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Objective To evaluate the SUMMIT-07 trial opioid withdrawal results of NKTR-181 (oxycodegol), a new molecular entity mu-opioid receptor agonist. Design Phase 3, enriched-enrollment, double-blind, randomized-withdrawal study in patients with chronic low back pain (CLBP). Setting Conducted in the United States at multiple sites. Methods SUMMIT-07 was comprised of five periods: screening; NKTR-181 open-label titration (100 to 400 mg twice daily); 12-week randomized, double-blind study drug (NKTR-181 or placebo); one-week study drug taper; and two-week safety follow-up. Permitted rescue medication included hydrocodone 5 mg/acetaminophen 300 mg (two tablets daily) for two weeks after randomization, then acetaminophen 1.0 gm daily for the remainder of the trial. Signs and symptoms of drug withdrawal were evaluated using the Clinical Opiate Withdrawal Scale (COWS); Subjective Opiate Withdrawal Scale (SOWS); Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS); and withdrawal-related adverse events. Results Of 1,190 patients entering titration, one patient had moderate withdrawal (COWS score 13/48 maximum) three days after discontinuing NKTR-181. Of 610 patients randomized (N = 309, NKTR-181; N = 301, placebo), no COWS scores indicating withdrawal at a moderate level or greater (i.e. score ≥13) were observed at any time point. At day 8 after randomization, week 12, and the end of tapering, COWS scores indicating mild withdrawal (<13) were observed in seven (2.4%), one (0.4%), and one (0.5%) placebo patients, respectively, and three (1.0%), one (0.4%), and five (2.3%) NKTR-181 patients, respectively. Mean SOWS scores in both arms were ≤2.8 of 64 possible points at all time points. During the randomized period, of 35 events identified by MADDERS, adjudicators identified 20 possible "withdrawal" events (9 [2.9%] NKTR-181 and 11 [3.7%] placebo). Conclusions NKTR-181 exhibited a low rate and severity of opioid withdrawal in SUMMIT-07 patients with CLBP. [ABSTRACT FROM AUTHOR]

Objective To evaluate the human abuse potential, pharmacokinetics, pharmacodynamics, and safety of oral NKTR-181 (oxycodegol), a novel full mu-opioid receptor agonist, relative to oral oxycodone. Design This double-blind, randomized, single-dose, crossover human abuse potential study was conducted in healthy, adult, non–physically dependent recreational opioid users. Setting Inpatient clinical research site. Subjects Seventy-one subjects randomized (95.7% male, 65.2% African American, mean age = 31.7 years). Methods The primary objective was to compare two therapeutic doses of NKTR-181 (400 and 600 mg) with 40 and 60 mg of oxycodone and a supratherapeutic dose (1200 mg) of NKTR-181 with 60 mg of oxycodone using visual analog scale (VAS) ratings for Drug Liking "at this moment" (Drug Liking). Secondary objectives included VAS ratings for other subjective measures, and central nervous system (CNS) mu-opioid effects were assessed using pupillometry. Each subject received single oral doses of five treatments and matching placebo. Results Compared with 40 and 60 mg of oxycodone, the maximum mean Drug Liking score at 400 and 600 mg NKTR-181 was significantly lower, and the rate of onset and extent of Drug Liking for all NKTR-181 doses in the first two hours postdose were also significantly lower. Delayed attenuated Drug Liking and pupillary miosis response following administration of NKTR-181 vs oxycodone were consistent with slower NKTR-181 CNS entry kinetics and mu-opioid receptor binding. No adverse events were rated as severe, and somnolence and dizziness occurred more frequently when subjects received oxycodone. Conclusions NKTR-181 at oral doses of 400 and 600 mg showed significantly fewer and less severe subjective effects accepted as representative of opioid abuse potential, such as lower peak Drug Liking in recreational opioid users, than 40 and 60 mg of oxycodone. [ABSTRACT FROM AUTHOR]

Purpose: Etirinotecan pegol (EP) is a long-acting topoisomerase-I inhibitor designed to provide sustained exposure to SN-38 (active metabolite of irinotecan). This phase II study compared EP versus irinotecan as second-line treatment for KRAS-mutant, irinotecan-naïve, metastatic colorectal cancer (mCRC).Methods: Patients were randomized to EP 145 mg/m2 or irinotecan 350 mg/m2 Q21d until disease progression/unacceptable toxicity. The primary endpoint was progression-free survival (PFS) with response determined by central radiologic review (RECIST version 1.1).Results: The study was terminated before completing accrual due to evolving standards of care. Eighty-three patients were randomized. Median PFS was longer with EP versus irinotecan (4.0 versus 2.8 months, respectively; HR 0.65; 95% CI 0.40-1.04; P = 0.07). Six-month PFS rates were 32.8 and 15.4%, respectively. Median OS was 9.6 and 8.4 months in EP and irinotecan arms, respectively (HR 0.91; 95% CI 0.56-1.49). ORRs were 10 and 5%, respectively (P = 0.676); median DOR was significantly longer in EP arm (7.9 versus 1.4 months; P = 0.018). The most common grade-3/4 adverse events for EP and irinotecan were diarrhea (21 vs 20%), neutropenia (10 vs 22%), abdominal pain (14 vs 5%), nausea (14 vs 2%), and vomiting (12 vs 7%), respectively.Conclusion: EP is active and safe for second-line treatment of KRAS-mutant, irinotecan-naïve mCRC. [ABSTRACT FROM AUTHOR]

Background Health-related quality of life (HRQoL) enhances understanding of treatment effects that impact clinical decision-making. Although the primary end-point was not achieved, the BEACON (BrEAst Cancer Outcomes with NKTR-102) trial established etirinotecan pegol, a long-acting topoisomerase-1 (TOP1) inhibitor, as a promising therapeutic for patients with advanced/metastatic breast cancer (MBC) achieving clinically meaningful benefits in median overall survival (OS) for patients with stable brain metastases, with liver metastases or ≥ 2 sites of metastatic disease compared to treatment of physician's choice (TPC). Reported herein are the findings from the preplanned secondary end-point of HRQoL. Patients and methods HRQoL, assessed by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) (version 3.0) supplemented by the breast cancer-specific Quality of Life Questionnaire (QLQ-BR23), was evaluated post randomisation in 733 of 852 patients with either anthracycline-, taxane- and capecitabine-pretreated locally recurrent or MBC randomised to etirinotecan pegol ( n = 378; 145 mg/m 2 every 3 weeks (q3wk)) or single-agent TPC ( n = 355). Patients completed assessments at screening, every 8 weeks (q8wk) during treatment, and end-of-treatment. Changes from baseline were analysed, and the proportions of patients achieving differences (≥5 points) in HRQoL scores were compared. Results Differences were seen favouring etirinotecan pegol up to 32 weeks for global health status (GHS) and physical functioning scales ( P < 0.02); numerical improvement was reported in other functional scales. The findings from HRQoL symptom scales were consistent with adverse event profiles; etirinotecan pegol was associated with worsening gastrointestinal symptoms whereas TPC was associated with worsened dyspnoea and other systemic side-effects. Analysis of GHS and physical functioning at disease progression showed a decline in HRQoL in both treatment arms, with a mean change from baseline of −9.4 and −10.8 points, respectively. Conclusion There was evidence of benefit associated with etirinotecan pegol compared with current standard of care agents in multiple HRQoL measurements, including global health status and physical functioning, despite worse gastrointestinal symptoms (e.g. diarrhoea). Patients in both arms had a decline in HRQoL at disease progression. Study number NCT01492101 . [ABSTRACT FROM AUTHOR]

Background: New options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that prolongs exposure to, but reduces the toxicity of, SN38 (the active metabolite of irinotecan). We assessed whether etirinotecan pegol is superior to currently available treatments for patients with previously treated, locally recurrent or metastatic breast cancer.Methods: In this open-label, multicentre, randomised phase 3 study (BEACON; BrEAst Cancer Outcomes with NKTR-102), conducted at 135 sites in 11 countries, patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline, a taxane, and capecitabine (and two to five previous regimens for advanced disease) were randomly assigned (1:1) centrally via an interactive response system to etirinotecan pegol (145 mg/m(2) as a 90-min intravenous infusion every 3 weeks) or single-drug treatment of physician's choice. Patients with stable brain metastases and an Eastern Cooperative Oncology Group performance status of 0-1 were eligible. Randomisation was stratified with a permuted block scheme by region, previous eribulin, and receptor status. After randomisation, patients and investigators were aware of treatment assignments. The primary endpoint was overall survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01492101.Findings: Between Dec 19, 2011, and Aug 20, 2013, 852 patients were randomly assigned; 429 to etirinotecan pegol and 423 to treatment of physician's choice. There was no significant difference in overall survival between groups (median 12·4 months [95% CI 11·0-13·6] for the etirinotecan pegol group vs 10·3 months [9·0-11·3] for the treatment of physician's choice group; hazard ratio 0·87 [95% CI 0·75-1·02]; p=0·084). The safety population includes the 831 patients who received at least one dose of assigned treatment (425 assigned to etirinotecan pegol and 406 to treatment of physician's choice). Serious adverse events were recorded for 128 (30%) patients treated with etirinotecan pegol and 129 (32%) treated with treatment of physician's choice. Fewer patients in the etirinotecan pegol group had grade 3 or worse toxicity than those in the treatment of physician's choice group (204 [48%] vs 256 [63%]; p<0·0001). The most common grade 3 or worse adverse events were diarrhoea (41 [10%] in the experimental group vs five [1%] in the control group), neutropenia (41 [10%] vs 125 [31%]), and peripheral neuropathy (two [<1%] vs 15 [4%]). Three patients in the etirinotecan pegol group died of treatment-related adverse events (pneumonia, myelodysplastic syndrome, and acute renal failure) and two in the treatment of physician's choice group (neutropenic sepsis and septic shock).Interpretation: This trial did not demonstrate an improvement in overall survival for etirinotecan pegol compared to treatment of physician's choice in patients with heavily pre-treated advanced breast cancer. The toxicity profile noted in the etirinotecan pegol group differed from that in the control group. In view of the frequency of cross-resistance and overlapping toxicities noted with many available drugs and the need for effective drugs in highly refractory disease, etirinotecan pegol may warrant further research in some subgroups of patients.Funding: Nektar Therapeutics. [ABSTRACT FROM AUTHOR]