectively. Total exposure (AUC240) to PF-05199265 was decreased in the presence of SS PX (33.5 vs 322 ng.hr/mL). There were no serious adverse events (AEs), severe AEs, or deaths during the study. The majority of AEs were mild (including all 14 events reported during DC treatment alone) and resolved. Conclusions: PX inhibited DC metabolism resulting in 90% reduction in exposure (AUC240) of the CYP2D6 metabolite, PF-05199265. No meaningful change in absorption was observed when DC was given with SS concentrations of PX. DC seems to present a low extraction profile and high variability during the absorption phase, the latter probably due to its physicochemical characteristics (BCS Class II). In the presence of PX, there was an approximate 37% increase in DC exposure (AUCinf) with a wide CI, reflecting large intra-subject variability. The DC change in exposure reported in this study is likely to be less in the clinical setting (45 mg QD). As the exposure of DC reported in the presence of PX is within the range shown to be tolerated and efficacious, no dose adjustment is recommended for DC when administered concomitantly with a CYP2D6 inhibitor, such as PX. SD DC administered alone and in combination with PX was well tolerated. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 763. doi:1538-7445.AM2012-763