Sujata Arora

Multicenter Study of Decitabine Administered Daily for 5 Days Every 4 Weeks to Adults With Myelodysplastic Syndromes: The Alternative Dosing for Outpatient Treatment (ADOPT) Trial

PURPOSE Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 mg/m(2) administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices. PATIENTS AND METHODS Patients were treated with decitabine 20 mg/m(2) by IV infusion daily for 5 consecutive days every 4 weeks. Eligible patients were > or = 18 years of age and had MDS (de novo or secondary) of any French-American-British (FAB) subtype and an International Prognostic Scoring System (IPSS) score > or = 0.5. The primary end point was the overall response rate (ORR) by International Working Group (IWG 2006) criteria; secondary end points included cytogenetic responses, hematologic improvement (HI), response duration, survival, and safety. RESULTS Ninety-nine patients were enrolled; the ORR was 32% (17 complete responses [CR] plus 15 marrow CRs [mCRs]), and the overall improvement rate was 51%, which included 18% HI. Similar response rates were observed in all FAB subtypes and IPSS risk categories. Among patients who improved, 82% demonstrated responses by the end of cycle 2. Among 33 patients assessable for a cytogenetic response, 17 (52%) experienced cytogenetic CR (n = 11) or partial response (n = 6). CONCLUSION Decitabine given on a 5-day schedule provided meaningful clinical benefit for patients with MDS, with more than half demonstrating improvement. This suggests that decitabine can be administered in an outpatient setting with comparable efficacy and safety to the United States Food and Drug Administration-approved inpatient regimen.

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of cisplatin-based highly emetogenic chemotherapy in patients with cancer: two randomised, active-controlled, double-blind, phase 3 trials

BACKGROUND Highly emetogenic chemotherapy induces emesis in almost all patients in the absence of prophylaxis. Guidelines recommend use of a neurokinin-1 (NK-1) receptor antagonist in conjunction with a 5-HT3 receptor antagonist and corticosteroid in patients receiving highly emetogenic chemotherapy. We aimed to assess rolapitant, an NK-1 receptor antagonist, for prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of cisplatin-based highly emetogenic chemotherapy. METHODS We conducted two global, randomised, double-blind, active-controlled, phase 3 trials (HEC-1 and HEC-2) at 155 cancer centres (76 in HEC-1 and 79 in HEC-2) in 26 countries (17 in HEC-1 and 14 in HEC-2). We enrolled patients with cancer aged 18 years or older, who had not previously been treated with cisplatin, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly assign patients to treatment. Patients were stratified by sex and randomly allocated to either oral rolapitant (180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) about 1-2 h before administration of highly emetogenic chemotherapy. All patients received granisetron (10 μg/kg intravenously) and dexamethasone (20 mg orally) on day 1, and dexamethasone (8 mg orally) twice daily on days 2-4. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients were allowed to receive the same study drug they were assigned in cycle 1, unless removed at the clinicians discretion. Patients could also choose to leave the study at any point. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a cancer centre compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. These studies are registered with ClinicalTrials.gov, numbers NCT01499849 and NCT01500213. Both studies have been completed. FINDINGS Between Feb 21, 2012, and March 12, 2014, 532 patients in HEC-1 and 555 patients in HEC-2 were randomly assigned to treatment. 526 patients in HEC-1 (264 rolapitant and 262 active control) and 544 in HEC-2 (271 rolapitant and 273 active control) received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients in the rolapitant group had complete responses in the delayed phase than did patients in the active control group (HEC-1: 192 [73%] vs 153 [58%]; odds ratio 1·9, 95% CI 1·3-2·7; p=0·0006; HEC-2: 190 [70%] vs 169 [62%]; 1·4, 1·0-2·1; p=0·0426; pooled studies: 382 [71%] vs 322 [60%]; 1·6, 1·3-2·1; p=0·0001). The incidence of adverse events was similar across treatment groups. The most commonly reported treatment-related treatment-emergent adverse events in the rolapitant versus active control groups were headache (three [<1%] vs two [<1%]), hiccups (three [<1%] vs four [<1%]), constipation (two [<1%] vs three [<1%]), and dyspepsia (two [<1%] vs three [<1%]). For cycle 1, the most common grade 3-5 adverse events in patients allocated rolapitant versus active control were neutropenia (HEC-1: nine [3%] vs 14 [5%]; HEC-2: 16 [6%] vs 14 [5%]), anaemia (HEC-1: one [<1%] vs one [<1%]; HEC-2: seven [3%] vs two [<1%]), and leucopenia (HEC-1: six [2%] vs two [<1%]; HEC-2: two [<1%] vs two [<1%]). No serious treatment-emergent adverse events were treatment related, and no treatment-related treatment-emergent adverse events resulted in death. INTERPRETATION Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well-tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the at-risk period (120 h) after administration of highly emetogenic cisplatin-based chemotherapy. FUNDING TESARO, Inc.

Safety and efficacy of rolapitant for prevention of chemotherapy-induced nausea and vomiting after administration of moderately emetogenic chemotherapy or anthracycline and cyclophosphamide regimens in patients with cancer: A randomised, active-controlled, double-blind, phase 3 trial

BACKGROUND Chemotherapy-induced nausea and vomiting is a common side-effect of many antineoplastic regimens and can occur for several days after treatment. We aimed to assess the neurokinin-1 receptor antagonist rolapitant, in combination with a serotonin (5-HT3) receptor antagonist and dexamethasone, for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. METHODS We conducted a global, randomised, double-blind, active-controlled, phase 3 study at 170 cancer centres in 23 countries. We included patients with cancer aged 18 years or older, who had not received moderately or highly emetogenic chemotherapy before, with a Karnofsky performance score of 60 or higher, and a predicted life expectancy of 4 months or longer. We used an interactive web-based randomisation system to randomly allocate patients to receive either oral rolapitant (one 180 mg dose; rolapitant group) or a placebo that was identical in appearance (active control group) 1-2 h before administration of moderately emetogenic chemotherapy. Patients were stratified by sex. All patients also received granisetron (2 mg orally) and dexamethasone (20 mg orally) on day 1 (except for patients receiving taxanes as part of moderately emetogenic chemotherapy, who received dexamethasone according to the package insert) and granisetron (2 mg orally) on days 2-3. Every cycle was a minimum of 14 days. In up to five subsequent cycles, patients received the same study drug they were assigned in cycle 1, unless they chose to leave the study or were removed at the treating clinicians discretion. Efficacy analysis was done in the modified intention-to-treat population (comprising all patients who received at least one dose of study drug at a study site compliant with Good Clinical Practice [GCP]). The primary endpoint was the proportion of patients achieving a complete response (defined as no emesis or use of rescue medication) in the delayed phase (>24-120 h after initiation of chemotherapy) in cycle 1. This study is registered with ClinicalTrials.gov, number NCT01500226. The study has been completed. FINDINGS Between March 5, 2012, and Sept 6, 2013, 1369 patients were randomised to receive either rolapitant (n=684) or active control (n=685). 666 patients in each group received at least one dose of study drug at a GCP-compliant site and were included in the modified intention-to-treat population. A significantly greater proportion of patients receiving rolapitant had complete responses in the delayed phase than did those receiving active control (475 [71%] vs 410 [62%]; odds ratio 1·6, 95% CI 1·2-2·0; p=0·0002). The incidence of adverse events was similar in the rolapitant and control groups, with the most frequently reported treatment-related treatment-emergent adverse events being fatigue, constipation, and headache. For cycle 1, the most common grade 3-4 adverse event in the rolapitant versus active control groups was neutropenia (32 [5%] vs 23 [3%] patients). No serious adverse event was treatment-related, and no treatment-related treatment-emergent adverse event resulted in death. INTERPRETATION Rolapitant in combination with a 5-HT3 receptor antagonist and dexamethasone is well tolerated and shows superiority over active control for the prevention of chemotherapy-induced nausea and vomiting during the 5-day (0-120 h) at-risk period after administration of moderately emetogenic chemotherapy or regimens containing an anthracycline and cyclophosphamide. FUNDING TESARO, Inc.

Efficacy and safety of rolapitant for prevention of chemotherapy-induced nausea and vomiting over multiple cycles of moderately or highly emetogenic chemotherapy.

OBJECTIVE Rolapitant, a novel neurokinin-1 receptor antagonist (RA), was shown to protect against delayed chemotherapy-induced nausea and vomiting (CINV) during the first cycle of moderately emetogenic chemotherapy (MEC) or highly emetogenic chemotherapy (HEC) in randomized, double-blind trials. This analysis explored the efficacy and safety of rolapitant in preventing CINV over multiple cycles of MEC or HEC. PATIENTS AND METHODS Patients in one phase III MEC, one phase II HEC, and two phase III HEC clinical trials were randomized to receive oral rolapitant (180 mg) or placebo in combination with a 5-hydroxytryptamine type 3 RA and dexamethasone. Regardless of response in cycle 1, patients could continue the same antiemetic treatment for up to six cycles. On days 6-8 of each subsequent chemotherapy cycle, patients reported the incidence of emesis and/or nausea interfering with normal daily life. Post hoc analyses of pooled safety and efficacy data from the four trials were performed for cycles 2-6. RESULTS Significantly more patients receiving rolapitant than control reported no emesis or interfering nausea (combined measure) in cycles 2 (p = 0.006), 3 (p < 0.001), 4 (p = 0.001), and 5 (p = 0.021). Over cycles 1-6, time-to-first emesis was significantly longer with rolapitant than with control (p < 0.001). The incidence of treatment-related adverse events during cycles 2-6 was similar in rolapitant (5.5%) and control (6.8%) arms. No cumulative toxicity was observed. CONCLUSIONS Over multiple cycles of MEC or HEC, rolapitant provided superior CINV protection and reduced emesis and nausea interfering with daily life compared with control and remained well tolerated.

Bioequivalence of Intravenous and Oral Rolapitant: Results From a Randomized, Open‐Label Pivotal Study

Rolapitant, a selective and long‐acting neurokinin‐1 receptor antagonist, is approved in an oral formulation for the prevention of delayed chemotherapy‐induced nausea and vomiting in adults. The objective of this pivotal study was to assess the bioequivalence of a single intravenous infusion of rolapitant versus a single oral dose of rolapitant. In this randomized, open‐label phase 1 study, healthy volunteers were administered rolapitant as a 180‐mg oral dose or a 30‐minute 166.5‐mg intravenous infusion. Blood samples for pharmacokinetic analysis were collected predose and at points up to 912 hours postdose. Criteria for bioequivalence of the intravenous dose versus the oral dose were met if the 90% confidence intervals (CIs) for the ratios of the geometric least‐squares means (GLSMs) for the area under the plasma concentration‐time curve (AUC) from time 0 to the time of the last quantifiable concentration (AUC0–t) and AUC from time 0 extrapolated to infinity (AUC0–∞) for rolapitant were within 0.80–1.25. Mean rolapitant systemic exposure and half‐lives were similar in the oral (n = 62) and intravenous (n = 61) rolapitant groups. The 90%CIs of the ratio of GLSMs were within the 0.80–1.25 range for AUC0–t (0.94–1.09) and AUC0–∞ (0.93–1.10). The incidence of treatment‐emergent adverse events, all mild or moderate in severity, was similar in the intravenous and oral groups. A 166.5‐mg intravenous infusion of rolapitant met the bioequivalence criteria based on AUC to a 180‐mg oral dose and was well tolerated.

Effects of Rolapitant Administered Intravenously or Orally on the Pharmacokinetics of Digoxin (P‐glycoprotein Substrate) and Sulfasalazine (Breast Cancer Resistance Protein Substrate) in Healthy Volunteers

Rolapitant is a selective and long‐acting neurokinin‐1 receptor antagonist approved in an oral formulation in combination with other antiemetic agents for the prevention of delayed chemotherapy‐induced nausea and vomiting in adults. Four open‐label phase 1 studies evaluated the safety and drug–drug interactions of a single dose of rolapitant given intravenously (166.5 mg) or orally (180 mg) with oral digoxin (0.5 mg) or sulfasalazine (500 mg), probe substrates for the P‐glycoprotein (P‐gp) and breast cancer resistance protein (BCRP), respectively. Administration of intravenous rolapitant with the substrates did not result in clinically significant effects on digoxin and sulfasalazine pharmacokinetics. In contrast, peak concentration and area under the curve for last quantifiable plasma concentrations increased by 71% (geometric mean ratio [GMR], 1.71; 90% confidence interval [CI], 1.49–1.95) and 30% (GMR, 1.30; 90%CI, 1.19–1.42), respectively, when rolapitant was coadministered orally with digoxin compared with digoxin alone; they increased by 140% (GMR, 2.40; 90%CI, 2.02–2.86) and 127% (GMR, 2.27; 90%CI, 1.94–2.65), respectively, when rolapitant was given orally with sulfasalazine compared with sulfasalazine alone. Adverse events were mild to moderate in severity in the absence or presence of rolapitant. There were no abnormal clinical laboratory or electrocardiogram findings. Thus, whether administered orally or intravenously, rolapitant was safe and well tolerated. Patients taking oral rolapitant with P‐gp and BCRP substrates with a narrow therapeutic index should be monitored for potential adverse events; although increased plasma concentrations of these substrates may raise the risk of toxicity, they are not contraindicated.

Assessment of ATRX expression in patients with myelodysplastic syndromes treated with decitabine

Treatment with one of the DNA methyltransferase inhibitors (DNMTIs, “hypomethylating agents”), azacitidine or decitabine, is now considered standard care for patients with higherrisk myelodysplastic syndromes (MDS) (1) – especially since results were released from the AZA-001 trial (2), which demonstrated a 9-month survival advantage with azacitidine therapy compared to supportive care. However, many patients with MDS do not respond to treatment with DNMTIs as they are currently used, and adverse events are common. It is desirable to be able to predict a priori which patients are most likely to benefit from DNMTI therapy, in order to spare patients unlikely to respond from the risks and cost of treatment, but there are currently no well-established molecular methods for DNMTI response prediction.(3) ATRX is an X-encoded chromatin-associated protein with an evolutionarily conserved Nterminal DNA methyltransferase (DNMT3-like) domain.(4) Germline mutations in ATRX cause a mental retardation-dysmorphology syndrome often associated with mild alpha thalassemia, which gave the gene its name (ATR-X syndrome: alpha thalassemia, retardation, X-linked) (5); in contrast, somatic point mutations in ATRX have been linked to acquired alpha thalassemia arising in the context of MDS, which may be present in as many as 8% of patients. (6-8) Germline mutations in ATRX are associated with widespread and diverse DNA methylation abnormalities across the genome.(9) Recent evidence suggests that the ATRX protein also has an important role in chromosome dynamics during mitosis, as ATRX-depleted cells exhibit defective sister chromatid cohesion and congression at the metaphase plate, as well as abnormal chromosome alignment. (10,11) Circumstantial evidence for a role of ATRX in neoplasia is increasing. In an array-based gene expression profiling study of 42 children with acute myeloid leukemia (AML) associated with somatic FLT3 mutations, the expression ratio of the transcription factor RUNX3 (formerly AML2) to ATRX predicted event-free survival (EFS).(12) In a subsequent study of 132 adults with de novo AML by another investigative group, low ATRX expression correlated with highrisk karyotype and poor clinical outcome.(13) Altered ATRX expression levels have also been reported in gene expression profiling experiments using prostate cancer primary cells (14), esophageal squamous cell carcinoma cell lines (15), chronic lymphocytic leukemia primary cells (Neil Kay, personal communication October 2007), and irradiated breast cancer cell lines (16).

Rolapitant for the prevention of nausea in patients receiving moderately or highly emetogenic chemotherapy.

224 Background: Nausea control remains an unmet need for patients receiving moderately or highly emetogenic chemotherapy (MEC, HEC). The objective of this analysis was to determine the effect of the neurokinin-1 (NK-1) receptor antagonist rolapitant (VARUBI) on the prevention of nausea in patients receiving either MEC or HEC. METHODS Post hoc analyses of nausea from three randomized, double-blind, active-controlled, phase 3 clinical trials were performed for carboplatin-based MEC (n = 401), non-carboplatin-based MEC (n = 228), total MEC (n = 629), anthracycline/cyclophosphamide (AC)-based chemotherapy (n = 703), and cisplatin-based HEC (n = 1070). Patients were randomized 1:1 to oral rolapitant 180 mg or placebo ~1-2 h before chemotherapy. All patients received active control: granisetron 2 mg oral or 10 mcg/kg IV and oral dexamethasone 20 mg. Granisetron was continued on days 2 and 3 for patients receiving MEC or AC-based therapy and dexamethasone 8 mg twice daily on days 2-4 for patients receiving HEC. Patients self-assessed nausea on days 1-6 using a 100-mm visual analog scale (VAS). Percentage of patients with no nausea (NN; maximum VAS < 5 mm) or no significant nausea (NSN; maximum VAS < 25 mm) was determined for overall, delayed, and acute phases of CINV in cycle 1. RESULTS Rates of NN in the carboplatin-based MEC and total MEC subgroups were significantly higher (P < 0.05) with rolapitant than active control in the delayed and overall phases. In the cisplatin-based HEC subgroup, rates of NN and NSN were significantly higher (P < 0.05) with rolapitant than active control in the delayed, acute, and overall phases. CONCLUSIONS Rolapitant prevents nausea during all CINV phases in patients receiving cisplatin-based HEC, and during the delayed and overall phases in patients receiving carboplatin-based MEC. CLINICAL TRIAL INFORMATION NCT01500226, NCT01499849, NCT01500213.

Rolapitant for control of chemotherapy-induced nausea and vomiting (CINV) in patients with gynecologic cancer.

223 Background: Rolapitant, a long-acting neurokinin-1 receptor antagonist, protected against CINV in patients receiving highly or moderately emetogenic chemotherapy (HEC or MEC). METHODS In 3 double-blind phase 3 studies, patients were randomized to receive oral rolapitant 180 mg or placebo before administration of HEC or MEC. All patients received a 5-hydroxytryptamine type 3 receptor antagonist and dexamethasone. In a post hoc analysis of 3 pooled studies (2 HEC and 1 MEC), we assessed the efficacy and safety of rolapitant in patients with gynecologic (ovarian, uterine, or cervical) cancer. Endpoints included complete response (CR; no emesis and no use of rescue medication), no emesis, no nausea (maximum visual analogue scale [VAS] < 5 mm), and complete protection (CP; no emesis, no use of rescue medication, and no significant nausea [maximum VAS < 25 mm]) in the overall (0-120 h), acute (≤ 24 h), and delayed (> 24-120 h) phases. RESULTS Of 201 patients with gynecologic cancer (60% ovarian, 28% uterine, and 12% cervical cancer), 55% received cisplatin-based HEC and 44% received MEC (99% of whom received carboplatin-based therapy). In the overall and delayed phases, improved rates of CR, no emesis, no nausea, and CP were observed with rolapitant compared with control (Table). The overall incidence of treatment-emergent adverse events was similar in the rolapitant and control groups (45% vs 54%). CONCLUSIONS Rolapitant protected against overall and delayed CINV in patients with gynecologic cancer receiving HEC or MEC. CLINICAL TRIAL INFORMATION NCT01500226, NCT01499849, NCT01500213. [Table: see text].

Abstract C62: Effects of rolapitant on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects

Introduction: Rolapitant is a selective and long acting NK-1 receptor antagonist for the prevention of chemotherapy-induced nausea and vomiting (CINV). In vitro results indicated rolapitant mildly inhibited cytochrome P450 (CYP450) enzymes (2D6/2C9/2C19/2B6/2C8) at high concentrations (IC50s > 7 μM). The major metabolite SCH720881 did not inhibit these CYP enzymes. This study aimed to 1) evaluate the effects of rolapitant on the pharmacokinetics (PK) of CYP probe substrates (dextromethorphan [DET] for CYP2D6, tolbutamide [TOL] for CYP2C9, omeprazole [OMP] for CYP2C19, efavirenz [EFA] for CYP2B6 and repaglinide [REP] for CYP2C8), and 2) evaluate the safety and tolerability of rolapitant co-administered with these substrates in healthy subjects. Methods: This was an open-label, multi-part drug-drug interaction study in cohorts of 20 to 26 healthy subjects of orally-administered CYP probe substrates (Part-A: 30 mg DET; Part-B: 500 mg TOL plus 40 mg OMP; Part-C: 600 mg EFA; Part-D: 0.25 mg REP) in the absence and presence of single oral dose 180 mg rolapitant. Blood samples for determination of plasma concentration of CYP substrates and relevant metabolites were collected during 3 dosing periods in each part: 1) Period-1: CYP probe substrate alone as baseline; 2) Period-2: CYP probe substrate plus rolapitant concomitantly after a washout of probe given in Period 1 to evaluate the potential impact of rolapitant on probe substrate; and 3) Period-3: CYP probe substrate alone 7 days after the concomitant dose in Period-2 (approximating the peak time of metabolite SCH720881) to evaluate the impact of metabolite/rolapitant on probe substrate. Results: Rolapitant inhibited CYP2D6 following concomitant dose (Period-2) and 7 days after concomitant dose (Period-3), resulting in 2.2- to 3.3-fold higher exposure (Cmax and AUC) of DET. Rolapitant did not inhibit CYP2C9 following exposure to TOL. The exposure (Cmax & AUC) of CYP2C19 substrate OMP was minimally increased by rolapitant (1.1- to1.4-fold) and is unlikely to be clinically relevant. Rolapitant did not inhibit CYP2B6 or result in clinically relevant changes in exposure of EFA. Rolapitant did not inhibit CYP2C8 or result in clinically relevant changes in exposure of REP. There were no noteworthy adverse events or laboratory findings in any part of the study. Conclusions: Rolapitant was well-tolerated when co-administered with CYP probe substrates. Co-administration of rolapitant increased the exposure of DET. The inhibition of CYP2D6 can last at least 7 days following single dose of rolapitant. No clinically significant interaction was observed between rolapitant and substrates of CYP2C9, CYP2C19, CYP2B6 or CYP2C8; therefore no dosing adjustment is necessary for drugs which are metabolized by these CYPs. Citation Format: Xiaodong Wang, Zhi-Yi Zhang, Jing Wang, Sharon Lu, Sujata Arora, Lorraine Hughes, Jennifer Christensen, Vikram Kansra. Effects of rolapitant on the pharmacokinetics of dextromethorphan (CYP2D6), tolbutamide (CYP2C9), omeprazole (CYP2C19), efavirenz (CYP2B6), and repaglinide (CYP2C8) in healthy subjects. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C62.