Intravenous Dose Escalation Research Articles

Assessment of Subcutaneous vs Intravenous Administration of Anti–PD-1 Antibody PF-06801591 in Patients With Advanced Solid Tumors

We assessed feasibility of monthly subcutaneous administration of PF-06801591, a humanized immunoglobulin G4 monoclonal antibody that binds to the programmed cell death (PD-1) receptor and blocks its interaction with PD-1 ligands. To evaluate the safety, efficacy, and pharmacokinetics of PF-06801591 administered intravenously vs subcutaneously. Ongoing phase 1, open-label, multicenter, dose-escalation study of 40 patients, 18 years or older, with locally advanced or metastatic solid tumors, enrolled between March 8, 2016, and March 5, 2018, from 4 US medical centers. An intravenous dose of 0.5, 1, 3, or 10 mg/kg of PF-06801591 was administered every 3 weeks or a subcutaneous dose of 300 mg was administered every 4 weeks. Dose escalation occurred after 2 to 4 patients were enrolled per dose level, with additional patients enrolled in each cohort for further assessment. The primary end points were dose-limiting toxic effects and safety. Secondary end points included pharmacokinetics, immunogenicity, PD-1 receptor occupancy, and efficacy. Of 40 enrolled patients (12 men and 28 women; mean [SD] age, 61 [13] years) in this phase 1 dose-escalation trial, 25 received PF-06801591 intravenously at escalating dose levels (0.5, 1, 3, or 10 mg/kg) and 15 patients received the monoclonal antibody subcutaneously at a single dose level. No dose-limiting toxic effects were observed. Grade 3 or higher treatment-related adverse events occurred in 4 (16%) patients treated intravenously and 1 (6.7%) patient treated subcutaneously. Immune-related adverse events occurred in 10 (40%) patients treated intravenously and 3 (20%) treated subcutaneously. No dose-adverse event associations were observed during intravenous dose escalation, and no serious skin toxic effects occurred with subcutaneous delivery. Responses were seen in 5 patients receiving PF-06801591 intravenously and in 2 patients treated subcutaneously for an overall objective response rate of 18.4%. Median overall survival was not reached with intravenous dosing vs 10.7 months with subcutaneous administration. Exposure to PF-06801591 increased in a dose-proportional manner over the range of intravenous doses. Median time to maximum observed serum concentration was 8 days after subcutaneous administration. Full PD-1 receptor occupancy was seen in all dose cohorts. Anti-PD-1 antibody PF-06801591 was tolerable and showed antitumor activity in a variety of tumor types across all dose levels of intravenous and subcutaneous administration. Monthly subcutaneous administration of PF-06801591 offers a convenient, effective alternative to currently available intravenously administered checkpoint inhibitors. ClinicalTrials.gov identifier: NCT02573259.

CCL20 neutralization by a monoclonal antibody in healthy subjects selectively inhibits recruitment of CCR6+ cells in an experimental suction blister.

GSK3050002, a humanized IgG1κ antibody with high binding affinity to human CCL20, was administered in a first-in-human study to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD). An experimental skin suction blister model was employed to assess target engagement and the ability of the compound to inhibit recruitment of inflammatory CCR6 expressing cells. This study was a randomized, double-blind (sponsor open), placebo-controlled, single-centre, single ascending intravenous dose escalation trial in 48 healthy male volunteers. GSK3050002 (0.1-20mgkg-1 ) was well tolerated and no safety concerns were identified. The PK was linear over the dose range, with a half-life of approximately 2 weeks. Complex of GSK3050002/CCL20 increased in serum and blister fluid with increasing doses of GSK3050002. There were dose-dependent decreases in CCR6+ cell recruitment to skin blisters with maximal effects at doses of 5mgkg-1 and higher, doses at which GSK3050002/CCL20 complex in serum and blister fluid also appeared to reach maximum levels. These results indicate a relationship between PK, target engagement and PD, suggesting a selective inhibition of recruitment of CCR6+ cells by GSK3050002 and support further development of GSK3050002 in autoimmune and inflammatory diseases.

Ketamine augmentation for outpatients with treatment-resistant depression: Preliminary evidence for two-step intravenous dose escalation.

Preliminary evidence supports the safety and efficacy of subanesthetic ketamine as an experimental antidepressant, although its effects are often not sustained beyond one week. Studies are lacking that have examined the sustained effects of escalating ketamine doses as augmentation in outpatients with treatment-resistant depression. Therefore, the aims of this study were twofold: (1) to assess the safety and antidepressant efficacy of two-step, repeated-dose ketamine augmentation and (2) to assess the duration of ketamine's antidepressant efficacy as augmentation to ongoing antidepressant pharmacotherapy for 3 months after the final infusion. Fourteen patients with treatment-resistant depression were eligible to receive augmentation with six open-label intravenous ketamine infusions over 3 weeks. For the first three infusions, ketamine was administered at a dose of 0.5 mg/kg over 45 minutes; the dose was increased to 0.75 mg/kg over 45 minutes for the subsequent three infusions. The primary outcome measure was response (as measured on Hamilton Depression Rating Scale-28 items). After the completion of three ketamine infusions, 7.1% (1/14) responded; after all six ketamine infusions, 41.7% (5/12) completers responded and 16.7% (2/12) remitted. Intent-to-treat response and remission rates at the end of the final infusion were 35.7% (5/14) and 14.3% (2/14), respectively. However, all but one responder relapsed within 2 weeks after the final infusion. Repeated, escalating doses of intravenous ketamine augmentation were preliminarily found to be feasible, efficacious and well tolerated. Interaction with concomitant medications and elevated level of treatment resistance are possible factors for non-response.

Effect of intravenous dose escalation with alfaxalone and propofol on occurrence of apnoea in the dog

Spontaneous ventilation after induction of anaesthesia with intravenous alfaxalone or propofol was evaluated in a dose escalation study using 6 dogs. Each dog was dosed at 1×, 2×, 5×, 10× and 20× multiples of the labelled doses (2mg/kg for alfaxalone; 6.5mg/kg for propofol), until apnoea was observed. For each administration, the entire calculated dose was delivered over 1min. All 6 dogs ventilated spontaneously after labelled (1×) doses of each drug but became apnoeic at 5× dose of propofol versus 20× dose of alfaxalone. For propofol at 2× and 5× doses, 4 and 0 dogs ventilated spontaneously respectively. For alfaxalone at 2×, 5× and 10× doses all 6, 4 and 1 dog ventilated spontaneously, respectively. The median dose which induced apnoea was higher for alfaxalone (5×) than for propofol (2×) (p=0.05). We concluded that induction of anaesthesia with propofol is more likely to induce apnoea than with alfaxalone.

Randomized, Double-Blind, Placebo-Controlled, Single Intravenous Dose-Escalation Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of the Novel Coronary Smooth Muscle Cell Proliferation Inhibitor Biolimus A9 in Healthy Individuals

Biolimus A9 (BA9) is a novel proliferation inhibitor of coronary smooth muscle cells that has been specifically designed for coating drug-eluting stents. The goals of this study were to identify the highest safe intravenous dose of BA9, to evaluate the dose-dependent pharmacokinetics of BA9 after intravenous administration in humans, and to characterize early clinical symptoms of BA9 toxicity in healthy subjects. This phase 1 trial in healthy subjects was designed as a double-blind, placebo-controlled, randomized, ascending single-dose study. After screening and randomization, 28 volunteers received either placebo (n = 7) or BA9 (n = 21) in a double-blinded fashion. Doses from 0.0075 mg/kg were escalated to 0.25 mg/kg in 4 cohorts. BA9 concentrations were measured using liquid chromatography-tandem mass spectrometry. BA9 doses up to 0.075 mg/kg were well tolerated. Only the highest BA9 dose of 0.25 mg/kg produced reversible drug-related adverse events. The most frequent adverse events were headache, nausea, and mouth ulcers, most likely due to immunosuppression. Exposure to BA9 did not result in electrocardiographic or clinical laboratory changes. BA9 had a terminal half-life of 90.0 ± 40.0 hours (all n = 21, mean ± standard deviation), an apparent clearance from blood of 0.96 ± 1.07 L/kg/h, and a volume of distribution of 96.5 ± 72.6 L/kg.

Subcutaneous Campath-1H (Alemtuzumab) in Fludarabine-Refractory Cll: Interim Analysis of the CLL2h Study of the German Cll Study Group (GCLLSG).

The prognosis of fludarabine-refractory CLL is poor with a median survival time of 10 months. Intravenous Campath-1H (Alemtuzumab) was approved for fludarabine refractory CLL based on a remission rate of 33% and a median survival time of 16 months (Keating et al., Blood 2002). While the standard route of Campath-1H administration is by 2 hour intravenous infusion, the subcutaneous route was shown to be safe and efficacious in first line treatment (Lundin et al., Blood, 2002). The CLL2H trial of the GCLLSG was initiated to evaluate the subcutaneous application of 3 x 30 mg Campath-1H weekly for a maximum of 12 weeks in fludarabine refractory CLL after intravenous dose escalation (3, 10, 30 mg). The current interim analysis is based on the first 50 consecutive patients enrolled until April 2004. Median age was 63 (range 35–79) years, 70% were male, and a median number of 4 (range 1–7) prior lines of therapy had been given. Dose escalation was given in 46, subcutaneous continuation of therapy in 44, and treatment has not been started in 4 patients, respectively. Intravenous dose escalation was accompanied by no or mild (grade I-II) rigors and fever after premedication with paracetamol and antihistamines in the majority of patients, while grade III/IV infusion reactions were rare (n=3). Subcutaneous treatment was continued on an outpatient basis in all cases but had to be temporarily interrupted in 28 patients due to neutropenia (n=18), anemia (n=1), thrombocytopenia (n=3), infections (n=6; CMV reactivations n=3), and was stopped early in 22 cases due to progression (n=9), CMV reactivation (n=3), hematotoxicity (n=7), hemolysis (n=1), side effects (n=1), and infection (n=1). There were 6 cases of CMV reactivation, 5 of which promptly responded to oral valgancyclovir. During subcutaneous treatment toxicity was mostly grade I/II apart from hematotoxicity (grade III/IV anemia: 14%, thrombocytopenia: 34%, neutropenia: 66%) and grade III/IV infections (24%). After a median follow up time of 9.3 months 18 deaths have occurred (progression n=12, sepsis n=3, not CLL related n=2, before treatment start n=1). The overall response rate was 36% (CR 2%, PR 34%), the median progression free survival time was 9.7 months, and median overall survival time was 13.1 months. Analyses of genetic risk factors showed an unmutated VH status in 62% and high-risk genomic aberrations in the majority of patients (17p-: 29%, 11q-: 29%, +12q: 18%, 13q- single: 16%). Responses (CR or PR) were observed in 14 of 27 VH unmutated, 5 of 13 11q-, and 7 of 13 17p- cases. In conclusion, Campath-1H given via the subcutaneous route appears to be feasible in an outpatient setting in a high risk population of fludarabine-refractory CLL and appears to be of similar efficacy as compared to intravenous administration. Most importantly, genetic high risk subgroups with unmutated VH, 11q- or 17p- appear to respond to Campath-1H. An amendment has been activated including prophylactic pegfilgrastim and allowing subcutaneous dose-escalation. An update of this trial with ongoing recruitment and extended follow-up will be presented.

Phase I study of intravenous 4-hydroxyanisole

4-Hydroxyanisole is a depigmenting agent which has been shown to have activity against malignant melanoma when given intra-arterially in man. An intravenous dose escalation study has been carried out with the aim of obtaining maximum plasma concentrations in a 5 day schedule. 8 patients entered this study which was stopped because of drug toxicity after 3 patients had been treated at the third dose escalation of 15 g/m 2. 2 patients had WHO grade 4 liver and one also grade 4 renal toxicity and another had grade 4 haemoglobin toxicity. Extrapolated plateau plasma levels between 112 and 860 μmol/l were obtained, which in vitro studies suggested would be cytotoxic. Hopefully, newer analogues will have a greater specificity for the melanin pathway with less toxicity.