Phase Ib/II Study of Enzalutamide with Samotolisib (LY3023414) or Placebo in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: To report efficacy and safety of samotolisib (LY3023414; PI3K/mTOR dual kinase and DNA-dependent protein kinase inhibitor) plus enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) following cancer progression on abiraterone. PATIENTS AND METHODS: In this double-blind, placebo-controlled phase Ib/II study (NCT02407054), following a lead-in segment for evaluating safety and pharmacokinetics of samotolisib and enzalutamide combination, patients with advanced castration-resistant prostate cancer with progression on prior abiraterone were randomized to receive enzalutamide (160 mg daily)/samotolisib (200 mg twice daily) or placebo. Primary endpoint was progression-free survival (PFS) assessed by Prostate Cancer Clinical Trials Working Group criteria (PCWG2). Secondary and exploratory endpoints included radiographic PFS (rPFS) and biomarkers, respectively. Log-rank tests assessed treatment group differences. RESULTS: Overall, 13 and 129 patients were enrolled in phase Ib and II, respectively. Dose-limiting toxicity was not reported in patients during phase Ib and mean samotolisib exposures remained in the targeted range despite a 35% decrease when administered with enzalutamide. In phase II, median PCWG2-PFS and rPFS was significantly longer in the samotolisib/enzalutamide versus placebo/enzalutamide arm (3.8 vs. 2.8 months; P = 0.003 and 10.2 vs. 5.5 months; P = 0.03), respectively. Patients without androgen receptor splice variant 7 showed a significant and clinically meaningful rPFS benefit in the samotolisib/enzalutamide versus placebo/enzalutamide arm (13.2 months vs. 5.3 months; P = 0.03). CONCLUSIONS: Samotolisib/enzalutamide has tolerable side effects and significantly improved PFS in patients with mCRPC with cancer progression on abiraterone, and this may be enriched in patients with PTEN intact and no androgen receptor splice variant 7.

APF530 versus ondansetron, each in a guideline-recommended three-drug regimen, for the prevention of chemotherapy-induced nausea and vomiting due to anthracycline plus cyclophosphamide-based highly emetogenic chemotherapy regimens: a post hoc subgroup analysis of the Phase III randomized MAGIC trial.

BACKGROUND: APF530, a novel extended-release granisetron injection, was superior to ondansetron in a guideline-recommended three-drug regimen in preventing delayed-phase chemotherapy-induced nausea and vomiting (CINV) among patients receiving highly emetogenic chemotherapy (HEC) in the double-blind Phase III Modified Absorption of Granisetron In the prevention of CINV (MAGIC) trial. PATIENTS AND METHODS: This MAGIC post hoc analysis evaluated CINV prevention efficacy and safety of APF530 versus ondansetron, each with fosaprepitant and dexamethasone, in patient subgroup receiving an anthracycline plus cyclophosphamide (AC) regimen. Patients were randomized 1:1 to APF530 500 mg subcutaneously (granisetron 10 mg) or ondansetron 0.15 mg/kg intravenously (IV) (≤16 mg); stratification was by planned cisplatin ≥50 mg/m2 (yes/no). Patients were to receive fosaprepitant 150 mg IV and dexamethasone 12 mg IV on day 1, then dexamethasone 8 mg orally once daily on day 2 and twice daily on days 3 and 4. Patients were mostly younger females (APF530 arm, mean age 54.1 years, female, 99.3%; ondansetron arm, 53.8 years, female 98.3%). The primary end point was delayed-phase (>24-120 hours) complete response (CR). RESULTS: APF530 versus ondansetron regimens achieved numerically better CINV control in delayed and overall (0-120 hours) phases for CR, complete control, total response, rescue medication use, and proportion with no nausea. APF530 trends are consistent with the overall population, although not statistically superior given the underpowered AC subgroup analysis. The APF530 regimen in this population was generally well tolerated, with safety comparable to that of the overall population. CONCLUSION: APF530 plus fosaprepitant and dexamethasone effectively prevented CINV among patients receiving AC-based HEC, a large subgroup in whom CINV control has traditionally been challenging.

Efficacy of the neurokinin-1 receptor antagonist rolapitant in preventing nausea and vomiting in patients receiving carboplatin-based chemotherapy.

BACKGROUND: Rolapitant, a novel neurokinin-1 receptor antagonist, provided effective protection against chemotherapy-induced nausea and vomiting (CINV) in a randomized, double-blind phase 3 trial of patients receiving moderately emetogenic chemotherapy or an anthracycline and cyclophosphamide regimen. The current analysis explored the efficacy and safety of rolapitant in preventing CINV in a subgroup of patients receiving carboplatin. METHODS: Patients were randomized 1:1 to receive oral rolapitant (180 mg) or a placebo 1 to 2 hours before chemotherapy administration; all patients received oral granisetron (2 mg) on days 1 to 3 and oral dexamethasone (20 mg) on day 1. A post hoc analysis examined the subgroup of patients receiving carboplatin in cycle 1. The efficacy endpoints were as follows: complete response (CR), no emesis, no nausea, no significant nausea, complete protection, time to first emesis or use of rescue medication, and no impact on daily life. RESULTS: In the subgroup administered carboplatin-based chemotherapy (n = 401), a significantly higher proportion of patients in the rolapitant group versus the control group achieved a CR in the overall phase (0-120 hours; 80.2% vs 64.6%; P < .001) and in the delayed phase (>24-120 hours; 82.3% vs 65.6%; P < .001) after chemotherapy administration. Superior responses were also observed by the measures of no emesis, no nausea, and complete protection in the overall and delayed phases and by the time to first emesis or use of rescue medication. The incidence of treatment-emergent adverse events was similar for the rolapitant and control groups. CONCLUSIONS: Rolapitant provided superior CINV protection to patients receiving carboplatin-based chemotherapy in comparison with the control. These results support rolapitant use as part of the antiemetic regimen in carboplatin-treated patients. Cancer 2016;122:2418-2425. © 2016 American Cancer Society.

APF530 (granisetron injection extended-release) in a three-drug regimen for delayed CINV in highly emetogenic chemotherapy.

AIM: APF530, extended-release granisetron, provides sustained release for ≥5 days for acute- and delayed-phase chemotherapy-induced nausea and vomiting (CINV). We compared efficacy and safety of APF530 versus ondansetron for delayed CINV after highly emetogenic chemotherapy (HEC), following a guideline-recommended three-drug regimen. METHODS: HEC patients received APF530 500 mg subcutaneously or ondansetron 0.15 mg/kg intravenously, with dexamethasone and fosaprepitant. Primary end point was delayed-phase complete response (no emesis or rescue medication). RESULTS: A higher percentage of APF530 versus ondansetron patients had delayed-phase complete response (p = 0.014). APF530 was generally well tolerated; treatment-emergent adverse event incidence was similar across arms, mostly mild-to-moderate injection-site reactions. CONCLUSION: APF530 versus the standard three-drug regimen provided superior control of delayed-phase CINV following HEC. ClinicalTrials.gov : NCT02106494.

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 clinician's 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.

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 clinician's 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.

Dosing patterns, toxicity, and outcomes in patients treated with first-line sunitinib for advanced renal cell carcinoma in community-based practices.

BACKGROUND: This retrospective study by McKesson Specialty Health (MSH)/US Oncology Network (USON) evaluates dosing patterns of first-line sunitinib for patients with advanced renal cell carcinoma (aRCC) and its association with toxicities and clinical outcomes in community practices. PATIENTS AND METHODS: Patients with aRCC who started first-line sunitinib between June 1, 2007, and May 31, 2011, were identified from 17 MSH/USON practices. Clinical data were extracted from iKnowMed electronic medical records linked to the MSH/USON pharmacy database. RESULTS: In total, 134 patients were included; mean age was 63.9 years, 85% of the patients had an Eastern Cooperative Oncology Group performance score of 0 or 1, 82% had clear-cell renal cell carcinoma, and 65% had undergone nephrectomy. The median treatment duration was 4 cycles (range, 1-19). Overall, 113 patients discontinued sunitinib, mainly because of disease progression (45.1%) or toxicities (16.8%). Of all discontinuations, 77% occurred within the first 5 cycles. A total of 45 patients were dose-reduced, mostly because of toxicities (93%); 67% of all dose reductions occurred in the first 3 cycles. The objective response rate was 16.4%, median overall survival (OS) was 15.5 months, and progression-free survival (PFS) was 7.5 months. Multivariate analysis showed that OS and PFS were associated with sunitinib treatment duration. CONCLUSIONS: Patients with aRCC from community practices undergo sunitinib dose reductions more frequently because of toxicities and discontinue therapy sooner than in clinical trials. Clinical outcomes were inferior to those reported in clinical trials, potentially because of shorter duration of therapy. Sunitinib therapy optimization remains an important challenge in community practices.

Optimal timing of chemotherapy in androgen independent prostate cancer.

PURPOSE: To interpret available docetaxel clinical trial data in order to define optimal timing of the initiation of chemotherapy in androgen independent prostate cancer (AIPC). MATERIALS AND METHODS: Published literature on the natural history of nonmetastatic AIPC was reviewed. Phase III clinical trials using docetaxel-based therapy were analyzed as well as their associated quality of life (QOL) findings. Trials using docetaxel in earlier stage of the disease, as well those using novel agents were examined. RESULTS: Based on one report, non-metastatic AIPC is relatively indolent, and there is currently no evidence that supports the use of chemotherapy in this disease subset. The results of TAX 327 and SWOG 9916 demonstrate that chemotherapy is indicated for metastatic AIPC. However, based on available data, more than one hormonal maneuver can be offered to patients before chemotherapy is initiated. Timing of docetaxel therapy can further be individualized based on risk, clinical status, and patients' values and preferences. Building on the success of docetaxel, several novel agents that target different pathways are being tested in combination with, or as an alternative to, docetaxel-based therapy in Phase III clinical trials. CONCLUSIONS: Currently, docetaxel therapy should be reserved for patients with metastatic AIPC who have progressed despite one or more hormonal therapies. In most patients, more than one hormonal treatment can be offered before chemotherapy is initiated. Studies that test the efficacy of chemotherapy early in the natural history of prostate cancer are under way or are planned.

Patient-physician disagreement regarding performance status is associated with worse survivorship in patients with advanced cancer.

BACKGROUND: Physician-reported performance status (PS) is an important prognostic factor and frequently influences treatment decisions. To the authors' knowledge, the extent, prognostic importance, and predictors of disagreements in PS assessment between physicians and patients have not been adequately examined. METHODS: Using North Central Cancer Treatment Group (NCCTG) clinical trial data from 1987 through 1990, the authors compared PS (Eastern Cooperative Oncology Group [ECOG] and Karnofsky [KPS]) and nutrition scores reported by physicians and patients individually. Differences were analyzed using a Student t test for paired data and degree of disagreement by kappa statistic. The effect of disagreement on overall survival was determined by the Kaplan-Meier method and Cox regression analysis. Predictors of disagreement were identified by logistic regression. RESULTS: In all, 1636 patients with advanced lung and colorectal cancer had a median survival of 9.8 months (95% confidence interval [95% CI], 9.4-10.4 months). Percent disagreement between patients and physicians regarding KPS, ECOG PS, and nutrition score were 67.1%, 56.6%, and 58.0%, respectively. Physicians were more likely to rate patients better than individual patients were to rate themselves: ECOG (mean 0.91 vs 1.30; P < .0001), KPS (mean 83.3 vs 81.7; P < .0001), and nutrition score (mean 1.6 vs 2.1; P < .0001). Disagreement between patients and their physicians was associated with increased risk of death: KPS (hazards ratio [HR] of 1.16; 95% CI, 1.04-1.30 [P = .008]) and nutrition scores (HR of 1.44; 95% CI, 1.29-1.61 [P < .0001]) after adjustment for covariates. Patient sociodemographic factors that predict disagreement were identified. CONCLUSIONS: Physicians and patients frequently disagree regarding PS and nutritional status. Disagreement is associated with an increased risk of death in patients with advanced malignancies. These findings illustrate the limitations of physician-only assessed PS.

Gastrointestinal stromal tumors: imatinib and beyond.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Clinicians previously classified GISTs as "benign" or "malignant," but now place resected tumors in risk categories that are based on size and mitotic rate. Historically, GIST patients were managed with surgery alone, as chemotherapy and radiotherapy have minimal activity in this disease. In the pre-imatinib era, patients with recurrent or metastatic disease generally did very poorly. GIST therapy was revolutionized following the discovery of oncogenic mutations in the c-kit gene, as well as in the platelet-derived growth factor receptor. Subsequently, it has been confirmed that the KIT receptor tyrosine kinase is both a diagnostic marker and a useful therapeutic target in GIST. Imatinib, a potent inhibitor of KIT activity, is now standard front-line therapy for advanced GIST. With the introduction of imatinib, there have been dramatic improvements in response rates, time to progression, and survival. Imatinib is now being investigated and shows promise in the neoadjuvant and adjuvant settings. Unfortunately, many patients eventually recur or progress during imatinib therapy. For these patients, imatinib dose escalation and/or surgical evaluation are appropriate. Additionally, a novel tyrosine kinase inhibitor such as SU11248 (sunitinib) is a reasonable option for progressive, imatinib-resistant disease. With the identification of other downstream pathways, several other promising therapies are under current investigation either alone or in combination with imatinib and surgery.