1098. A Phase 1 Safety and Tolerability of Single Ascending Doses of a Novel Engineered Cationic Peptide, PLG0206, in Healthy Subjects

Abstract Background PLG0206 is a novel engineered cationic antimicrobial peptide being evaluated for treatment of prosthetic joint infections (PJI). This abstract presents the results from the first in human study to evaluate the safety, tolerability and pharmacokinetic (PK) profile of PLG0206 when administered as an intravenous (IV) infusion. Methods 6 cohorts of 8 participants were planned to receive escalating single 1-hour IV infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, 1, 2 and 3 mg/kg dose or placebo. Participants were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). At each dose level, there were 2 sentinel participants (1 active, 1 placebo) who were dosed at least 48 hours in advance of the other participants in their group. Serial pharmacokinetic samples were taken prior to infusion and up to 48 post infusion. Safety and tolerability was assessed throughout the study. There was at least a 7-day period after dosing at each of the dose levels before dose escalation. Results PLG0206 was safe and well tolerated when administered to healthy volunteers at doses ranging from 0.05 and 1 mg/kg. Therapeutic exposures were achieved at 1 mg/kg. The 2 and 3 mg/kg cohorts were not studied. The incidence of treatment emergent adverse events related to study drug administration was low and most events mild (Grade 1) in severity and was similar between the PLG0206 treatment and placebo groups. There were no SAEs, life-threatening events or deaths throughout the study. IV PLG0206 exhibited linear PK over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t½) ranged from 7.37 to 19.97 hours. AUC0-∞ increased with increasing PLG0206 dose ranging between 1581.41 and 21141.52 ng.hr/mL. Cmax ranged between 256 and 2653 ng/mL. The mean apparent volume of distribution (Vz) increased was between 25.49 and 94.2 L, mean clearance (CL) were similar across all and ranged from 2.42 to 4.18 L/hour. Conclusion Following single IV infusion to healthy volunteers, PLG0206 was safe and well tolerated at doses ranging from 0.05 to 1 mg/kg. IV PLG0206 exhibits linear PK over the dose range. These findings support the ongoing development of IV PLG0206 and will inform dosing regimens in future studies to investigate its utility as an antimicrobial agent. Disclosures David Huang, MD, PhD, Peptilogics (Employee) Despina Dobbins, BS, Peptilogics (Employee) Parviz Ghahramani, PhD, PharmD, MSc, MBA, Peptilogics (Consultant) Jonathan Steckbeck, PhD, Peptilogics (Employee)

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A Phase 1 Study of Safety, Tolerability and Pharmacokinetics of Single Ascending Doses of a First in Human Engineered Cationic Peptide, PLG0206, Intravenously Administered in Healthy Subjects

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01441-21 ◽

2021 ◽

Author(s):

David Huang ◽

Despina Dobbins ◽

Parviz Ghahramani ◽

Ian Friedland ◽

Jonathan Steckbeck

Keyword(s):

Adverse Events ◽

Healthy Subjects ◽

Phase 1 ◽

Dose Range ◽

Human Study ◽

Serious Adverse Events ◽

Cationic Antimicrobial Peptide ◽

Post Infusion ◽

Life Threatening ◽

To Receive

Background : In this first in human study, PLG0206, a novel engineered cationic antimicrobial peptide was evaluated for safety, tolerability and pharmacokinetics when intravenously administered as a single dose to healthy subjects. Methods : Six cohorts of 8 subjects received escalating single IV infusions of PLG0206 at 0.05, 0.125, 0.25, 0.5, or 1 mg/kg dose or placebo over 1-to-4-hours. Subjects were randomized to receive either PLG0206 (6 per cohort) or placebo (2 per cohort). Serial pharmacokinetic samples were taken prior to infusion and up to 48 hours post infusion. Safety and tolerability were assessed throughout the study. Results : The demographic characteristics of subjects were comparable between those treated with PLG0206 and placebo and between dose groups. The incidence of treatment emergent adverse events (TEAE) related to PLG0206 was low and most events were mild in severity and were similar between the PLG0206 treatment and placebo groups. The most common adverse events reported for PLG0206 were infusion related reactions, which were mitigated with increasing infusion time and volume. There were no serious adverse events (SAE), life-threatening events, or deaths throughout the study. IV PLG0206 exhibited linear pharmacokinetics over the dose range of 0.05 to 1.0 mg/kg. The median terminal half-life (t ½ ) ranged from 7.37 to 19.97 hours. Conclusion : Following a single IV infusion to healthy subjects, PLG0206 was safe and well tolerated and exhibited linear PK at doses ranging from 0.05 to 1 mg/kg. These findings support the ongoing development of IV PLG0206 as an antimicrobial agent.

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A phase 1 study of single and repeat oral doses of GSK3439171A, a highly selective H-PGDS inhibitor, in healthy adult participants

10.22541/au.162552379.93685989/v1 ◽

2021 ◽

Author(s):

Thomas Haws ◽

Nilay Thakkar ◽

Summer Goodson ◽

Caroline Sychterz ◽

Nisha George ◽

...

Keyword(s):

Therapeutic Potential ◽

Drug Hypersensitivity ◽

Phase 1 ◽

Geometric Mean ◽

Human Study ◽

Study Drug ◽

Prostaglandin D2 ◽

Dose Escalation Study ◽

Double Blind ◽

Oral Doses

Aim: Prostaglandin D2 (PGD2) is implicated in the pathophysiology of inflammatory diseases. GSK3439171A is a potent, reversible, and highly selective azetidine urea inhibitor of haematopoietic prostaglandin D synthase (H-PGDS, a key promoter of PGD2 production in several inflammatory cell types). Based on favourable preclinical data, we performed a first-time-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK3439171A, and the effect of food on these parameters. Methods: This was a phase 1, randomized, double-blind, placebo-controlled, dose-escalation study. Single and repeat oral doses of GSK3439171A were administered to healthy males aged 18–65 years. Levels of inflammatory markers including tetranor-prostaglandin D metabolite (tPGDM) were measured in urine samples. Results: Sixty-six participants were enrolled, with 57 receiving GSK3439171A. Single doses (5–180 mg) and repeat once-daily doses (5 and 11 mg for 14 days; 40 mg for 7 days) were administered. Seven participants (12%) had adverse events (AEs) related to study drug, mainly drug hypersensitivity (n=4 [7%]; non-serious, transient skin rash). There were no serious AEs (SAEs) or clinically significant changes in vital signs, electrocardiogram, or laboratory parameters. Dose-proportional increases in Cmax and AUC(0–inf) were observed, and the geometric mean half-life of GSK3439171A was up to 12 hours. Results were similar when GSK3439171A was taken with or without food. No consistent suppression of tPGDM levels was observed. Conclusion: GSK3439171A was well tolerated in healthy participants and there were no SAEs. Selective inhibition of H-PGDS offers therapeutic potential for muscle-related disorders (e.g. Duchenne Muscular Dystrophy) and muscular recovery following injury.

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Phase 1 Clinical Trials of Small Molecules: Evolution and State of the Art

Reviews on Recent Clinical Trials ◽

10.2174/1574887116666210204125844 ◽

2021 ◽

Vol 16 ◽

Author(s):

John J. Sramek ◽

Michael F. Murphy ◽

Sherilyn Adcock ◽

Jeffrey G. Stark ◽

Neal R. Cutler

Keyword(s):

Clinical Trials ◽

Drug Development ◽

Healthy Volunteers ◽

Small Molecules ◽

Phase 1 ◽

Dose Range ◽

Pharmacodynamic Modeling ◽

Inpatient Setting ◽

Conducting Phase ◽

Safe Dose

Background: Phase 1 studies comprise the first exposure of a promising new chemical entity in healthy volunteers or, when appropriate, in patients. To assure a solid foundation for subsequent drug development, this first step must carefully assess the safety and tolerance of a new compound, and often provide some indication of potential effect, so that a safe dose or dose range can be confidently selected for the initial Phase 2 efficacy study in the target patient population. Methods: This review was based on a literature search using both Google Scholar and PubMed, dated back to 1970, using search terms including “healthy volunteers”, “Phase 1”, and “normal volunteers” , and also based on the authors’ own experience conducting Phase 1 clinical trials. This paper reviews the history of Phase 1 studies of small molecules and their rapid evolution, focusing on the critical single and multiple dose studies, their designs, methodology, use of pharmacokinetic and pharmacodynamic modeling, application of potentially helpful biomarkers, study stopping criteria, and novel study designs. Results: We advocate for determining the safe dose range of a new compound by conducting careful dose escalation in a well-staffed inpatient setting, defining the maximally tolerated dose (MTD) by reaching the minimally intolerated dose (MID). The dose immediately below the MID is then defined as the MTD. This is best accomplished by using appropriately screened patients for the target indication, as patients in many CNS indications often tolerate doses differently than healthy non-patients. Biomarkers for safety and pharmacodynamic measures can also assist in further defining a safe and potentially effective dose range for subsequent clinical trial phases. Conclusion: Phase 1 studies can yield critical insights to the pharmacology of a new compound in man and offer perhaps the only development period in which the dose range can be safely and thoroughly explored. Phase 1 studies often contain multiple endpoint objectives, the reconciliation of which can present a dilemma for drug developers and study investigators alike, but which can crucially determine whether a compound can survive to the next step in the drug development process.

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Comprehension and recall from the informed consent process by phase I healthy volunteers before dose administration

Clinical Trials ◽

10.1177/1740774519834257 ◽

2019 ◽

Vol 16 (3) ◽

pp. 283-289 ◽

Cited By ~ 1

Author(s):

Rami Tadros ◽

Gillian E Caughey ◽

Sally Johns ◽

Sepehr Shakib

Keyword(s):

Clinical Trials ◽

Informed Consent ◽

Phase I ◽

Healthy Volunteers ◽

Drug Administration ◽

Study Drug ◽

Informed Consent Process ◽

Consent Process ◽

Phase I Clinical Trials ◽

Study Drug Administration

Aims/Background A fundamental part of all clinical trials is informed consent, reflecting the respect for the volunteer’s autonomy. Research participation is voluntary; therefore, certain aspects of the proposed study must be disclosed so that volunteers can make an informed decision. In this study, we aimed to examine the level of comprehension and recall of healthy volunteers from the informed consent process. Methods The study was carried out at a single phase I clinical trials unit. A questionnaire was administered to each volunteer to assess recall of important aspects of the study at the day-1 visit following the informed consent process. The questionnaire contained seven questions regarding study objectives, route, frequency and type of drug administration, adverse effects, number of subjects previously exposed and remuneration. One point was awarded for each correct answer. Results A total of 266 volunteers were administered the questionnaire. The mean total score (±standard deviation) for all volunteers was 4.5 ± 1.1 points out of 7, with a range of 0.8–6.7. For all 10 studies, 91% of volunteers responded correctly when answering about the route of administration, and 90% were able to accurately state the correct payment amount. Only 7% were able to repeat the aims of the study correctly. Conclusion The poor performance of our study volunteers raises concerns about recall of information prior to study drug administration. This has implications for the volunteer’s safety and ability to provide true informed consent. Interventions to improve recall prior to dosing should be undertaken.

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EXTENDED ABSORPTION OF LIOTHYRONINE FROM POLY-ZINC LIOTHYRONINE (PZL) IN HUMANS

10.1101/2021.06.14.21258437 ◽

2021 ◽

Author(s):

Alexandra Dumitrescu ◽

Erin C Hanlon ◽

Marilyn Arosema ◽

Olga Duchon ◽

Matthew Ettleson ◽

...

Keyword(s):

Single Dose ◽

Healthy Volunteers ◽

Drug Product ◽

Phase 1 ◽

Placebo Administration ◽

Double Blind ◽

Serum T3 ◽

To Receive ◽

Administration Methods ◽

Hypothyroid Patients

Background: Liothyronine (LT3) has been increasingly used in combination with levothyroxine (LT4) in the treatment of hypothyroidism. A metal coordinated form of LT3, known as poly-zinc-liothyronine (PZL), avoided in rats the typical T3 peak seen after oral administration of LT3. Objectives: To evaluate in healthy volunteers (i) the pharmacokinetics of PZL-derived T3 after a single dose, (ii) the pharmacodynamics of PZL-derived T3, (iii) monitoring for the adverse events; (iv) exploratory analysis of the sleep patterns after LT3, PZL or placebo administration. Methods: 12 healthy volunteers 18 to 50 years of age were recruited for a Phase 1, double-blind, randomized, single-dose placebo-controlled, cross-over study to compare PZL against LT3 or placebo. Subjects were admitted three separate times to receive a randomly assigned capsule containing placebo, 50-mcg LT3, or 50-mcg-PZL, and were observed for 48h. A 2-week wash-out period separated each admission. Results: LT3-derived serum T3 levels exhibited the expected profile, with a Tmax at 2h and return to basal levels by 24-36h. PZL-derived serum T3 levels exhibited a ~30% lower Cmax that was 1 h delayed and extended into a plateau that lasted up to 6h. This was followed by a lower but much longer plateau; by 24 hours serum T3 levels still exceeded 1/2 of Cmax. TSH levels were similarly reduced indistinguishably in both groups. Conclusion: PZL possesses the necessary properties to achieve a much improved T3 pharma-cokinetic. Drug product development of PZL should improve the delivery of T3 even further. PZL is on track to provide hypothyroid patients with stable levels of serum T3.

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Efficacy and safety of IMO-2055, a novel TLR9 agonist, in combination with erlotinib (E) and bevacizumab (bev) in patients (pts) with advanced or metastatic non-small cell lung cancer (NSCLC) who have progressed following prior chemotherapy.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e18047 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e18047-e18047 ◽

Cited By ~ 1

Author(s):

David A. Smith ◽

Paul Conkling ◽

Donald A. Richards ◽

Maria Regina C. Flores ◽

John J. Nemunaitis ◽

...

Keyword(s):

Small Molecules ◽

Response Rate ◽

Dose Range ◽

Study Drug ◽

Primary Objective ◽

Study Drug Administration ◽

Ajcc Stage ◽

Heavily Pretreated ◽

Grade 3 ◽

Expansion Cohort

e18047 Background: IMO-2055 is a novel TLR-9 agonist with potential to enhance the efficacy of biologics and small molecules through immune stimulation. Xenograft data show anti-tumor synergy between IMO-2055, E and bev; E-bev has been evaluated in 2nd line NSCLC. Methods: Primary objective was to determine the recommended dose (RD) of IMO-2055 (dose range 0.08-0.48 mg/kg/w s.c.) with E 150mg/day p.o. and bev 15mg/kg q3w i.v. in a standard 3+3 design. An expansion cohort at the RD further determined safety and efficacy. Pts had AJCC stage 3/4 inoperable, histologically proven NSCLC where standard chemotherapy was not an option. Treatment was until progression (PD) or toxicity. Results: 36 pts were enrolled at 10 US sites from Nov ‘07 to Mar '11. 35 were treated/evaluable for safety; 33 for efficacy. Median age was 64, 58% were men, 81% white, 81% PS 1 with 69% adenocarcinomas and median 17 months since diagnosis. 44% pts were >2nd line. Pts received a median of 4.3 3-week cycles. 19 pts entered dose-escalation: 4 at 0.08 mg/kg, 6 at 0.16 mg/kg, 6 at 0.32 mg/kg, and 3 at 0.48 mg/kg IMO-2055. Two pts had DLTs: 1 grade 3 dehydration at 0.16 mg/kg, and 1 grade 3 fatigue at 0.48 mg/kg. RD was 0.32 mg/kg based on pharmacodynamic and clinical data: 17 more pts were treated at this dose. The most common AEs were diarrhea, nausea, fatigue and rash; most frequent grade 3-4 AEs were fatigue (9%), diarrhea (9%), anemia and dyspnea (both 6%), with no clear dose-relationship to IMO-2055. G3-4 hypertension was 0%, ATE 6% and hemorrhage 3%. Five pts died of PD on or within 30 days of study drug administration. Response rate was 12% with 79% disease control (SD+PR). Median PFS was 5.6 months (95% CI 3.9-7.2) and OS 16 months (95% CI 7.5-17.8) with 55% pts alive at 1 year. Conclusions: Addition of IMO-2055 to E-bev was well tolerated with no unexpected toxicity. The RD of IMO-2055 with E-bev is 0.32 mg/kg/w s.c. Median PFS and OS in this heavily pretreated population compare favorably with published E-bev data. IMO-2055 should be further explored in NSCLC.

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Phase I study of Solulin, a novel recombinant soluble human thrombomodulin analogue

Thrombosis and Haemostasis ◽

10.1160/th10-05-0287 ◽

2011 ◽

Vol 105 (02) ◽

pp. 302-312 ◽

Cited By ~ 21

Author(s):

Thijs van Iersel ◽

Heimo Stroissnig ◽

Peter Giesen ◽

Johan Wemer ◽

Karin Wilhelm-Ogunbiyi

Keyword(s):

Healthy Volunteers ◽

Clinical Investigation ◽

Dose Range ◽

Plasma Concentrations ◽

Human Study ◽

Bleeding Risk ◽

High Dose ◽

Multiple Dosing ◽

Relevant Dose

SummarySolulin is a novel recombinant soluble derivative of human thrombomodulin. In this first human study of Solulin, the safety, tolerability, pharmacokinetics and pharmacodynamics of Solulin in 30 healthy volunteers in response to single (0.6–30 mg) and 12 healthy volunteers in response to multiple (1 and 10 mg) ascending intravenous bolus doses compared to placebo are described. Solulin was shown to be well tolerated, and demonstrated linear pharmacokinetics over the clinically relevant dose range, with a plasma elimination half-life of 15–30 hours, indicating that a less than daily dose may be required for therapeutic use. Steady-state plasma levels after multiple dosing were reached after 48 hours. Solulin has shown to be able to inhibit thrombin generation without increasing levels of aPC/PCI complexes. Coagulation parameters INR and PT were not changed, aPTT was elevated to about 10% above the upper limit of normal after the highest single dose only. Thrombin clotting time was prolonged after administration of high dose Solulin (10, 30 mg). No effect on in vitro bleeding time has been found. There was no evidence of bleeding risk with Solulin administration. The pharmacodynamic effects correlated with Solulin plasma concentrations. This demonstrates that the antithrombotic effect of Solulin is predictable, suggesting that patient monitoring is not expected. The results of this study provide evidence that Solulin can be expected to be an effective and safe anticoagulant, and further clinical investigation is warranted.

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First-in-Human study of JNJ-55920839 in healthy volunteers and patients with systemic lupus erythematosus: a randomised placebo-controlled phase 1 trial

The Lancet Rheumatology ◽

10.1016/s2665-9913(20)30223-x ◽

2020 ◽

Vol 2 (10) ◽

pp. e613-e622 ◽

Cited By ~ 3

Author(s):

Jarrat Jordan ◽

Jacqueline Benson ◽

Walter Winn Chatham ◽

Richard Alan Furie ◽

William Stohl ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Healthy Volunteers ◽

Lupus Erythematosus ◽

Phase 1 ◽

Human Study ◽

Systemic Lupus ◽

Phase 1 Trial

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GMI-1070, a Pan-Selectin Inhibitor: Safety and PK In a Phase 1/2 Study In Adults with Sickle Cell Disease

Blood ◽

10.1182/blood.v116.21.1632.1632 ◽

2010 ◽

Vol 116 (21) ◽

pp. 1632-1632 ◽

Cited By ~ 3

Author(s):

Lori Styles ◽

Ted Wun ◽

Laura M. De Castro ◽

Marilyn J. Telen ◽

William Kramer ◽

...

Keyword(s):

Clinical Trial ◽

Steady State ◽

Adverse Events ◽

Healthy Volunteers ◽

Phase 1 ◽

Study Drug ◽

Cell Disease ◽

Employment Equity ◽

The Past ◽

Equity Ownership

Abstract Abstract 1632 GMI-1070 is a pan-selectin inhibitor that targets E-, P-, and L-selectins and has shown activity in multiple animal models of disease. Sickle cell disease (SCD) is characterized by periodic vaso-occlusive (VOC) episodes in which cell adhesion and aggregation play a crucial role. GMI-1070 has previously been shown to restore blood flow and improve survival in a mouse model of VOC, and safety and PK have been evaluated in normal, healthy volunteers in phase 1. Here we report clinical, safety, and PK results from the first study of GMI-1070 in individuals with SCD. Methods: An open-label phase 1/2 study was performed, enrolling adults with SCD at steady state. GMI-1070 was administered in two IV doses given on the same day: 20 mg/kg in the first dose, followed 10 hours later by 10 mg/kg. Patients were evaluated for safety on days 0, 1, 2, 7 and 28, including adverse events (AEs), routine clinical labs, and clinical exam. Plasma and urine concentrations of GMI-1070 were measured on days 0, 1, and 2, and PK parameters calculated and compared with those from healthy volunteers. Results: Fifteen adults were enrolled at three centers; 13 with HbSS, 2 with HbSB0thal. All were African-American, 9 were male, mean age was 32 years (range 18–50), mean weight was 64.7 kg; 4 were on hydroxyurea. In the past year, 6 had experienced VOC requiring medical care; 2 had ACS; 2 required transfusions; and 1 had an episode of priapism. Five were hospitalized in the past year; 12 were hospitalized in the past 5 years. All subjects received both doses of study drug; all but one were followed for 28 days. The PK in adults with SCD was in good agreement with that in the controls. The elimination half-life of GMI-1070 averaged 7.73 ± 2.45 hours (Figure). Renal clearance averaged 18.0 ± 7.93 mL/min and accounted for essentially all elimination. Physical exam parameters after dosing were unchanged, and all infusions were well tolerated. Four subjects reported headache within 24 hours of dosing, all of which were mild or moderate and resolved within 24 hours. Two subjects experienced VOC not requiring hospitalization, at 2 and 4 weeks after dosing. One subject had worsening anemia requiring transfusion 5 days after dosing. Other adverse events typical of SCD were reported without apparent association with study drug; none were serious adverse events. Routine labs demonstrated no changes from baseline (Hb, reticulocytes, platelets, electrolytes, glucose, ALT, LDH, BUN, Cr, bilirubin, urinalysis) with the exception of white blood cell counts (WBC) and absolute neutrophil counts (ANC). At 24 hours, mean WBC change from baseline was 1.9K/mm3, or 20% (p=0.076, using parametric test with mixed model); mean ANC change was 2.7, or 67% (p=0.019); all returned to baseline by 7 days. One individual had marked leukocytosis 24 hours after dosing (from 10.4 to 28K/mm3), returning to baseline by day 7; no other effects were observed in this subject. Mean C-reactive protein (CRP) increased at 24 and 48 hours, returning to baseline by day 7. Two subjects had marked increases in CRP: one exhibited leukocytosis with dosing and the other had a high baseline WBC count. There was otherwise no apparent correlation between PK, WBC/ANC, hydroxyurea use, or adverse events. In conclusion, GMI-1070, a pan-selectin inhibitor, when administered to adults with SCD at steady state, has a similar safety and PK profile to that in healthy volunteers. However, SCD patients had moderate WBC and ANC increases at 24–48 hours after dosing, which return to baseline without other observed symptomatic adverse events. This study supports further evaluation of GMI-1070 for the treatment of vaso-occlusive crisis. Disclosures: Styles: GlycoMimetics: Consultancy, clinical trial sponsorship. Wun:GlycoMimetics: Consultancy, clinical trial sponsorship. De Castro:GlycoMimetics: clinical trial sponsorship. Telen:GlycoMimetics: Consultancy, clinical trial sponsorship. Kramer:GlycoMimetics: Consultancy. Flanner:GlycoMimetics: Employment, Equity Ownership. Magnani:GlycoMimetics: Employment, Equity Ownership. Thackray:GlycoMimetics: Employment, Equity Ownership. Off Label Use: This drug (GMI-1070) has not been approved for any clinical indication.

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Interim results from a first-in-human study with AMG102, a fully human monoclonal antibody that neutralizes hepatocyte growth factor (HGF), the ligand to c-Met receptor, in patients (pts) with advanced solid tumors

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.3551 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 3551-3551 ◽

Cited By ~ 10

Author(s):

M. S. Gordon ◽

D. S. Mendelson ◽

C. Sweeney ◽

N. Erbeck ◽

R. Patel ◽

...

Keyword(s):

Monoclonal Antibody ◽

Solid Tumors ◽

Phase 1 ◽

Human Monoclonal Antibody ◽

Dose Range ◽

Human Study ◽

Advanced Solid Tumors ◽

Met Receptor ◽

Dose Escalation Study ◽

Grade 3

3551 Background: AMG102 is a fully human IgG2 monoclonal antibody against HGF that prevents tumorigenesis in preclinical models through blockade of the HGF/c-Met receptor tyrosine kinase pathway. We describe interim results from the first-in-human study of AMG102. Methods: This ongoing phase 1, open-label, dose-escalation study is evaluating safety, pharmacokinetics (PK), and preliminary pharmacodynamics (PD) of AMG102 after single and multiple intravenous doses in pts with advanced solid tumors. Sequential dose cohorts of 4–6 pts were administered AMG102 at 0.5, 1, 3, 5, 10, or 20 mg/kg. Pts received a single dose, followed by a 4-wk treatment- free period during which safety and PK were assessed. If no dose-limiting toxicity (DLT) was observed, treatment was resumed every 2 wks at the same dose until pts exhibited drug intolerance or disease progression. Results: As of 10 August 2006, 31 pts have been treated with AMG102 at doses up to 20 mg/kg ( Table ). AMG102 appears to be well tolerated. One pt with non-small cell lung cancer had a grade 3 DLT of dyspnea/hypoxia after the first dose (0.5 mg/kg); a second pt with pancreatic cancer had a grade 3 DLT/serious adverse event of gastrointestinal hemorrhage after the first dose (1 mg/kg). The most frequently reported, treatment-related adverse events (AEs) have been fatigue (13%), constipation (10%), anorexia (6%), nausea (6%), and vomiting (6%). No anti-AMG102 antibodies have been detected. Initial PK analysis indicates approximately linear PK in the dose range of 0.5 to 20 mg/kg. The overall mean (SD) [median] clearance and half-life estimates based on day-1 dosing were 12.1 (5.21) [10.7] mL/hr and 15.4 (5.84) [15.5] days, respectively. Tumor response is described ( Table ). Conclusions: In this study, interim results suggest that AMG102 at doses up to 20 mg/kg appears to be well-tolerated, with preliminary PK data supporting every-2-wk administration. [Table: see text] No significant financial relationships to disclose.

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