Eltrombopag for Post-Transplant Thrombocytopenia: Results of Phase II Randomized Double Blind Placebo Controlled Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 738-738 ◽  
Author(s):  
Uday R. Popat ◽  
Genevieve Ray ◽  
Roland L Bassett ◽  
Man-Yin C Poon ◽  
Benigno C. Valdez ◽  
...  
Keyword(s):  
Platelet Count ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Platelet Transfusion ◽  
Response Rate ◽  
Credible Interval ◽  
Double Blind ◽  
Platelet Recovery ◽  
Double Blind Placebo ◽  
Post Transplant

Background: Delayed platelet recovery and secondary thrombocytopenia, defined as a drop in platelet count not due to disease relapse after initial platelet recovery, occur in 5-25% of patients after hematopoietic cell transplantation (HCT) and indicate adverse prognosis. Platelet transfusion to prevent bleeding remains a mainstay of therapy and role of thrombopoietic agents is not known. Eltrombopag, a non-peptide small molecule, thrombopoietin receptor agonist, is licensed for use in refractory ITP and aplastic anemia. In this phase II randomized double blind placebo controlled study, we investigated the safety and efficacy of eltrombopag for post HCT thrombocytopenia. Methods: Patients 35 days or more after HCT were eligible for the study if they had 1) platelet count ≤ 20 x 109/l sustained for 7 days or if they were platelet transfusion dependent, and 2) neutrophil count ≥ 1.5 x 109/l with or without G-CSF in the previous 7 days. Patients were excluded if they had abnormal liver function tests (ALT ≥ 2.5 ULN, or Bilirubin >2mg/dl) or had prior venous thrombosis. Patients were randomized to receive placebo or eltrombopag using a Bayesian adaptive algorithm in which the probability of randomization to each arm was based upon the ongoing response rate. Eltrombopag was started at a dose of 50mgs and escalated every 2 weeks to 75mgs, 125 mgs and 150mgs if platelet count was < 50 x 109/l. The primary endpoint was platelet count at end of the treatment (8 weeks). A patient was considered responsive if platelet count was ≥ 30 x 109/l. The primary endpoint was evaluated by calculating the Bayesian posterior probability in each arm that the response rate was higher than the other arm. A Beta (0.4, 1.6) prior distribution was assumed for each arm. Given the observed study data, the probability of response in each arm was calculated and the probability that Eltrombopag is superior was computed. Results: Sixty patients were randomized to eltrombopag (n=42) or placebo (n=18) and received at least one dose of drug. 7 patients had an autograft and 53 patients had an allograft. Donor was related for 22 and unrelated for 31 patients. Stem cell source was peripheral blood in 36 patients, bone marrow in 23 patients and cord blood in 1 patient. There were no significant differences in patient characteristics between the 2 treatment arms. The probability that the response rate in the Eltrombopag arm is superior to the response rate in the placebo arm was 0.75, given the observed data. The protocol required this probability to be > 0.975 to declare a winner; thus, the results are inconclusive. Fifteen (36%) of patients in eltrombopag arm responded compared to 5 (28%) of patients in placebo arm. A 95% credible interval for response in the Eltrombopag arm is 22% to 50%, and a 95% credible interval for response in the placebo arm is 11% to 48%. 37 patients completed all 8 weeks of therapy; however, all patients (n=60) who received at least one dose of study treatment were included in the intention to treat evaluation of this endpoint. A secondary objective was to compare proportion of patients achieving a platelet count ≥ 50 x 109/l. Response rate was higher in the eltrombopag arm for this endpoint as well: 9 (21.4%) patients achieved success compared with 0 (0%) patients in the placebo arm (p=0.0466; Fisher's exact test). OS, PFS, relapse rate, and non-relapse mortality were similar in two arms. Conclusion: Eltrombopag improves platelet count in patients with post-transplant thrombocytopenia. Disclosures Kim: Eli Lilly: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bayer: Consultancy.

scholarly journals Oral levosimendan in amyotrophic lateral sclerosis: a phase II multicentre, randomised, double-blind, placebo-controlled trial

2019 ◽  
Vol 90 (10) ◽  
pp. 1165-1170 ◽  
Author(s):  
Ammar Al-Chalabi ◽  
Pamela Shaw ◽  
P Nigel Leigh ◽  
Leonard van den Berg ◽  
Orla Hardiman ◽  
...  
Keyword(s):  
Heart Rate ◽  
Amyotrophic Lateral Sclerosis ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Iii ◽  
Open Label ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Lateral Sclerosis

ObjectiveTo evaluate the efficacy and safety of oral levosimendan in patients with amyotrophic lateral sclerosis (ALS). This phase II, randomised, double-blind, placebo-controlled, crossover, three-period study with 6 months open-label follow-up enrolled adults with ALS and sitting slow vital capacity (SVC) 60%–90 % of predicted from 11 sites in four countries.MethodsPatients received levosimendan 1 mg daily, 1 mg two times a day or placebo during three 14-day crossover periods and levosimendan 1–2 mg daily during open-label follow-up. Primary endpoint was sitting SVC; secondary endpoints included supine SVC, ALS Functional Rating Scale-Revised (ALSFRS-R), tolerability and safety.ResultsOf 66 patients randomised, 59 contributed to the double-blind results and 50 entered open-label follow-up. Sitting SVC was not significantly different between the treatments. In post hoc analysis using period-wise baselines, supine SVC favoured levosimendan over placebo, estimated mean differences from baseline being −3.62% on placebo, +0.77% on levosimendan 1 mg daily (p=0.018) and +2.38% on 1 mg two times a day (p=0.001). Headache occurred in 16.7% of patients during levosimendan 1 mg daily (p=0.030), 28.6% during 1 mg two times a day (p=0.002) and 3.3% during placebo. The respective frequencies for increased heart rate were 5.1% (p=0.337), 18.5% (p=0.018) and 1.7%. No significant differences between the treatments were seen for other adverse events.ConclusionsLevosimendan did not achieve the primary endpoint of improving sitting SVC in ALS. Headache and increased heart rate were increased on levosimendan, although it was otherwise well tolerated. A phase III study to evaluate the longer term effects of oral levosimendan in ALS is ongoing.

A randomized, double-blind, placebo-controlled, multicenter, multinational, phase II trial of L-BLP25 in patients with colorectal carcinoma following R0/R1 hepatic metastasectomy.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS3641-TPS3641
Author(s):  
Carl Christoph Schimanski ◽  
Markus Hermann Moehler ◽  
Hauke Lang ◽  
Michael Schoen ◽  
Victoria Smith-Machnow ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Controlled Trial ◽  
Hepatic Metastases ◽  
Primary Objective ◽  
R0 Resection ◽  
Double Blind ◽  
Double Blind Placebo

TPS3641^ Background: Approximately 15-20% of patients diagnosed with colorectal cancer (crc) develop metastatic disease. Surgical resection remains the only potentially curative treatment. 5-year survival following R0-resection of liver metastases lies ~28 -39%. Recurrence occurs in ~70% of pts. Adjuvant chemotherapy has not significantly improved clinical outcomes. The primary objective of the LICC trial (L-BLP25 in Colorectal Cancer) is to analyze whether L-BLP25, an active cancer immunotherapy, extends recurrence-free survival (RFS) time over placebo in colorectal cancer pts following R0/R1 resection of hepatic metastases. L-BLP25 targets MUC1 glycoprotein, which is highly expressed in hepatic metastases from crc. In a phase IIB trial, L-BLP25 showed acceptable tolerability and a trend toward longer survival in pts with stage IIIB NSCLC. Methods: This is a multinational, phase II, multicenter, randomized, double-blind, placebo-controlled trial with a sample size of 159 pts from 20 centers in 3 countries. Pts must have stage IV cr adenocarcinoma limited to liver metastases. Following complete resection of the primary tumor and all syn-/metachronous metastases, eligible pts are randomized 2:1 to receive either L-BLP25 or placebo. Those allocated to L-BLP25 receive a single dose of 300 mg/m2 cyclophosphamide (CP) 3 days before first L-BLP25 dose, then primary treatment with sc L-BLP25 930 μg once weekly for 8 weeks, followed by maintenance doses at 6-week (years 1 and 2) and 12-week (year 3) intervals until recurrence. In the control arm, CP is replaced by saline solution and L-BLP25 by placebo. Primary endpoint: RFS time. Secondary endpoints: OS time, safety status, tolerability, RFS/OS in MUC-1 positive cancers. Exploratory immune response analyses are planned. First recruitment was of Q3 2011. To date, 8 of 20 centers are initiated and 4 pts recruited. Completion of recruitment is scheduled for Q3 2013. Primary endpoint will be assessed in Q3 2016: Follow-up will end Q3 2017. No interim analysis is planned. Design and implementation of this vaccination study in colorectal cancer is feasible. No major issues identified during setup of the study.

A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Comparative Trial of AMD3100 (Plerixafor)+G-CSF vs. G-CSF+Placebo for Mobilization in Multiple Myeloma (MM) Patients for Autologous Hematopoietic Stem Cell (aHSC) Transplantation.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 445-445 ◽  
Author(s):  
John DiPersio ◽  
Edward A. Stadtmauer ◽  
Auayporn P. Nademanee ◽  
Patrick Stiff ◽  
Ivana Micallef ◽  
...  
Keyword(s):  
Adverse Events ◽  
Primary Endpoint ◽  
Rescue Therapy ◽  
Phase Iii ◽  
Controlled Study ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Post Transplant ◽  
Transplant Patients ◽  
Cd34 Cells

Abstract AMD3100, Plerixafor (A)+G-CSF (G) have effectively allowed aHSC mobilization in Phase I and II studies. This Phase III, multicenter, randomized, double-blind, placebo controlled study compares the safety and efficacy of A+G Vs. placebo (P)+G to mobilize and transplant patients with MM. Methods: Adult MM patients requiring an aHSC transplant, in first or second CR or PR were eligible to participate. Patients were declared for single or tandem transplant with the second transplant occurring within 6 months from the first. Patients received G (10μg/kg/day) subcutaneously (SQ) for 4 days; on the evening of Day 4 they received either A (240μg/kg SQ) or P. Patients underwent apheresis on Day 5 after an AM dose of G and 10–11 hours after administration of study treatment. Patients continued to receive the evening dose of study treatment followed by AM dose of G and apheresis for up to a total of 4 apheresis or until ≥6 x 106 CD34+ cells/kg were collected. Patients who failed to collect ≥2 x 106 CD34+ cells/kg were eligible for rescue therapy with A+G, without unblinding of randomized treatment. Only study cells were used for transplant. The primary endpoint was the percentage of patients who achieved ≥6 x 106 CD34+ cells/kg in 2 or less apheresis days. All patients will be followed for ≥12 months post-transplant. Results: 302 patients were enrolled and randomized into the study. All have completed 100 days follow-up and are included in this intent-to-treat analysis. Baseline characteristics were similar between groups. The primary endpoint was met in 106/128 (72%) patients in the A+G group and 53/154 (34%) patients in the P+G group, p<0.0001. The figure shows that 54% of A+G patients reached target after 1 day of apheresis but 56% P+G patients required up to 4 days of apheresis to reach target. 7 patients in the P+G group required rescue therapy and all collected ≥2 x 106 CD34+ cells/kg after A+G rescue. 142 patients (96%) in A+G group and 136 patients (88%) in the P+G group underwent transplant. Tandem transplants were performed in 32 and 28 patients in A+G and P+G groups, respectively. Median time to engraftment was Day 11 for PMN and Day 18 for platelets in both groups. Grafts were durable in all patients in both group at ≥100 days post-transplant. Patients in the A+G group experienced more GI effects and injection site erythema than patients in the P+G group. These adverse events were generally mild. There were no drug related serious adverse events in either group. Conclusions: In this study, the addition of AMD3100 to G-CSF is generally safe and well tolerated and is superior to G-CSF alone for aHSC mobilization in MM patients. A+G patients were statistically significantly more likely to achieve target earlier than P+G patients and had successful transplant. Figure Figure

Randomized double-blind placebo-controlled phase 2 study of bemarituzumab combined with modified FOLFOX6 (mFOLFOX6) in first-line (1L) treatment of advanced gastric/gastroesophageal junction adenocarcinoma (FIGHT).

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 160-160
Author(s):  
Zev A. Wainberg ◽  
Peter C. Enzinger ◽  
Yoon-Koo Kang ◽  
Kensei Yamaguchi ◽  
Shukui Qin ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Response Rate ◽  
Statistical Significance ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase 2 ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Phase 2 Study

160 Background: Bemarituzumab (bema), a first-in-class humanized IgG1 monoclonal antibody, selectively binds to FGFR2b, inhibits ligand binding and mediates antibody-dependent cell-mediated cytotoxicity. A phase 1 study of bema monotherapy in solid tumors had no dose-limiting toxicities and a confirmed objective response rate (ORR) of 18% in patients (pts) with refractory FGFR2b+ gastric cancer (GC). Methods: The FIGHT study (NCT03343301) is a global, randomized, double-blind, placebo-controlled phase 2 trial. Pts with unresectable locally advanced or metastatic GC that was not HER2+ were eligible if their tumor was positive for FGFR2b overexpression by centrally performed immunohistochemistry (IHC) or for FGFR2 amplification by circulating tumor DNA (ctDNA). Pts were treated with mFOLFOX6 and randomized 1:1 to bema 15mg/kg or placebo (pbo) every 2 weeks with 1 additional 7.5mg/kg bema/pbo dose on day 8. Treatment was continued until disease progression, intolerable toxicity, or death. The primary endpoint was investigator-assessed progression-free survival (PFS) and key secondary endpoints include overall survival (OS), overall response rate (ORR), and frequency of adverse events. Statistical significance (2-sided a of 0.2) was tested sequentially for PFS, OS and ORR. Results: Of 910 1L GC pts whose tumors were evaluated 275 (30%) were FGFR2b+. Of 155 pts randomized, 77 to bema+mFOLFOX6 and 78 to pbo+mFOLFOX6, 149 were FGFR2b+ by IHC and 26 by ctDNA. The primary endpoint was met with an improvement in median PFS of 9.5 mo (bema) vs 7.4 mo (pbo) (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.44-1.04; p=0.07). The secondary endpoint of OS was met; median not reached in the bema arm vs 12.9 mo for pbo (HR, 0.58, 95% CI, 0.35-0.95; p=0.03). Among patients with measurable disease, ORR improved from 40% (pbo) to 53% (bema). Improved efficacy was observed across all 3 endpoints (PFS, OS, ORR) with increasing levels of overexpression of FGFR2b on tumor cells. Grade ≥3 AEs were reported in 83% of pts in the bema arm vs 74% pts in the pbo arm with serious AEs in 32% and 36% respectively. Stomatitis was higher in the bema arm (31.6% vs 13.0%) and corneal AEs were more common in the bema arm (67% vs 10%). There were no reported AEs of retinal detachment or hyperphosphatemia in the bema arm. Conclusion: Approximately 30% of 1L pts with advanced GC not HER2+, were identified to be FGFR2b+, primarily by IHC. In this randomized, placebo controlled, double-blind phase 2 study, the addition of bema to mFOLFOX6 led to clinically meaningful and statistically significant improvements in PFS, OS and ORR. An increase in corneal AEs and stomatitis was associated with bema. These results support a prospective randomized phase 3 study in GC and the evaluation of bema in other FGFR2b+ tumor types. Clinical trial information: NCT03694522.

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