Common Drug-related Adverse Events Research Articles

Pharmacokinetics, efficacy, and safety of caspofungin in Japanese pediatric patients with invasive candidiasis and invasive aspergillosis.

The antifungal agents approved in Japan for pediatric use are limited and many unapproved drugs are actually used without clear instruction for dosage. We investigated the pharmacokinetics of caspofungin for the treatment of invasive candidiasis and invasive aspergillosis in 20 Japanese pediatric patients using a pediatric-specific dosage based on body surface area. Caspofungin was administered intravenously over 60 min as 70 mg/m(2) on Day 1, followed by 50 mg/m(2) per day. Five or 4 point blood sampling were done in 15 patients on Day 4-5 to calculate AUC0-24 h. The geometric means (95% confidence interval) of C24 h and AUC0-24 h in the pediatric patients were 3.3(2.5, 4.4) μg/mL and 175.1 (139.3, 220.1) μg hr/mL, respectively, which were comparable to those in Japanese adult patients [3.2 (2.8, 3.5) μg/mL and 144.9 (131.7, 159.3) μg hr/mL, respectively]. Among the 20 patients, 10 (50%) had at least 1 drug-related adverse event which was considered related to caspofungin therapy. No drug-related serious adverse event and no death occurred. The most common drug-related adverse events were events relating to hepatic function (mainly increases in ALT and AST). The overall success in efficacy was observed in 13 of 20 patients. In conclusion, once daily administration of caspofungin (70 mg/m(2) on Day 1, followed by 50 mg/m(2) [maximum daily dose not to exceed 70 mg]), which is the same dosage being used in overseas, achieved sufficient drug exposure and a favorable efficacy and acceptable safety profile in Japanese pediatric patients with invasive fungal infections.

Phase 1 Study Results of a Novel Controlled-Release Formulation of Anagrelide (GALE-401) for the Treatment of Thrombocytosis

Introduction: Despite recent advances in the diagnosis and management of myeloproliferative neoplasms (MPNs), treatment of essential thrombocythemia (ET) has remained largely unchanged since the introduction of anagrelide in the US during 1997. Anagrelide is indicated for the treatment of thrombocythemia, to reduce the elevated platelet count and risk of thrombosis, and to ameliorate symptoms including thrombohemorrhagic events. The primary pharmacological effect of anagrelide is inhibition of megakaryocyte hypermaturation leading to reduced platelet production. Anagrelide also inhibits cyclic AMP phosphodiesterase III (PDE3), and common drug related adverse events (AEs; e.g., headache, palpitations, fluid retention, nausea and diarrhea) are believed to be due to this mechanism. Although initiating treatment at low doses and slowly increasing the dose to reach a target decreased platelet count may mitigate AEs, over 20% of patients still withdraw from treatment due to poor tolerability. As the currently marketed anagrelide product is an immediate release (IR) formulation with peak plasma concentrations (Cmax) that may exceed that needed for platelet reduction and cause unwanted PDE3 inhibition and AEs, an alternate formulation that modifies this pharmacokinetic (PK) profile may improve patient tolerability, adherence and treatment outcomes. This has led to the development and study of a controlled-release (CR) formulation of anagrelide (GALE-401).Methods: 98 healthy adult subjects were enrolled among 5 Phase 1 clinical trials of anagrelide CR, including 12 placebo-control subjects and 86 subjects who received single or multiple doses ranging from 0.2 to 0.6 mg twice daily (b.i.d.) for up to 41 days. The trials included an open-label, single dose developmental study; two placebo-controlled multiple dose ranging studies; a food effect study; and a comparative crossover PK study vs. IR reference product. Safety parameters included routine laboratory, ECG, and clinical evaluations. PK was assessed by measurements of plasma anagrelide and its active metabolite using a validated HPLC-MS/MS method. Pharmacodynamic activity was assessed by daily platelet count determinations in the multiple dosing studies.Results: Single doses of anagrelide CR were well tolerated, and the only drug-related AE reported in 2 or more subjects was headache. In the b.i.d. dose-ranging studies, the frequency and severity of AEs were similar between anagrelide CR and placebo groups, with the exception of decreased platelet counts in subjects receiving anagrelide CR. All AEs were transient, mild or moderate in severity, and no severe or serious AEs were reported.Anagrelide CR demonstrated dose proportional PK characteristics. Following a single 0.5 mg dose in the fasted state, the mean time to maximum plasma concentration (Tmax) and terminal elimination half-life (t1/2) were 2.0±1.5 hrs and 10.4±9.3 hrs (mean ± SD), respectively; in contrast, Tmax and t1/2 following IR was 1.0±0.9 hrs and 1.4±0.2 hrs, respectively. Cmax and total plasma exposure (AUC0-inf) with anagrelide CR were reduced to 26% and 59% of IR, respectively. However, steady-state PK following 6 daily 0.5 mg b.i.d. doses of anagrelide CR or IR showed similar AUC0-inf values, while Cmax with anagrelide CR remained nearly unchanged (29%). Plasma exposure was higher when anagrelide CR was administered in the fed state, as demonstrated by the ratio of least-squares mean values for Cmax and AUC0-t, which were increased by 100% and 60%, respectively.The platelet lowering effect of anagrelide CR was evident in the 2 multiple dose ranging studies. In a placebo-controlled study of 0.2 to 0.6 mg b.i.d. dosing for up to 21 days, a dose-related decrease in platelet counts was observed, and the 0.6 mg cohort was halted early due to excessive platelet reductions. Anagrelide CR did not have a relevant impact on platelet function as assessed by template bleeding time. [Display omitted] Conclusion: Anagrelide CR is a promising, novel formulation of anagrelide that exhibited the desired PK profile of a significantly reduced Cmax, while maintaining plasma exposure to induce platelet count reductions. The product was well tolerated with an AE profile that was not distinguishable from placebo. These data support the importance of an ongoing Phase 2 study in patients with MPN-related thrombocytosis, including ET. DisclosuresLaliberte:Galena Biopharma, Inc.: Employment, Equity Ownership. Glidden:Galena Biopharma, Inc.: Consultancy, Equity Ownership, Patents & Royalties. Hamilton:Galena Biopharma, Inc.: Employment, Equity Ownership.

PD-1 Blockade with the Monoclonal Antibody Pembrolizumab (MK-3475) in Patients with Classical Hodgkin Lymphoma after Brentuximab Vedotin Failure: Preliminary Results from a Phase 1b Study (KEYNOTE-013)

The programmed death-1 (PD-1) pathway serves as an immune checkpoint to temporarily dampen immune responses upon chronic antigen stimulation. Normal antigen presenting cells and certain tumor cells express the PD-1 ligands, PD-L1 and PD-L2, which engage PD-1 receptors on activated T cells and induce T-cell exhaustion. PD-1 signaling is a potent mechanism of tumor immune escape and a compelling target for therapy. Antibody-mediated PD-1 blockade has already been successfully exploited as a therapeutic strategy in solid tumors and is currently being evaluated in hematologic malignancies. Classical Hodgkin lymphoma (cHL) may represent a uniquely vulnerable target for PD-1 blockade therapy. This disease is characterized by an extensive inflammatory immune cell infiltrate and a dominant genetic alteration in chromosome 9p24.1 that leads to PDL1 and PDL2 copy gain and associated overexpression of these PD-1 ligands. In cHL, Epstein-Barr virus infection represents an additional mechanism of upregulating PD-1 ligand expression. For these reasons, cHL was included as a cohort of the ongoing, multicenter, open-label, phase 1b clinical trial of the monoclonal antibody pembrolizumab (MK-3475; Merck, Whitehouse Station, NJ) in hematologic malignancies (KEYNOTE-013; ClinicalTrials.gov identifier, NCT01953692).Eligibility criteria for the cHL arm of KEYNOTE-013 include relapsed or refractory cHL, relapse from or failure to respond to brentuximab vedotin treatment, and adequate performance status and organ function. Patients with autoimmune disease or interstitial lung disease are excluded. Treatment consists of single-agent pembrolizumab 10 mg/kg administered intravenously every 2 weeks until confirmed tumor progression, excessive toxicity, or completion of 2 years of therapy. The main end points of this study are safety, tolerability, and complete remission (CR) rate. The first time point for radiologic restaging is at week 12 (ie, after 6 cycles of treatment).Herein, we report preliminary results from the 15 patients with cHL who were evaluable for response to pembrolizumab at the 12-week time point. The median patient age was 28 years (range, 21-67), and the median number of prior therapies was 4. By design, all patients previously failed brentuximab vedotin; 67% also failed prior autologous stem cell transplantation. Pembrolizumab was well tolerated. There were no serious adverse events (AEs), and only 1 patient experienced grade 3-5 AEs (grade 3 pain and grade 3 joint swelling, both considered to be unrelated to study drug). Overall, 10 patients experienced ≥1 AE. The most common drug-related AEs were grade 1-2 respiratory events (20%) and thyroid disorders (20%). One patient discontinued study treatment because of an AE (grade 2 pneumonitis), and 3 patients ended therapy after progressive disease (PD). Based on investigator assessment using the Cheson 2007 International Harmonization Project response criteria, 3 patients (20%) had a CR at 12 weeks. Five additional patients (33%) had partial remission as best overall response, for an overall response rate of 53%. Four patients (27%) experienced PD, although all 4 experienced a decrease in their overall tumor burden (Figure 1). In conclusion, pembrolizumab therapy appears to be safe, tolerable, and associated with clinical benefit in patients with heavily pretreated cHL.Figure 1: Best percentage change from baseline in tumor size for all patients. [Display omitted] DisclosuresMoskowitz:Merck: Research Funding. Off Label Use: Pembrolizumab is a humanized, monoclonal IgG4-kappa isotype antibody against PD-1 that is currently in clinical development for multiple advanced solid tumors and hematologic malignancies.. Ribrag:Servier: Consultancy, Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Epizyme: Research Funding; Pharmamar: Consultancy; Celgene: Consultancy. Martinelli:Novartis: Speakers Bureau; Ariad: Consultancy; Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau. Giallella:Merck: Employment. Weimer Anderson:Merck: Employment. Derosier:Merck: Employment. Wang:Accenture: Employment. Yang:Merck: Employment. Rubin:Merck: Employment. Rose:Merck: Employment. Shipp:Merck: Membership on an entity’s Board of Directors or advisory committees; Pharmacyclics: Membership on an entity’s Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity’s Board of Directors or advisory committees; Bayer: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R&D: Membership on an entity’s Board of Directors or advisory committees. Armand:Merck: Consultancy.

A Double-Blind, Multicentre, Randomised, Placebo-Controlled Study to Assess the Efficacy, Safety and Tolerability of Prophylactic Liposomal Amphotericin B (AmBisome®) for the Prevention of Invasive Fungal Infections in Subjects Receiving Remission-Induction Chemotherapy for Acute Lymphoblastic Leukaemia (AmBiGuard trial)

Background: Adult patients undergoing remission-induction (RI) chemotherapy for newly diagnosed acute lymphoblastic leukaemia (ALL) are at high risk of invasive fungal disease (IFD), particularly invasive aspergillosis. The prevalence of IFD in this population has not been widely studied. There is currently no approved standard for antifungal prophylaxis and it is recommended by the European Working Group for Adult ALL that azole antifungal agents be avoided because of drug interactions with vincristine, a standard component of induction chemotherapy regimens.Methods: This was a double-blind, multicentre, placebo-controlled study in patients aged ≥18 years receiving RI chemotherapy for newly diagnosed ALL. Study subjects received either liposomal amphotericin B (L-AMB) 5mg/kg or placebo by IV infusion twice weekly in a 2:1 random allocation. The primary endpoint of the study was the proportion of subjects with proven or probable invasive fungal infection (IFI) assigned in a blinded review by an independent data review board (IDRB) using EORTC/MSG (European Organization for Research and Treatment of Cancer/Mycoses Study Group) definitions (1). Subjects were closely monitored for signs and symptoms of IFI, including biweekly galactomannan and β-D-glucan assessments. Clinical, laboratory or radiographic findings suggestive of IFI prompted further investigation according to a specified protocol. Subjects with defined clinical and mycological criteria or a halo sign on chest CT had prophylaxis interrupted and pre-emptive antifungal therapy initiated while further diagnostic procedures were undertaken. Prophylaxis was stopped when subjects met protocol-specified criteria for proven or probable IFI and appropriate antifungal therapy started. Secondary objectives included safety and tolerability of prophylactic L-AMB and the impact of IFI prevention on the efficacy of RI chemotherapy.Results: A total of 355 subjects from 83 centres in 13 countries in Europe (including Turkey and Israel) and South America were randomised and received at least 1 dose of either L-AMB (n=237) or placebo (n=118). Sixteen subjects were excluded from the efficacy analysis, 1 due to misdiagnosis (AML) and 15 due to protocol-prohibited antifungal treatment. 7.9% (18/228) subjects in the L-AMB group and 11.7% (13/111) subjects in the placebo group were considered by the IDRB to have experienced a proven or probable IFI (p=0.24, RR 0.33 [CI -0.32 to 0.66]). Of these, 1 case (0.4%) in the L-AMB group and 3 cases (2.7%) in the placebo group were considered proven. In subjects who were neutropenic (absolute neutrophil count <0.5x109/L) ≥10 days, the incidence was 6.9% (12/174) in the L-AMB group versus 13.1% (11/84) in the placebo group (p=0.10). Overall mortality was similar: 7.2% (17/237) in the L-AMB group vs 6.8% (8/118) in the placebo group (p=1.00) as was the incidence of serious adverse events (SAEs; 33.3% (79/237) vs 32.2% (38/118), [p=0.90]). SAEs of any grade related to the study drug were reported for 8.4% subjects (20/237) in the L-AMB group compared with 1.7% subjects (2/118) (p=0.02) in the placebo group. The most common (>5%) study drug-related adverse events (AEs) were hypokalaemia (10.5% [25/237] vs 3.4% [4/118] p=0.02) and increased creatinine (6.3% [15/237] vs. 0% [p=0.003]). Complete remission at the end of RI chemotherapy was achieved by 72.6% (172/237) subjects in the L-AMB group versus 78.8% (93/118) subjects in the placebo group (p=0.24).Conclusions: In this study, the largest of its kind to date, the rate of IFI among adult patients undergoing RI chemotherapy for newly diagnosed ALL was 11.7% in the placebo group. Study subjects who received L-AMB at 5mg/kg twice weekly for prophylaxis showed a reduction in IFIs relative to placebo (RR 0.33 [CI -0.32 to 0.66]), although this did not reach statistical significance (p=0.24). L-AMB prophylaxis was generally well tolerated. The incidence of IFI in patients with ALL receiving RI therapy indicates that antifungal prophylaxis is merited in this patient population. Further analysis is needed to determine which patients might benefit the most.clinicaltrials.gov number: NCT01259713(1) De Pauw et al 2008 Clin Infect Dis 46: 1813–1821 DisclosuresCornely:Gilead Sciences: Consultancy, Research Funding, Speakers Bureau. Off Label Use: Liposomal Amphotericin B (AmBisome®) is a broad spectrum antifungal agent indicated for the treatment of severe systemic and/or deep mycoses, empiric treatment of presumed fungal infections in febrile neutropenic patients and treatment of visceral leishmaniasis. In this study the efficacy, safety and tolerability of prophylactic liposomal amphotericin B (AmBisome®) was explored for the prevention of invasive fungal infections in subjects receiving remission-induction chemotherapy for Acute Lymphoblastic Leukaemia (the AmBiGuard trial).. Leguay:Gilead Sciences: Research Funding. Maertens:Gilead Sciences: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau. Castagnola:Gilead Sciences: Research Funding. Anagnostopoulos:Gilead Sciences: Research Funding. Allione:Gilead Sciences: Research Funding. Heussel:Gilead Sciences: Consultancy, Speakers Bureau. Donnelly:Astellas, Gilead, Merck, Pfizer: Consultancy, Honoraria, Research Funding. Agrawal:Gilead, Pfizer, Astellas, MSD, Bio-Rad: Honoraria, Research Funding. Garner:Gilead Sciences: Employment, Equity Ownership. Simcock:Gilead Sciences: Employment, Equity Ownership. Hawkins:Gilead Sciences: Employment, Equity Ownership. Goekbuget:Gilead Sciences: Consultancy, Honoraria.

Long-Term Outcome of a Phase 1 Study of the Investigational Oral Proteasome Inhibitor (PI) Ixazomib at the Recommended Phase 3 Dose (RP3D) in Patients (Pts) with Relapsed or Refractory Systemic Light-Chain (AL) Amyloidosis (RRAL)

Long-Term Outcome of a Phase 1 Study of the Investigational Oral Proteasome Inhibitor (PI) Ixazomib at the Recommended Phase 3 Dose (RP3D) in Patients (Pts) with Relapsed or Refractory Systemic Light-Chain (AL) Amyloidosis (RRAL)

A multicenter, 12-month, open-label, single-arm safety study of oxycodone-hydrochloride/naltrexone-hydrochloride extended-release capsules (ALO-02) in patients with moderate-to-severe chronic noncancer pain

To evaluate the long-term safety of oxycodone-hydrochloride and sequestered naltrexone-hydrochloride (ALO-02) administered for up to 12 months. Open-label, single-arm safety study. Thirty-two US research centers (ClinicalTrials.gov identifier NCT01428583). Three hundred ninety-five adults (opioid experienced and opioid naïve) with moderate-to-severe chronic noncancer pain (CNCP). Open-label, oral ALO-02 capsules, daily dose ranging from 20 to 160 mg oxycodone for up to 12 months. Number and type of adverse events (AEs) and drugrelated AEs, including assessments of withdrawal (Clinical Opiate Withdrawal Scale; COWS), pharmacokinetics, efficacy, and aberrant behaviors (Current Opioid Misuse Measure). A total of 193 (48.9 percent) patients received ALO-02 for ≥181 days and 105 (26.6 percent) patients for ≥361 days. The most common treatment-emergent AEs were nausea (25.3 percent), constipation (21.3 percent), vomiting (13.9 percent), and headache (11.6 percent). The most common drug-related AEs were constipation (18.0 percent), nausea (14.9 percent), somnolence (8.4 percent), fatigue (6.8 percent), dizziness (5.6 percent), and vomiting (5.1 percent). A majority of patients (86.6 percent) had a maximum COWS total score below the level for mild withdrawal symptoms at every visit throughout the study. Pain severity scores as measured by the short Form of the Brief Pain Inventory (BPI-SF) decreased over time. Repeat dosing of ALO-02 for up to 12 months is safe and well tolerated in a CNCP population of both opioid-experienced and opioid-naïve patients. ALO-02 demonstrated a safety profile consistent with extended-release opioids and the expected analgesic efficacy. The addition of sequestered naltrexone had no significant clinical effect on patients when taken as directed.

An Assessment of Gastric and Small Bowel Pressure Profiles in Diabetics With Gastroparesis Before and During 28 Days of Treatment With the Motilin Receptor Agonist Camicinal (GSK962040)

Introduction: Exploratory assessment of gastric and small bowel contractility response to the motilin receptor agonist camicinal (C), using the wireless motility capsule (WMC). Methods: Patients with diabetes with gastroparesis (confirmed by 13 C oral breath test) with at least moderate symptoms were enrolled in a double blind randomized study of placebo, 10, 50, or 125 mg doses of C daily for 28 days. The study design, primary efficacy, and safety results of this study have been previously reported (Barton ME, DDW 2014). The WMC was given 3 times over the course of the 4-week study: at baseline (day 0) prior to treatment, day 1 of treatment, and day 28 of treatment. The frequency of contractions (CT), area under the pressure curve (AUC), and motility index (MI) were analyzed in the 1-hour period prior to (antral [A] window) and post WMC gastric emptying (duodenal [D] window) with GIMS Data Viewer 3.0. Subjects whose WMC data included >70% of available pressure samples in A and D analyses windows and for whom a paired t test analyses between day 0 and 1, day 0 and 28, and day 1 and 28 was appropriate were evaluated. The 3 dosage groups were combined in 1 data set for analyses. Results: Seventy-nine subjects were in the study. The most common drug-related AEs were headache, UTI, and GI symptoms, similar in frequency across treatment groups. There were no study withdrawals due to AEs, nor any drug-related serious adverse events. A paired t test analysis combining all treatment levels except placebo between day 0 and 1 included 23 subjects in the A window and 28 subjects in the D window. In A window, significant increases were observed in mean CT from 64 to 106 CT/hr (p=0.02), AUC from 4,008 to 6485 mmHg/sec (p=0.02), and MI from 11.17 to 12.21 in (CT x Sum Amp+1) (p=0.02). The corresponding analyses for differences in mean pressure parameters between day 0 and day 28 included 27 and 33 subjects in the A and D windows, respectively, and showed no significant difference in pressure parameters on day 28 (p>0.3). Mean values for CT, AUC, and MI increased between day 1 and 28 for the 28 and 31 subjects in the A and D windows, respectively (p>0.09). When analyzing the placebo group only, there were no significant changes in motility parameters for either A or D windows on day 1 or day 28 compared to day 0. No significant changes in the small bowel pressure profiles were observed. Conclusion: Data suggests gastric pressure profiles prior to gastric emptying improve in diabetic gastroparesis patients following motilin receptor agonist treatment, whereas small bowel motility parameters following gastric emptying are not affected significantly. Disclosure - George Dukes - Employee, GSK; Matthew Barton - Employee, GSK; Kenneth Barshop - none; Braden Kuo - Consultant, GSK; Jack Semler - Consultant, GSK, Given Imaging. This research was supported by an industry grant from GSK.

Abstract 2588: Antiangiogenic and immunomodulatory effects of metronomic cyclophosphamide (CPM) treatment in prostate cancer patients with PSA failure

Abstract Background: After curative local therapy, patients (pts) will experience rising PSA as an early indicator of recurrent prostate cancer and no standard of care exists. Previous studies demonstrated the clinical interest of cyclophosphamide metronomic chemotherapy (CMC) in several cancers. Multifactorial modes of action including immunological and anti-angiogenic effects have been well described by Kerbel et al and Ghiringhelli et al (Cancer Research 2006 and European Journal of immunology 2004, respectively). In the current study, we investigated the safety and immuno-modulatory effects of CMC in prostate cancer patients with PSA failure (biochemical relapse). Methods: We conducted a prospective phase II study to characterize the clinical and immunological interest of CMC in histologically proven prostate cancer patients previously treated by prostatectomy and with biochemical relapse (defined as PSA &amp;gt; 1 and &amp;lt; 20ng/mL and progressive PSA level on 3 different measures). CMC was administered per os, at daily dose of 50 mg during 6 months. PSA level, serum VEGF and immune parameters were monitored every month in blood samples. Results: Thirty-four consecutive pts were enrolled in this study and all received CMC. The median age was 68,3 (range, 56,9-82,1) and all pts had good performance status (ECOG-PS = 0). Gleason Score was 7 in 58%, ≤6 in 13%, and ≥ 8 in 13%. No serious adverse events (grade 3-5) were observed. The most common drug-related adverse event was grade 1 lymphopenia. Baseline PSA was 2,92 ng/mL (range, 1,1-9,35). Twenty-two pts presented stable PSA (64.7%), one patient had partial response defined by &amp;gt;50% decline in the serum PSA (3%), and 11 pts (32%) had PSA progression before 6 months. The immuno-monitoring performed in all pts who completed 6 months CMC. A decrease of immunosuppressive regulatory T cells (Treg) was observed in 56% (10/18). In addition, high rate of activated HLA-DR+ cytotoxic CD8 T cells was also detected in these pts. Furthermore, serum VEGF level decreased at month 1 but it returned to baseline level at the end of treatment in 9/17 pts evaluated (52%). In some patients the correlation was observed between the control of PSA level, the decrease of Treg and VEGF parameters. Conclusions: This study demonstrated the clinical benefit and the ability of CMC to promote the blockage of angiogenesis and immuno-modulatory effect in prostate cancer patients treated for a biochemical relapse. It will be of interest to combine CMC to vaccination in these patients. Citation Format: Olivier Adotevi, Fabien Calcagno, Tristan Maurina, Stefano Kim, Antoine Thiery-Vuillemin, Christophe Borg, Yann Godet, Caroline Laheurte. Antiangiogenic and immunomodulatory effects of metronomic cyclophosphamide (CPM) treatment in prostate cancer patients with PSA failure. [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 2588. doi:10.1158/1538-7445.AM2014-2588

A Phase Ib Study of Pembrolizumab (Pembro; Mk-3475) in Patients (Pts) with Human Papiilloma Virus (Hpv)-Positive and Negative Head and Neck Cancer (Hnc)

ABSTRACT Aim: Background: The highly selective, anti-PD-1 humanized monoclonal antibody pembro has shown antitumor activity in several solid tumors, including HNC. We present updated safety, tolerability, and antitumor activity of pembro for recurrent/metastatic HNC (Clinicaltrials.gov: NCT01848834). Methods: During screening, PD-L1 expression in archival or newly obtained tumor samples was assessed using a prototype immunohistochemistry assay; PD-L1 expression in stroma or ≥1% of tumor cells was required for study entry. Pembro 10 mg/kg was given every 2 wk until complete response, progression, unacceptable toxicity, physician decision, or consent withdrawal. Adverse events (AEs) were recorded throughout the study. Response was assessed every 8 wk. Primary end point was overall response rate (ORR) per RECIST v1.1. Results: Out of 104 HNC pts screened, 81 (78%) were PD-L1-positive, 61 enrolled, and 60 received ≥1 pembro dose: 23 HPV+, 37 HPV-. After a median follow-up of 10.2 mo, 15 pts (25%) remain on pembro. ORR (confirmed + unconfirmed) per RECIST v1.1 by investigator review was 20%, and response duration ranged from 8+ to 41+ weeks (median not reached). 9 of 11 responders had a smaller target lesion burden (ie, sum below the median) at baseline. ORR was similar in HPV+ and HPV- pts, whereas PFS and OS were longer in HPV+ pts (Table). PD-L1 expression was positively correlated with ORR (P = 0.018) and PFS (P = 0.024). ORR was 50% in the 12 pts with high PD-L1 expression. Drug-related AEs of any grade occurred in 58% of pts (grade ≥3 in 17%). The most common drug-related AEs were fatigue (18%), pruritus (10%), and nausea (8%). There were no drug-related deaths. Conclusions: Pembro is safe and tolerable and shows antitumor activity in both HPV+ and HPV- advanced HNC. These findings support further development of pembro in advanced HNC. Overall N = 61* HPV+ n = 23* HPV– n = 38* ORR, n (%) 11 (20) 4 (20) 7 (19) Median PFS (95% CI), wk 9.3 (8.0-20.1) 17.2 (8.0-41.7) 8.1 (7.9-15.6) Median OS (95% CI), mo 12.6 (8.2-12.6) NR (9.6-NR) 9.5 (3.9-12.6) *ORR and PFS were evaluated in the 56 pts (20 HPV+, 36 HPV-) who received ≥1 pembro dose and had measurable disease per RECIST v1.1 by investigator review. Disclosure: L.Q. Chow: Advisory Board Member for Bristol Myers Squibb, Novartis, Celgene; Research funding from Bristol Myers Squibb, Novartis, AstraZeneca/Medimmune, Genentech/Roche, VentiRx, Pfizer, Lily/Imclone; B. Burtness: Advisory board membership for VentiRx and Novartis; Research funding from Merck, Genentech, Boehringer Ingelheim, and Pfizer; E.J. Gonzalez, J.K. Lunceford, C. Gause and J.D. Cheng: Employee of and stock ownership in Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; J. Pulini, J. Johnson, M. Dolled-Filhart, K. Emancipator and K. Pathiraja: Employee of Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc.; T. Seiwert: Advisory board membership for Novartis and Onyx/Bayer; Research funding from Boehringer Ingelheim and Genentech; Honoraria from Merck. All other authors have declared no conflicts of interest.

636P - Efficacy and Safety of Multiple Doses of Imab362 in Patients with Advanced Gastro-Esophageal Cancer: Results of a Phase Ii Study

ABSTRACT Aim: IMAB362 is a monoclonal antibody specifically targeting claudin 18 isoform 2 (CLDN18.2), which is expressed on gastric cancer cells, whereas it is only present on a fraction of healthy stomach cells. This may reduce the risk of target-related side effects. Single-agent IMAB362 appears safe in patients with advanced gastro-esophageal cancer (GEC) based on data from a phase I trial. Methods: This international, multicenter, non-randomized phase IIa study (NCT01197885) investigated the efficacy and safety of repeated doses of IMAB362 (300 and 600 mg/m2) in patients with metastatic, refractory/recurrent, CLDN18.2-positive GEC (i.e. cancer of the stomach, the lower esophagus and the GE junction). Patients received bi-weekly IMAB362 at 300 or 600 mg/m2 as 2-hour IV infusion. Response rate (RECIST criteria), progression-free-survival (PFS) and safety (NCI-CTCAE v3.0) were assessed. Pharmacokinetics (PK) were determined and an extensive biomarker program was conducted. Results: 54 patients were included in this study: 4 patients received 300 mg/m2 and 50 patients 600 mg/m2. The median age was 62 (range 45–66) years in the 300 mg/m2 and 60 (range 35–77) years in the 600 mg/m2 dose group. More than 50% of patients had received chemotherapy in the 6 months preceding this study. The full analysis set comprised 40 patients (all in 600 mg/m2 group) including 9 patients who continued to receive IMAB362 following the study period. The response rate was 10% and the disease control rate was 30% (best observed response: PR, n = 4 and SD, n = 8). Median PFS was 102 days (95% CI, 70–146 days). All observed adverse events were of grade 1–3, adverse events of grade 4/5 did not occur. Nausea and vomiting were the most common study drug-related adverse events in 31 (n = 8 with grade 3 nausea) and 27 (n = 13 with grade 3 vomiting) of 54 patients, respectively. PK supports 3-weekly IV dosing. Conclusions: Clinical efficacy of IMAB362 at repeated doses was observed in several patients. IMAB362 at 600 mg/m2 appears safe and feasible in patients with advanced late-stage GEC. Hence, IMAB362 may provide a promising new treatment option for this patient population and further clinical evaluation is ongoing. Disclosure: U. Sahin: Inventor of patents on CLDN18.2; O. Tureci: Employed by Ganymed Pharmaceuticals AG and inventor of patents on CLDN18.2. All other authors have declared no conflicts of interest.

Sorafenib Treatment of Advanced Renal Cell Carcinoma Patients in Daily Practice: The Large International PREDICT Study

BackgroundPatients with advanced renal cell carcinoma in routine clinical practice can differ considerably from those in phase III studies. Patients and MethodsPREDICT (Patient characteristics in REnal cell carcinoma and Daily practICe Treatment with sorafenib) was a prospective, noninterventional study of open-label sorafenib for the treatment of advanced RCC conducted in 18 countries. Patient characteristics, therapy duration, tumor status, and tolerability were assessed at baseline and during routine follow-up. ResultsOverall, 2599 patients were evaluable for safety and 2311 for efficacy. The diverse population included patients with brain metastases (5%), non-clear-cell histologies (17%), high Memorial Sloan-Kettering Cancer Center risk score (11%), poor Eastern Cooperative Oncology Group performance status (PS ≥ 2, 29%), and patients with no previous nephrectomy (16%) or no previous systemic therapy (37%). The median duration of sorafenib therapy was 7.3 months and was similar in clinically relevant subgroups (eg, patients with PS 2, brain metastases, or concomitant hypertension or diabetes [range, 6.7-7.0 months]). The median duration of therapy was shorter for patients with PS 3 or non-clear-cell histologies (4.6 and 4.8 months, respectively). The most common drug-related adverse events were hand–foot skin reaction (20%), diarrhea (17%), and rash (8%). ConclusionSorafenib was generally well tolerated and provided clinical benefit in a large, diverse population of patients with advanced RCC treated in routine clinical practice.

Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma

AbstractProteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m2. Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820.

Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial

The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov, number NCT01295827. 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses--21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI -14 to 13; p=0·96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 [33%] vs 31 [37%]), pruritus (23 [26%] vs 16 [19%]), and rash (16 [18%] vs 15 [18%]). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. Merck Sharp and Dohme.

A Phase I Trial of LY2510924, a CXCR4 Peptide Antagonist, in Patients with Advanced Cancer

Overexpression of C-X-C motif receptor 4 (CXCR4) is implicated in tumor progression. LY2510924 is a peptide antagonist, which blocks stromal cell-derived factor-1 (SDF1) from CXCR4 binding. This phase I study included two parts: a 3+3 dose escalation (part A) and dose confirmation (part B). LY2510924 was administered as a daily subcutaneous injection on a 28-day cycle. The primary objective was to determine the recommended phase II dose. Secondary objectives included safety, pharmacokinetics, efficacy, and pharmacodynamic response, including mobilization of CD34(+) hematopoietic stem cells into the peripheral blood. Forty-five patients were enrolled, 25 in part A and 20 in part B. Patients were administered increasing doses of LY2510924: 1.0, 2.5, 5.0, 10, 20, and 30 mg/day for part A and 2.5 or 20 mg/day for part B. Two patients (30-mg/day cohort) experienced dose-limiting toxicities of grade 3 increased neutrophil count. The maximum tolerated dose (MTD) was 20 mg/day. The most common drug-related treatment-emergent adverse events were fatigue (9%), injection-site reaction (9%), injection site pruritus (7%), and nausea (7%). The best response was stable disease for nine patients (20%). At the end of cycle 1, mean peak LY2510924 plasma concentration and the 24-hour area under the plasma concentration versus time curve increased slightly more than dose proportionally. LY2510924 dose dependently increased CD34(+) cell counts in peripheral blood up to 18-fold. LY2510924 demonstrated CD34(+) cell mobilization at doses ≥2.5 mg/day with a tolerable safety profile up to an MTD of 20 mg/day.

Stand Up to Cancer Phase Ib Study of Pan-Phosphoinositide-3-Kinase Inhibitor Buparlisib With Letrozole in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer

Buparlisib, an oral reversible inhibitor of all class I phosphoinositide-3-kinases, has shown antitumoral activity against estrogen receptor (ER)-positive breast cancer cell lines and xenografts, alone and with endocrine therapy. This phase Ib study evaluated buparlisib plus letrozole's safety, tolerability, and preliminary activity in patients with metastatic ER-positive breast cancer refractory to endocrine therapy. Patients received letrozole and buparlisib in two different administration schedules. Outcomes were assessed by standard solid-tumor phase I methods. [(18)F]fluorodeoxyglucose-positron emission tomography/computed tomography ([(18)F]FDG-PET/CT) scans were done at baseline and 2 weeks after treatment initiation. Tumor blocks were collected for phosphoinositide-3-kinase pathway mutation analysis. Fifty-one patients were allocated sequentially to continuous or intermittent (five on/two off days) buparlisib administration on an every-4-week schedule. Buparlisib's maximum-tolerated dose (MTD) was 100 mg/d. Common drug-related adverse events included ≤ grade 2 hyperglycemia, nausea, fatigue, transaminitis, and mood disorders. The clinical benefit rate (lack of progression ≥ 6 months) among all patients treated at the MTD was 31%, including two objective responses in the continuous dose arm. Of seven patients remaining on treatment ≥ 12 months, three had tumors with PIK3CA hot-spot mutation. Patients exhibiting metabolic disease progression by [(18)F]FDG-PET/CT scan at 2 weeks progressed rapidly on therapy. The letrozole and buparlisib combination was safe, with reversible toxicities regardless of schedule administration. Clinical activity was observed independent of PIK3CA mutation status. No metabolic response by [(18)F]FDG-PET/CT scan at 2 weeks was associated with rapid disease progression. Phase III trials of buparlisib and endocrine therapy in patients with ER-positive breast cancer are ongoing.

Phase I study of combination chemotherapy using sorafenib and transcatheter arterial infusion with cisplatin for advanced hepatocellular carcinoma

The aims of this study were to evaluate the frequency of dose-limiting toxicities and to find the recommended dose of combination chemotherapy with sorafenib and transcatheter arterial infusion (TAI) using cisplatin for patients with advanced hepatocellular carcinoma (HCC), for whom surgical resection, local ablation therapy, or transcatheter arterial chemoembolization were not indicated. Patients received 800 mg sorafenib daily. Cisplatin was given at one of three dosages (level 1, 35 mg/m2/cycle; level 2, 50 mg/m2/cycle; and level 3, 65 mg/m2/cycle) from feeding arteries to the HCC. The treatment was repeated every 4–6 weeks up to a maximum of six cycles, until there were signs of tumor progression or unacceptable toxicity. The dose-limiting toxicities experienced by the 20 enrolled patients were grade 4 increased aspartate aminotransferase at level 1, grade 3 gastrointestinal hemorrhaging at level 1, and grade 3 hypertension at level 3. The common drug-related adverse events that were of severity grade 3 or 4 included the elevation of aspartate aminotransferase (30%), alanine aminotransferase (20%), amylase (30%), and lipase (30%). Partial response was seen in four patients (20%), and 13 patients (65%) had stable disease. The median overall survival and progression-free survival were 9.1 and 3.3 months, respectively. The combination of sorafenib at 800 mg/day with TAI of cisplatin at 65 mg/m2/cycle was determined to be the recommended regimen. A randomized phase II trial of sorafenib alone versus sorafenib plus TAI of cisplatin is currently underway. This study was registered at UMIN as trial number UMIN000001496.

Randomized Phase II Trial of Nintedanib, Afatinib and Sequential Combination in Castration-Resistant Prostate Cancer

The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients. Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks. Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a ≥50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy. Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration-resistant prostate cancer patients.

Phase II study of i.v. interferon‐gamma in Japanese patients with mycosis fungoides

A multisite, open-label, non-randomized, single-arm phase II study was conducted to evaluate the efficacy and safety profiles of interferon-γ in Japanese patients diagnosed with stage IA-IIIA mycosis fungoides (MF). Interferon-γ was administrated i.v. to 15 patients at a dose of 2million Japan reference units once daily over 5days a week for the first 4weeks, followed by subsequent intermittent injection. The primary efficacy end-point was the overall skin response during the study as assessed according to the evaluation criteria for chemotherapeutics for malignant skin carcinomas. Of the 15 patients, 11 (73.3%) achieved the objective response. Of the other four patients, three remained on treatment during study with stable disease and one showed disease progression. The median duration of stable disease was not reached but was 170days or more (range, 29 to ≥253days). As assessed according to the modified severity weighted assessment tool, nine patients (60.0%) achieved the objective response. The most common drug-related adverse event (AE) was influenza-like illness occurring in all patients enrolled, which did not lead to discontinuation of the study. Two serious AE were reported in two patients: aggravation of MF and aggravation of cataract, neither of which was considered directly related to the study drug. The patient with aggravation of MF died 50days after the initiation of the study treatment. Another patient was withdrawn from the study due to drug-related cough, which disappeared after discontinuation of the drug. Overall, interferon-γ was effective and well-tolerated in Japanese patients with MF.

A phase I, open-label, single-arm, dose-escalation study of E7107, a precursor messenger ribonucleic acid (pre-mRNA) splicesome inhibitor administered intravenously on days 1 and 8 every 21 days to patients with solid tumors

The aim of this study was to determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic profile of E7107 in patients with advanced solid tumors. Patients in this phase I, open-label, single-arm, dose-escalation study had metastatic or locally advanced solid tumors and received E7107 as a 30-minute intravenous infusion at doses of 0.6, 1.2, 1.8, 2.4, 3.2, 4.3, and 5.7 mg/m(2). Twenty-six patients were enrolled in the study. At 5.7 mg/m(2), two patients experienced dose-limiting toxicities including diarrhea, vomiting, dehydration, and myocardial infarction on Days 1-3 following E7107 administration. Three additional patients were recruited at the lower dose and all six patients tolerated E7107 4.3 mg/m(2) with no dose-limiting toxicities. The maximum tolerated dose of E7107 was therefore 4.3 mg/m(2). The most common drug-related adverse events were nausea, vomiting, and diarrhea. Vision loss was experienced by two patients at Cycles 2 and 7, each patient receiving 3.2 mg/m(2) and 4.3 mg/m(2), respectively. This resulted in the study being put on clinical hold. Pharmacokinetic analysis showed that E7107 was rapidly distributed with a moderate elimination half-life (6-13 h) and high clearance. Exposure to E7107 was dose-related. The best tumor response was stable disease in eight patients. E7107 is a unique first-in-class molecule. The incidence of two cases of vision loss probably related to E7107 led to study discontinuation.

Outcome Of Dose-Adjusted Decitabine Regimen Compared With FLAG Regimen In The Treatment Of Relapsed/Refractory Acute Myeloid Leukemia

BackgroundThe salvage therapy in patients with relapsed/refractory acute myeloid leukemia still poses a highly unmet clinical need. Given the established activity and toxicity profiles of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine, DAC) in patients with untreated acute myeloid leukemia (AML), we explored the therapeutic effects of dose adjusted DAC in patients with relapsed / refractory AML, and compared treatment outcome with the conventional FLAG regimen. Patients and Methods27 patients with relapsed/refractory AML were included in this analysis. Twelve patients were treated with DAC 20 mg/m2 per day as 1-hour intravenous infusion for consecutive five days, with additional 1-3 doses of DAC added based on response and tolerability (Table 1). Another group of 15 patients received a course of FLAG regimen as controls.Table 1Adjustment for dose of DAC for relapsed/refractory acute myeloid leukemiaCharacteristicsDose addedCellularity0normal1increased0BM Blast %1No2<5%0®5%-1General condition-1Karnofsky performance score®800Karnofsky performance score<80Age®60<60 ResultsAlthough the overall response rates (ORR) were similar in DAC group (5/12) and FLAG group (9/15)£¨41.7 % versus 60 %, P=0.449£©, the complete remission (CR) rate plus CRi was lower in DAC group (2/12) than in FLAG group(10/15)£¨16.7 %versus 66.7 %, P=0.047£©. Induction mortality was 0 (0% at 8 weeks) and toxicities were manageable in both groups. Toxicities were predominantly hematologic. The most common drug-related adverse events (AEs£© were grade 4 myelosuppression which were comparable for DAC and FLAG., DAC group hadfewer infections£¨DAC, 6/12£»FLAG£€n=14/15, P=0.024£©. The 2-year survival rate was similar in the two groups: 25.0% in the DAC versus 26.7% in the FLAG group£¨P=0.574£©, while median survival times of the two groups were 4 and 12 months, respectively. ConclusionDose-adjusted DAC achieved similar overall response rate with lower infection risk compared to FLAG regimen in patients with relapsed / refractory AML. Disclosures:No relevant conflicts of interest to declare.