Abstract 13951: Safety, Tolerability and Efficacy of Single-dose Amg 890, a Novel Sirna Targeting Lp(a), in Healthy Subjects and Subjects With Elevated Lp(a)

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Michael J Koren ◽  
Patrick M Moriarty ◽  
Joel Neutel ◽  
Seth J Baum ◽  
Martha Hernandez-Illas ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase 1 ◽  
Plasma Concentrations ◽  
Vital Signs ◽  
Upper Respiratory Tract ◽  
Primary Endpoints ◽  
Subcutaneous Dose ◽  
Secondary Endpoints ◽  
To Receive ◽  
Common Teaes

Introduction: Mendelian and epidemiological randomization studies have identified lipoprotein(a) [Lp(a)] as a risk factor for myocardial infarction and other atherosclerotic events. There are currently no approved medicines that selectively target Lp(a) and have demonstrated reduction in CV events. AMG 890 is a siRNA designed to reduce the production of Lp(a) by targeting mRNA transcribed from the LPA gene. Methods: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMG 890. Adults with plasma concentrations of Lp(a) ≥ 70 to ≤ 199 nmol/L (cohorts 1-5), and ≥ 200 nmol/L (cohorts 6-7), were randomized 3:1 to receive a single subcutaneous dose of investigational product (IP; AMG 890 or placebo). The primary endpoints were treatment-emergent adverse events (TEAEs), safety laboratory analytes, vital signs and ECGs. Secondary endpoints included PK parameters and percent reduction from baseline in Lp(a). Results: 64 subjects were administered IP (cohorts 1-5: AMG 890, n=30, doses: 3 mg, 9 mg, 30 mg, 75 mg, 225 mg; placebo, n=10; cohorts 6-7: AMG 890, n=18, doses: 9 mg and 75 mg; placebo, n=6). The most common TEAEs were headache (10% AMG 890; 25% placebo) and upper respiratory tract infection (15% AMG 890; 13% placebo); no safety concerns were identified for AMG 890. In cohorts 1-5, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 71-96% (based on doses) at Day 43, and by 80-94% at Day 113 (cohorts 2-5). In cohorts 6 and 7, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 75% and 89% at Day 43, respectively, and by 61% and 80% at Day 113, respectively. Conclusions: In adults with elevated Lp(a), single-dose treatment of AMG 890 was well-tolerated and significantly reduced Lp(a) with observed maximal percent reductions of > 90% and effects persisting for more than 6 months at doses of 9 mg or higher.

scholarly journals Amino Acid Plasma Profiles from a Prolonged-Release Protein Substitute for Phenylketonuria: A Randomized, Single-Dose, Four-Way Crossover Trial in Healthy Volunteers

Nutrients ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1653 ◽  
Author(s):  
Mika Scheinin ◽  
Anna Barassi ◽  
Jouni Junnila ◽  
Zsófia Lovró ◽  
Giorgio Reiner ◽  
...  
Keyword(s):  
Single Dose ◽  
Amino Acid ◽  
Healthy Volunteers ◽  
Crossover Trial ◽  
Peak Plasma ◽  
Plasma Concentrations ◽  
Prolonged Release ◽  
Metabolic Markers ◽  
Primary Endpoints ◽  
Secondary Endpoints

Several disorders of amino acid (AA) metabolism are treated with a protein-restricted diet supplemented with specific AA mixtures. Delivery kinetics impacts AA absorption and plasma concentration profiles. We assessed plasma profiles after ingestion of an AA mixture engineered to prolong AA absorption with Physiomimic TechnologyTM (Test) in a randomized, single-dose, four-way crossover trial in healthy volunteers (Trial Registration: ISRCTN11016729). In a two-step hypothesis, the primary endpoints were (i) significant reduction in peak plasma concentrations (Cmax) of essential amino acids (EAAs) while (ii) maintaining EAA bioavailability (AUC0-300 min) compared to a free AA mixture (Reference). Secondary endpoints included effects on plasma profiles of other AA groups and effects on several metabolic markers. Thirty subjects completed the study. Both co-primary endpoints were met: Cmax for EAAs was 27% lower with the Test product compared to the Reference product (ratio, 0.726, p < 0.0001); overall plasma EAA levels from the two AA mixtures was within the pre-specified bioequivalence range (AUC0-300min ratio, 0.890 (95% CI: 0.865, 0.915)). These findings were supported by the results of secondary endpoints. Prolongation of AA absorption was associated with modulation of several metabolic markers. It will be important to understand whether this can improve the long-term management of disorders of AA metabolism.

Results of functional testing and pharmacokinetics comparing ABP 215 to bevacizumab.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 711-711 ◽  
Author(s):  
Richard Markus ◽  
Primal Kaur ◽  
Vincent Chow ◽  
Nan Zhang ◽  
Teresa Born ◽  
...  
Keyword(s):  
Single Dose ◽  
Serum Concentration ◽  
Phase 1 ◽  
Geometric Mean ◽  
Functional Similarity ◽  
Time Curve ◽  
Inhibition Of Proliferation ◽  
Primary Endpoints ◽  
Healthy Adult Male ◽  
Secondary Endpoints

711 Background: ABP 215 is a biosimilar candidate to bevacizumab (BEV), a monoclonal antibody (mAb) that binds and inhibits vascular endothelial growth factor (VEGF). Biosimilar mAbs are likely to have differences in product quality attributes due to different expression systems, bioprocess and purification, so demonstration of functional similarity and pharmacokinetic (PK) equivalence is the foundation for biosimilarity. Objectives: To assess functional similarity and PK equivalence of ABP 215 and BEV sourced from EU and US. Methods: Functional similarity testing included binding to VEGF and VEGF isoforms by surface plasmon resonance and to FcRn and FcγRIIIa. Inhibition of proliferation and VEGFR2 autophosphorylation was compared in endothelial cells. PK equivalence was evaluated in a randomized, single-dose, 3-arm study in healthy adult male subjects. Primary endpoints were area under the serum concentration-time curve from time 0 to infinity (AUCinf) and maximum observed serum concentration (Cmax). Secondary endpoints were safety, tolerability, and immunogenicity. Results: ABP 215 and BEV (EU) are functionally similar as previously presented. Binding affinity to VEGF was similar between ABP 215 (117 pM) and BEV (US) (126 pM) as was binding to VEGF165 and VEGF121. Binding to FcRn was similar between ABP 215 (95-102%) and BEV (96-111%). Binding to FcγRIIIa was also similar; ABP 215 (108-115%) and BEV (85-93%). Potency in proliferation inhibition was similar between ABP 215 (91-97%) and BEV (91-96%), as was inhibition of autophosphorylation. After a single dose, geometric mean (GM) of Cmax and AUCinf for ABP 215 were 87.2 µg/mL and 29,400 µg.h/mL, for BEV (US) were 89.1 µg/mL and 29,600 µg.h/mL, for BEV (EU) were 84.7 µg/mL and 30,600 µg.h/mL. The 90% CIs of GM ratio for Cmax and AUCinf were within pre-specified equivalence criterion of 0.80 to 1.25 confirming PK equivalence. There were no adverse events (AEs) or serious AEs leading to study discontinuation. Treatment-related AEs were reported for 22.1% in ABP 215, 16.4% in BEV (US) and 22.4% in BEV (EU) groups; no subjects developed anti-drug antibodies. Conclusions: ABP 215 is similar to BEV in sensitive functional tests and equivalent to BEV based on results of the phase 1 PK study.

scholarly journals Randomized, controlled trial of lasmiditan over four migraine attacks: Findings from the CENTURION study

Cephalalgia ◽  
2021 ◽  
Vol 41 (3) ◽  
pp. 294-304 ◽  
Author(s):  
Messoud Ashina ◽  
Uwe Reuter ◽  
Timothy Smith ◽  
Judith Krikke-Workel ◽  
Suzanne R Klise ◽  
...  
Keyword(s):  
Controlled Trial ◽  
Study Drug ◽  
Statistical Testing ◽  
Control Group ◽  
Double Blind ◽  
Treatment Groups ◽  
Primary Endpoints ◽  
Registration Number ◽  
Secondary Endpoints ◽  
Common Teaes

Background We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks. Methods Patients were randomized 1:1:1 to one of three treatment groups – lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity. Results Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( p < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity. Conclusions These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. Trial Registration Number: NCT03670810

scholarly journals 1099. Evaluation of the Safety and Pharmacokinetics (PK) following Administration of Single and Multiple Doses of Anti-Staphylococcal Lysin, LSVT-1701, in Healthy Adult Subjects

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S641-S641
Author(s):  
Mary Beth Wire ◽  
Soo youn Jun ◽  
In-Jin Jany ◽  
Jun Gi Hwang ◽  
David Huang
Keyword(s):  
Single Dose ◽  
Healthy Adult ◽  
Phase 1 ◽  
Vital Signs ◽  
Time Data ◽  
Serum Samples ◽  
Double Blind ◽  
Dose Study ◽  
Clinically Significant ◽  
New Treatments

Abstract Background LSVT-1701 is an anti-staphylococcal phage lysin being developed for treatment of MRSA infections in combination with SoC antibiotics. The safety and PK of single ascending doses of LSVT-1701 0.1 to 10 mg/kg in healthy adult volunteers were previously described (Jun, et.al, AAC 2017;61:e02629-16). We further evaluated the safety and PK of multiple ascending doses of LSVT-1701 in healthy adult subjects. Methods Study ITB-101-1b was a Phase 1, randomized, double-blind, placebo-controlled, multiple ascending dose study. 8 subjects were randomized 3:1 to active:placebo in each cohort. LSVT-1701 was administered as a 6 mg/kg single dose and twice daily (BID) doses of 1.5, 3.0, and 4.5 mg/kg for 4 days (24h between Doses 1-2, 12h between Doses 2-6). Study drugs were administered as a 1-hour IV infusion. Serial serum samples were collected over 24 hours following the first and last doses for measurement of LSVT-1701 concentrations by a validated ELISA method. PK analysis of LSVT-1701 concentration-time data was done using noncompartmental methods. Safety was assessed by AEs, clinical labs, vital signs, and ECG. Results 30/32 (94%) subjects completed the study. No subjects withdrew due to AEs, and there were no severe AEs, no serious AEs, and no deaths. AEs were of mild (97%) to moderate (3%) intensity and were reported by all subjects in the LSVT-1701 6 mg/kg single dose group and 1-3 (17-50%) of subjects receiving 1.5 to 4.5 mg/kg BID or placebo. The most common AEs of headache, chills, rigors, and fever generally lasted for ≤2 days with or without acetaminophen treatment, and no clinically significant changes in blood pressure, heart rate, ECG, or clinical labs (other than transient increases in CRP) were observed. Infusion site reactions (erythema, pain, induration, warmth) were observed with BID administration of LSVT-1701, but not with the single 6 mg/kg dose or placebo. LSVT-1701 exposure increased greater than in proportion to dose and t1/2 was concentration-dependent, increasing with higher doses. No accumulation in LSVT-1701 exposure was observed. Summary of LSVT-1701 PK Parameters Summary of LSVT-1701 PK Parameters Conclusion The safety and PK profile of LSVT-1701 is favorable for evaluation in patients with S. aureus infections, including bacteremia and infective endocarditis, for which new treatments are needed. Disclosures Mary Beth Wire, Pharm#, Lysovant (Consultant) Soo youn Jun, PhD, iNtRON Biotechnology (Consultant) In-Jin Jany, PhD, iNtRON (Consultant) Jun Gi Hwang, PhD, Lysovant (Consultant) David Huang, MD, PhD, Lysovant (Consultant)

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

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.

A randomized phase II/III study of naptumomab estafenatox plus IFN-α versus IFN-α in advanced renal cell carcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3073-3073 ◽  
Author(s):  
Robert E. Hawkins ◽  
Martin Eric Gore ◽  
Yaroslav Shparyk ◽  
Vladimir Bondar ◽  
Oleg Gladkov ◽  
...  
Keyword(s):  
Clin Oncol ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase 1 ◽  
Risk Scores ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Secondary Endpoints ◽  
To Receive

3073 Background: Naptumomab estafenatox/ANYARA (Nap) is a fusion protein of an antibody (5T4) and a superantigen (SEA/E-120). After phase I studies (Borghaei. J Clin Oncol. 2009, 27:4116) a prospective, randomized phase II/III trial of Nap + IFN-α (A) vs IFN-α (I) was conducted. Methods: Patients (pts) with RCC were randomized in an open label study to receive A or I. The primary endpoint was OS. Secondary endpoints were PFS, response rate and safety. Baseline (bl) plasma IL-6 was predictive of pazopanib (Tran. Lancet Oncol. 2012, 13:827) and MVA-5T4 vaccine (Harrop. Cancer Immunol Immunother. 2012, 61:2283) benefit in RCC pts. IL-6 and anti-SEA/E-120 antibodies (a-S) were analyzed. A subgroup SG1 had bl levels below median for IL-6 (<7 pg/ml) and a-S. Another subgroup SG2 had IL-6 below 13 pg/ml (Tran. Lancet Oncol. 2012, 13:827) and excluding upper quartile of a-S according to phase 1 levels (Borghaei. J Clin Oncol. 2009, 27:4116). Results: From 5/2007 to 10/2010 513 pts were treated (ITT) with a median follow-up time for censored pts of 43 months. Unexpectedly, pts in certain territories had increased bl a-S (median of 61 pmol/ml in Russia vs 34 in UK). The table summarizes efficacy results. The primary endpoint was not met. Multivariate analysis adjusted for risk scores and subsequent TKI usage verified Nap benefit in pts with low IL-6 and normal a-S. Nap was well tolerated. Pyrexia (A:46%/I:18%), nausea (21%/11%), back pain (18%/6%), vomiting (16%/7%) and chills (12%/4%) were more common after Nap. Conclusions: The study did not meet primary endpoint. In pts with low IL-6 and normal levels of a-S, addition of Nap to IFN-α improves OS and PFS. The results warrant further studies with Nap in sequence or combo with e.g. TKIs in this subgroup. More generally, as bl IL-6 appears to be prognostic and predictive of outcome on treatment with TKIs and immunotherapies this may be a stratification factor for RCC studies. Clinical trial information: NCT00420888. [Table: see text]

Efficacy of entrectinib in patients (pts) with solid tumors and central nervous system (CNS) metastases: Integrated analysis from three clinical trials.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3017-3017 ◽  
Author(s):  
Salvatore Siena ◽  
Robert Charles Doebele ◽  
Alice Tsang Shaw ◽  
Christos Stelios Karapetis ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Phase 1 ◽  
Locally Advanced ◽  
Integrated Analysis ◽  
Data Sets ◽  
Cns Metastases ◽  
Prior Therapy ◽  
Primary Endpoints ◽  
Secondary Endpoints ◽  
Clinical Trial Information

3017 Background: Entrectinib potently inhibits kinases encoded by the NTRK and ROS1 genes. It achieves therapeutic levels in the CNS with antitumor activity in intracranial tumor models. We report integrated data (31 May 2018 cut-off) from 3 Phase 1/2 entrectinib trials (ALKA-372-001, EudraCT 2012-000148-88; STARTRK-1, NCT02097810; STARTRK-2, NCT02568267) for a large cohort of adults with ROS1 fusion-positive NSCLC ( ROS1+) or NTRK fusion-positive solid tumors ( NTRK+), with/without baseline CNS metastases. Methods: Pts had locally advanced/metastatic NTRK+ or ROS1+ tumors by nucleic acid-based confirmation. Baseline CNS metastases were identified by CT/MRI. Tumor assessments were at wk 4, then every 8 wk by blinded independent central review (RECIST v1.1). Primary endpoints: ORR, DOR. Secondary endpoints: CBR, PFS, OS, intracranial efficacy and safety. Results: Most pts had ≥1 prior therapy; 33% had baseline CNS metastases. Outcomes for the ROS1+ NSCLC (n = 53) and NTRK+ solid tumors (n = 54; 24% sarcoma, 18% NSCLC) efficacy evaluable data sets are shown (table). Entrectinib was tolerable with a manageable safety profile; most treatment-related AEs were grade 1–2. Conclusions: Entrectinib induced clinically meaningful durable responses in pts with ROS1+ NSCLC or NTRK+ solid tumors with or without CNS disease. Clinical trial information: NCT02097810; NCT02568267. [Table: see text]

scholarly journals Effects of Vitamin D Plus Calcium Supplements on Pharmacokinetics of Isoflavones in Thai Postmenopausal Women

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Supanimit Teekachunhatean ◽  
Paveena Pongnad ◽  
Noppamas Rojanasthein ◽  
Maleeya Manorot ◽  
Chaichan Sangdee
Keyword(s):  
Vitamin D ◽  
Single Dose ◽  
Plasma Concentration ◽  
Postmenopausal Women ◽  
Plasma Concentrations ◽  
Pharmacokinetic Parameters ◽  
Calcium Supplements ◽  
Maximal Plasma Concentration ◽  
Maximal Plasma ◽  
To Receive

The objective of this study was to determine the effects of vitamin D3plus calcium supplements (D3-calcium) on pharmacokinetics of isoflavones in Thai postmenopausal women. This study was an open-labeled, randomized three-phase crossover study. Twelve healthy subjects were randomized to receive one of the following regimens: (a) a single dose of isoflavones, (b) a single dose of isoflavones, and D3-calcium, or (c) continuous D3-calcium for 7 days followed by a single dose of isoflavones on the 8th day. After a washout period, subjects were switched to receive the 2 remaining regimens according to their randomized sequences. Blood samples were collected before dose and at specific time points until 32 hours after isoflavone administration. Plasma was treated with β-glucuronidase/sulfatase to hydrolyze glucuronide and sulfate conjugates of daidzein and genistein. Plasma concentrations of daidzein and genistein were determined by high performance liquid chromatography. The estimated pharmacokinetic parameters of isoflavones were time to maximal plasma concentration (Tmax), maximal plasma concentration (Cmax), half-life (t1/2) and area under the plasma concentration-time curve (AUC).Tmaxof daidzein and genistein after regimen B was significantly longer than that of regimen A. Other pharmacokinetic parameters of daidzein and genistein obtained following the three regimens were not significantly different.

scholarly journals Effects of a single dose of tablets containing lactononadecapeptide on cognitive function in healthy adults: a randomized, double-blind, cross-over, placebo-controlled trial

2020 ◽  
Vol 85 (4) ◽  
pp. 948-956
Author(s):  
Masaki Sasai ◽  
Megumi Kato ◽  
Kazuhito Ohsawa ◽  
Koichi Sashihara ◽  
Yasunori Nakamura ◽  
...  
Keyword(s):  
Single Dose ◽  
Cognitive Function ◽  
Verbal Memory ◽  
Controlled Trial ◽  
Vital Signs ◽  
Japanese Version ◽  
Work Load ◽  
Double Blind ◽  
Japanese Men ◽  
To Receive

ABSTRACT Lactononadecapeptide (LNDP; NIPPLTQTPVVVPPFLQPE) is a memory-improving peptide. The current study aimed to determine the effects of a single dose of tablets containing LNDP on cognitive function in healthy Japanese men aged 30-59 years. A randomized, double-blind, cross-over, placebo-controlled trial was conducted in participants randomly assigned to receive LNDP or placebo tablets. The Uchida–Kraepelin test was used to induce cognitive load in participants as a model of work load. Cognitive function was evaluated using the Japanese version of the CNS Vital Signs. Composite memory and verbal memory were significantly higher following consumption of LNDP than placebo tablets. Carryover effects were observed in attention and concentration domains so that period 1 data was analyzed. LNDP consumption led to higher processing speed, executive function, and cognitive flexibility than placebo. Thus, supplementation with a single dose of LNDP tablets may improve cognitive functions including memory, attention, concentration, and information processing in daily life.

Pegfilgrastim Supports Delivery of BEACOPP Chemotherapy Administered Every 14 Days.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1316-1316 ◽  
Author(s):  
Andreas Engert ◽  
Hartmut Doehner ◽  
Anthony D. Ho ◽  
Norbert Schmitz ◽  
Henning Bredenfeld ◽  
...  
Keyword(s):  
Exploratory Study ◽  
Hodgkin’S Lymphoma ◽  
Hodgkin's Lymphoma ◽  
Severe Neutropenia ◽  
Serious Adverse Events ◽  
Primary Endpoints ◽  
Subcutaneous Dose ◽  
Response To Chemotherapy ◽  
Secondary Endpoints ◽  
Lymphoma Study Group

Abstract The German Hodgkin’s Lymphoma Study Group has previously demonstrated that dose-escalated BEACOPP chemotherapy administered every 21 days with filgrastim significantly improved failure-free and overall survival compared to COPP-ABVD in patients with advanced Hodgkin’s Lymphoma (Diehl et al, Annals of Oncology 1998). An alternative approach to dose escalation is reduction of cycle length to 14 days. BEACOPP given every 14 days (BEACOPP-14) with filgrastim has been demonstrated to be feasible and effective with moderate acute toxicity (Sieber et al, JCO 2003). The aim of this study was to explore the feasibility of pegfilgrastim to support full delivery of BEACOPP-14 in high-risk Hodgkin’s lymphoma. All patients received BEACOPP-14 for up to 8 cycles. Patients were randomised to receive a single, 6mg, subcutaneous dose of pegfilgrastim on day 4 (d4) or 8 (d8) of each cycle. Primary endpoints were proportion of chemotherapy cycles given at planned dose and on time and proportion of patients receiving all administered cycles of chemotherapy at planned dose and on time. A cycle was considered “on time” if it started ≤ 17 days after the start of the previous cycle, and at “planned dose” if a dose of &gt;75% was administered for each myelosuppresive agent. Secondary endpoints included incidence of severe neutropenia (SN: absolute neutrophil count [ANC] &lt;0.5 x 109/L) and response to chemotherapy. This exploratory study used descriptive statistics; therefore, no formal comparisons were made between groups. A total of 41 patients were randomised (d4: n=21, d8: n=20). In both groups 81% of chemotherapy cycles were given at planned dose and on time (d4: 122/151 cycles, d8: 116/143 cycles). Three of 29 cycles (d4) and 5/27 cycles (d8) had a delay and a reduction. Twenty-one of 29 cycles (d4) and 15/27 cycles (d8) were delayed only. Lack of haematological recovery (ANC &lt;2x109/L and/or platelet count &lt;80x109/L) led to delays in 9/21 (d4) and 2/15 (d8) cycles. Dose delays/reductions occurred more frequently in later chemotherapy cycles. Over 80% of patients in cycle 4, &gt;70% patients in cycle 6, and &gt;50% of patients in cycle 8 received chemotherapy at planned dose on time in both groups. Over all cycles administered, 33% d4 and 40% d8 patients received chemotherapy at planned dose and on time. Nine of 21 patients (43%) in the d4 group compared to 15/20 patients (75%) in the d8 group had at least one incidence of SN. Serious adverse events reported by more than one subject were pneumonia, fever, febrile neutropenia, anaemia and syncope, which were similar in incidence between groups. At least 85% of patients had a response to BEACOPP-14, the remaining patients (d4: 14%, d8: 15%) had no response recorded. This exploratory study suggests that full delivery of BEACOPP-14 with pegfilgrastim administered on d4 or d8 is feasible. The safety profile for the 2 groups was similar although the incidence of SN in the d4 group may indicate that administration of pegfilgrastim immediately after the end of myelosuppressive chemotherapy could offer enhanced protection against SN.

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