scholarly journals A Phase II Study to Assess the Sustained Response Off Treatment in Patients with ITP Receiving Eltrombopag, Who Had a Previous Insufficient Response to Corticosteroids (TAPER): A Recruitment Update

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 37-38
Author(s):  
Nichola Cooper ◽  
Waleed Ghanima ◽  
Jens Haenig ◽  
James Lee ◽  
Masiur Rahman ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Rescue Therapy ◽  
Sustained Response ◽  
Platelet Counts ◽  
Number Of Patients ◽  
Starting Dose ◽  
Insufficient Response ◽  
Sustained Responses

Corticosteriods (CSs) remain the standard of care for immune thrombocytopenia (ITP); however, many patients relapse after initial treatment, and long-term CS use is associated with considerable toxicity and tolerability issues (Provan et al. Blood 2010). Clinically, there is a need for a less toxic regimen that will provide sustained response. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) currently approved in the United States for the treatment of ITP in patients who have had an insufficient response to CSs, immunoglobulins, or splenectomy. Limited evidence from retrospective studies and the phase II ESTIT study (NCT02402998) suggests that earlier use of TPO-RAs after ITP diagnosis may allow a larger proportion of patients to achieve sustained responses after tapering off drug (Červinek et al. Int J Hematol 2015; Gonzalez-Lopez et al. Am J Hematol 2015; Newland et al. Br J Haematol 2016; Lucchini, et al. Haematologica 2019). TAPER (NCT03524612) is an ongoing phase II, open-label, prospective, single-arm study assessing sustained response off treatment in adult patients with ITP receiving eltrombopag, who had relapsed or failed to respond to initial CS treatment. Eligible patients are adults (≥ 18 years old) with ITP who are not responsive to or are in relapse after first-line CS therapy ± immunoglobulins used as rescue therapy, with platelet counts < 30×109/L, and assessed as needing treatment. Patients receive a starting dose of 50 mg eltrombopag QD (East/Southeast Asian ancestry: 25 mg QD; Japanese patients treated in Japan: 12.5 mg QD per approved starting dose in the Japanese prescribing information). The primary endpoint is the number (%) of patients with sustained responses off treatment by Month 12. Sustained response is defined as a complete response (platelet count ≥ 100×109/L) with platelet counts ≥ 70×109/L maintained for 2 months, followed by dose reduction and treatment discontinuation while maintaining platelet counts ≥ 30×109/L, without bleeding or rescue therapy, until Month 12. Platelet counts are assessed weekly during the first 8 weeks of treatment, and biweekly thereafter, depending on patient response. Rescue therapy is permitted within the first 14 days of study treatment and does not preclude patients from reaching the primary endpoint criteria, if successful discontinuation of eltrombopag is reached and maintained at Month 12. The proportion of patients who reach the primary endpoint will be summarized with the 95% confidence interval (Clopper-Pearson method). A binomial test for one proportion, H0: P = 0.15 vs. H1: P > 0.15 will be performed to test if the proportion of remission patients is greater than 15%, using a target alpha level of 0.05. Patients who meet the primary endpoint at 12 months will be followed up for an additional 12 months.Patients who relapse between Months 12 and 24 will be offered retreatment with eltrombopag until the end of Month 24. Secondary endpoints will include measures of quality of life, and exploratory endpoints will include biomarker assessments of immunomodulation. Here, we report an update on trial recruitment and patient baseline characteristic data from an early data cut (November 15, 2019). An estimated 101 patients across 50 sites will be enrolled; 47 sites are currently active and 3 are pending site initiation visits. As of November 15, 2019, 66 patients had been screened, 53 of whom had been enrolled and had undergone treatment. Of the patients enrolled, 60.4% were female and the mean (± standard deviation) age was 49.4 (± 19.0) years. The majority of patients were White (88.7%). On June 24, 2020, patients from 15 countries worldwide were committed to screening (Figure 1); the number of patients screened had risen to 98, with 82 patients enrolled. The planned study timeline has been disrupted due to the COVID-19 pandemic. Enrollment is expected to complete in November 2020, with final results expected in 2023. Conclusion: The purpose of this trial is to assess sustained response off treatment following eltrombopag therapy in patients with ITP who failed to respond to or have relapsed after initial treatment with steroids. The data generated by TAPER will provide insights into whether eltrombopag could be a viable treatment option after first-line steroid treatment. If this were confirmed, the earlier use of eltrombopag could have the potential to reduce the toxicity from repeated steroid exposure in patients with ITP. Disclosures Cooper: Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau. Ghanima:Amgen: Honoraria, Speakers Bureau; Bristol Myers Squibb: Research Funding; Bayer: Research Funding; Novartis: Honoraria, Speakers Bureau; Principia: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Haenig:Novartis: Current Employment. Lee:Novartis: Current Employment, Other: Novartis AG equity holder. Rahman:Novartis: Other: Full time employee of IQVIA which provides services to Novartis; IQVIA: Current Employment. Zaja:Kyowa Kirin: Honoraria, Speakers Bureau; Mundipharma: Honoraria, Speakers Bureau; Novartis: Honoraria, Patents & Royalties: Pending patent (No. PAT058521) relating to TAPER trial (NCT03524612), Speakers Bureau; Roche: Honoraria, Speakers Bureau; AbbVie: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Grifols: Honoraria, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Janssen-Cilag: Honoraria, Speakers Bureau.

scholarly journals Carfilzomib Thalidomide and Dexamethasone Is Safe and Effective in the Treatment of Relapsed/Refractory Multiple Myeloma: An Open Label Phase II Australasian Leukaemia and Lymphoma Group (ALLG) MM 018/ Asian Myeloma Network (AMN) 002 Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Hang Quach ◽  
Simon J Harrison ◽  
Je-Jung Lee ◽  
Nichloas Murphy ◽  
Jae Hoon Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Open Label ◽  
Advisory Committees ◽  
Open Label Phase ◽  
Grade 3

Background: The combination of carfilzomib with immunomodulatory drugs (IMiDs) and dexamethasone is active in multiple myeloma (MM). Carfilzomib, thalidomide, and dexamethasone (KTd) has been studied in upfront MM treatment but has not been studied in the setting of relapsed/refractory myeloma (RRMM). The ALLG MM018/ AMN002 is an open-label phase II study of KTd in patients with RRMM. This study was conducted across 16 sites across Australia, New-Zealand, Singapore, South Korea and Taiwan. Method: Patients with RRMM with 1-3 prior lines of treatment were given carfilzomib [K: 20mg/m2 IV cycle 1 days 1 and 2, 56mg/m2 (36mg/m2 for patients age ≥75 years) from cycle 1 day 8 onwards], thalidomide (T: 100mg po nocte) and dexamethasone [dex: 40mg (20mg for patients age ≥75 years) po weekly], in a 28-day cycle. After 12 cycles, T was omitted, and K was given on days 1,2,15,16 and dex days 1,15 every 28-day cycles for a further six cycles. The primary endpoint was PFS. Secondary endpoints were ORR, overall survival, adverse events, and quality of life (QoL). The study had an 80% power to detect a ≥70% PFS at 6.5 months compared to historical ≤50% PFS at 6.5 months expected with Td (Kropff, M. et al. Haematologica 2012), at a significance level of 0.05. Results: This study has completed accrual. Eighty-three patients [median age of 66 years (42-85)] were enrolled with a median follow up of 15.9 (0.9-26) months. ORR rates were 86.4% (≥VGPR 70.2%). Median PFS was 20m (95% CI 15.9-26m). PFS at 6.5 months was 76.2% (95% CI 73.6-84.9%). Median OS has not been reached, and was 75% at 20 months. The most common grade ≥3/4 AEs were peripheral neuropathy (16%), upper respiratory tract infections (12%), dyspnoea (14%), and hypertension (10%). Grade ≥3/4 cardiac AEs occurred in 6%. The median carfilzomib dose that was delivered was 70.7% (32.8-92.6%) of the target dose. Thus far, 41% of patients have completed the intended 18 cycles of treatment. 21% of patients ceased therapy early. The most common reason for early treatment cessation was disease progression (30%) and adverse events (15%). Fifteen patients (18%) have died, 11 were due to MM, two from infection, one from an ischaemic cardiac event, and one from a traffic accident. QoL, as measured by the EQ-5D-5L instrument, remained stable throughout treatment. Conclusion: The ALLG MM018/AMN 002 study has met its primary endpoint. The KTd schedule as outlined in this study is efficacious in patients with RRMM, resulting in a prolonged PFS and a safety profile in line with previous reports for each of carfilzomib and thalidomide. KTd is an active option in jurisdictions where the cost of other IMiDs prohibits regulatory funding. Comparisons of efficacy and adverse events between the Caucasian and Asian populations will be presented at the meeting. Disclosures Quach: Celgene: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Glaxo Kline Smith: Consultancy, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen Cilag: Consultancy, Honoraria; Sanofi: Consultancy, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Haemalogix: Consultancy. Augustson:Roche: Other: Support of parent study and funding of editorial support. Campbell:Amgen, Novartis, Roche, Janssen, Celgene (BMS): Research Funding; AstraZeneca, Janssen, Roche, Amgen, CSL Behring, Novartis: Consultancy. Soo:Hanmi: Research Funding. Durie:Amgen, Celgene, Johnson & Johnson, and Takeda: Consultancy.

[OPTIMAL 3] A phase III trial to evaluate the efficacy and safety of DHP107 (Liporaxel, oral paclitaxel) compared to Taxol (IV paclitaxel) as first line therapy in patients with recurrent or metastatic HER2 negative breast cancer (BC) (NCT03315364).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1106-TPS1106
Author(s):  
Sung-Bae Kim ◽  
Qingyuan Zhang ◽  
Tao Sun ◽  
Jae Hong Seo ◽  
Keun Seok Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Comparable Efficacy ◽  
Efficacy And Safety ◽  
Significance Level ◽  
Number Of Patients ◽  
Oral Paclitaxel

TPS1106 Background: Paclitaxel is a microtubule-stabilizing drug used for various cancers including breast cancer (BC) and gastric cancer (GC). DHP107 is an oral paclitaxel solution formulated with non-toxic excipients using DH-LASED technology, which doesn’t require pre-treatment. DHP107 demonstrated comparable efficacy and safety to IV paclitaxel for patients with advanced GC (Ann Oncol 2018), and was market approved as the first oral paclitaxel in 2016 for GC in Korea. In previous OPTIMAL phase II study, the primary endpoint objective response rate (ORR) was 54.5% in HER2 negative metastatic BC (MBC) patients and 44.4% in triple negative BC (TNBC) patients. Disease control rate (DCR) was 90.9% by the investigators’ assessment. Toxicity was manageable (2019 ESMO). OPTIMAL phase III is being conducted in Korea, China and Eastern Europe based on this result and another phase II study (OPERA) is being performed in USA. Methods: OPTIMAL 3 study is a multinational, multi-center, randomized and open-label trial enrolling HER2 negative (HR+/HER2- or TNBC) recurrent or metastatic BC patients. Patients are randomized to either study (DHP107) or control group (IV paclitaxel) in a 1:1 ratio and stratified by disease free interval (DFI≤48 weeks vs >48 weeks), visceral metastasis status (visceral vs non-visceral) and country. Patients are administrated with DHP107 (200mg/m2 p.o. bid) or IV paclitaxel (80mg/m2 infused) on D1, 8, 15, q4wks. Tumor assessments are performed on every 8 weeks (±7 days) from C1D1 until disease progression (RECIST V1.1). Key inclusion & exclusion criteria are hormone receptor (ER/PR) positive or negative, HER2 negative, ECOG performance status ≤1 and no prior chemotherapy in recurrent or metastatic disease. The primary endpoint is progression free survival (PFS). Secondary endpoints include ORR, overall survival (OS), time to treatment failure (TTF), DCR, quality of life (QoL) and safety. Total target number of patients is 476 with an estimated 10% drop-out rate. The test is based on non-inferiority hypothesis (HR=1.33) with 80% power. The primary endpoint will be analyzed using a one-sided test at a 2.5% significance level, and other endpoints will be analyzed using a two-sided test at a 5% significance level, with 95% confidence interval. The first subject was enrolled in Jan 2019 and recruitment is ongoing and is expected to be completed in Dec 2020. Final results of this study will be announced by the end of 2022. Clinical trial information: NCT03315364 .

Early Results of a Phase Ib/II Dose-Escalation Trial of Romidepsin in Association with CHOP in Patients with Peripheral T-Cell Lymphomas (PTCL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2673-2673
Author(s):  
Jehan Dupuis ◽  
Rene-Olivier Casasnovas ◽  
Franck Morschhauser ◽  
Herve Ghesquieres ◽  
Catherine Thieblemont ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
Phase Ii ◽  
Qt Interval ◽  
Research Funding ◽  
Hematological Toxicity ◽  
Phase Ii Studies ◽  
Starting Dose ◽  
Grade 3 ◽  
Previous Phase

Abstract Abstract 2673 Background: Romidepsin is a potent histone deacetylase inhibitor approved by the FDA for patients with cutaneous T-cell lymphoma and PTCL who have received at least 1 prior systemic therapy. In recurrent/refractory PTCL, it has been evaluated as a single agent in 2 previous phase II studies with overall response rates of 30–38% (Piekarz et al., Blood 2011;117:5827; Coiffier et al., Blood 2010;116(21S):114). The observed toxicity was mainly hematological and digestive. Prolongation of the QT interval has been reported. The aim of the present study was to evaluate the safety, tolerability and efficacy of escalating doses of romidepsin in association with CHOP in patients with previously untreated PTCL. Methods: Patients with biopsy-proven PTCL are planned to receive 8 cycles of CHOP (cyclophosphamide 750 mg/m2 day 1, doxorubicin 50 mg/m2 day 1, vincristine 1,4 mg/m2 day 1, prednisone 40 mg/m2 days 1–5) in association with escalating doses of romidepsin. Based on pharmacokinetic data and results of previous phase II studies, the starting dose of 10 mg/m2 on days 1 & 8 has been chosen as the starting dose. At least 3 patients are to be treated at each dose level, and 3 more at the same dose level if 1 of the first three exhibited dose-limiting toxicity (DLT) during the first 2 cycles. Results: Six patients (3 male, 3 female, aged 47 to 67) have been included so far and are analyzable for toxicity on the first two cycles. Diagnoses were: PTCL, not otherwise specified (n=3), angioimmunoblastic TCL (n=1), primary cutaneous CD4+ small-medium TCL (n=1), enteropathy-associated TCL (n=1). ECOG performance status was good (0–1) in all patients; 5/6 had stage IV disease; IPI score was 1 (n=1), 2 (n=3), 3 (n=1), 4 (n=1). Among the first 3 patients treated at the starting dose of 10 mg/m2, one exhibited a DLT (grade 3 malaise after cycle 2), thus 3 more patients were treated at this dose level. Among those 3, we observed 2 other DLTs: one grade 3 general status deterioration and grade 3 haematological toxicity lasting more than 7 days in the same patient, and one grade 4 hematological toxicity lasting more than 3 days. A total of 269 adverse events (AEs) were observed during 34 analyzable cycles. The most frequent AEs were: neutropenia n=22 (grade 3–4 =12), thrombocytopenia n=28 (grade 3–4 n=5), digestive complaints n=18 (no grade >2), and asymptomatic increase of liver enzymes n=7 (1 grade 3). The mean increase in the corrected QT interval between pre- and post-romidepsin EKGs was 19 ms (range −43 to +79). No clinically relevant cardiac event was reported. One patient progressed after 5 cycles, 2 have finished the 8 planned cycles and are both in CR, and 3 are still under treatment without evidence of progression. Conclusion: Romidepsin can be combined with CHOP without unexpected toxicity. The dose of 10 mg/m2 on days 1& 8 is associated with excessive hematological toxicity. The study is ongoing with a lower dose of 8 mg/m2 on day 1 & 8 of each cycle. Updated results will be presented at the meeting. Disclosures: Coiffier: CELGENE: Consultancy, Research Funding, Speakers Bureau; ALLOS THERAPEUTICS: Consultancy, Research Funding, Speakers Bureau; ESAI: Consultancy, Research Funding, Speakers Bureau.

Successful Discontinuation of Eltrombopag Treatment in Patients with Chronic ITP

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1085-1085 ◽  
Author(s):  
Emily Leven ◽  
Allison Miller ◽  
Nayla Boulad ◽  
Anis Haider ◽  
James B Bussel
Keyword(s):  
Platelet Count ◽  
Board Of Directors ◽  
Research Funding ◽  
Rescue Therapy ◽  
Primary Response ◽  
Additional Treatment ◽  
Advisory Committees ◽  
Platelet Counts ◽  
Rescue Treatment ◽  
Immature Platelet Fraction

Abstract Abstract 1085 Introduction: Patients with immune thrombocytopenia (ITP) commonly experience platelet increases while under treatment with thrombopoietin-receptor agonists (TPO-RA). Anecdotal evidence suggests certain patients have been able to discontinue TPO-RA and still maintain platelet counts above baseline without additional treatment. This prospective ongoing study was designed to investigate the frequency and characteristics of patients exhibiting sustained responses after electively discontinuing eltrombopag (a TPO-RA) without substituting additional therapy. Methods: Enrolled patients were required to have ITP defined by consensus guidelines (Provan, Blood, 2009) for at least 6 months and must have been taking eltrombopag for a minimum of 4 months prior to starting this observational study. Rescue therapy is permitted once in the first 4 weeks off eltrombopag. The primary response endpoint was prospectively defined as a platelet count of ≥30,000/μl and ≥20,000/μl above initial baseline for 6 months off eltrombopag without intervening treatment (other than rescue). The secondary endpoint was being stably off therapy at 4 weeks after discontinuing eltrombopag. All patients who meet the 2 inclusion criteria (ITP for 6 months and eltrombopag for 4 months) are eligible for the study. Results: Fifteen patients are currently enrolled. Ages range from 3 to 86 years, median 55 years, with 10 females. There are 5 responders of 5 months or more (3 females, 2 males) and 10 non-responders (7 females, 3 males). Four of 5 responders have been off therapy for 6 months or more; the fifth “responder” has been off therapy for 5 months, with platelet counts ≥195,000/μL (figure 1). Responders are aged 19–86 years and have had ITP for 5–34 years; all had been on eltrombopag for > 2 years. Two responders were splenectomized and all had 3 or more prior therapies. One responder and 9 non-responders received rescue treatment in the first 4 weeks. One patient was a responder at 4 weeks, but she lost her response before reaching 6 months off-treatment. Factors not significantly associated with response were: age, duration of ITP, duration of eltrombopag therapy, splenectomy status, number of prior ITP treatments, bleeding history, and platelet count at the time that eltrombopag was discontinued. However, a lower absolute immature platelet fraction (AIPF) value at cessation of eltrombopag was seen in responders (fig 2, p=0.022). AIPF data for 1 non-responder is not available. An AIPF of 900 × 10/μl at the time of discontinuation of eltrombopag exceeds the AIPF of all 5 responders, but also of 3 of 9 non-responders. Conclusions: A substantial fraction of patients with ITP treated with eltrombopag, approximately 1/3, appear able to discontinue eltrombopag treatment and nonetheless maintain an at least adequate platelet count indefinitely (at the very least 6 months). Similar preliminary data has been reported with romiplostim (EHA and ASH abstracts). AIPF values (platelet retics) may better predict a patient's likelihood of successfully stopping therapy than other variables such as those listed above. Disclosures: Bussel: Amgen: Family owns Amgen stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; GlaxoSmithKline: Family owns GSK stock, Family owns GSK stock Other, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; IgG of America: Research Funding; Immunomedics: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sysmex: Research Funding; Portola: Consultancy. Off Label Use: The use of romiplostim in pediatric patients was examined in this study.

Lenalidomide and Dexamethasone in the Treatment of AL Amyloidosis: Final Results of A Phase II Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4084-4084
Author(s):  
Divya Nair ◽  
Vaishali Sanchorawala ◽  
Anthony C Shelton ◽  
Salli A Fennessey ◽  
Kathleen T Finn ◽  
...  
Keyword(s):  
Side Effects ◽  
Phase Ii ◽  
Research Funding ◽  
Phase Ii Trial ◽  
High Dose ◽  
Al Amyloidosis ◽  
Weekly Dose ◽  
Hematologic Response ◽  
Starting Dose ◽  
Tract Infections

Abstract Abstract 4084 AL amyloidosis is a plasma cell dyscrasia in which clonal immunoglobulin light chains misfold, forming fibrils that are deposited in tissues and vital organs. Immunomodulatory drugs including thalidomide, lenalidomide (LEN), and pomalidomide have activity in AL amyloidosis. We conducted a prospective phase II trial of LEN with dexamethasone (DEX) in the treatment of AL amyloidosis (ClinicalTrials.gov: NCT00091260), enrolling 82 patients from 2004–2011. We now report the final results of this trial. The majority of the patients were treated with LEN at a starting dose of 15 mg/d for 21 days out of a 28 day cycle, and received DEX at 20 or 40 mg weekly, depending upon age, congestive heart failure, and/or peripheral edema, and aspirin prophylaxis for venous thromboembolism (VTE) was used for most. Of the 82 patients, the median age was 62 (range, 40–84) and 63% were men. 95% of the patients had prior therapy for AL, often including high dose melphalan and autologous stem cell transplantation. The median number of cycles delivered was 11 (range, 1–69). Of the 68 evaluable patients, 16% achieved a complete hematologic response, 44% achieved a partial hematologic response, 9% achieved a minor hematologic response, and 29% had no response to treatment. The median time to best hematologic response was 6 months. Sixty-three patients had quantifiable organ involvement prior to treatment with LEN/DEX, and 44% of those patients had measurable organ response. Reasons for discontinuation of study drug were side effects (29%), non-response (39%) and complete response or completion of trial (15%). The most common side effects during treatment were fatigue (88%), anemia (67%), muscle cramps (66%), dizziness/lightheadedness (60%), respiratory tract infections (55%), increased creatinine (56%) and skin rash (48%). In conclusion, LEN administration achieved a 60% hematologic response rate (CR+PR) even in heavily pre-treated AL patients, when used at a starting dose of 15 mg/d with weekly dose-modified DEX, VTE prophylaxis, and appropriate management of side effects. Disclosures: Off Label Use: Lenalidomide for AL amyloidosis. Sanchorawala:Millennium: Research Funding. Zeldis:Celgene: Employment. Seldin:Celgene: Research Funding.

scholarly journals New Film-Coated Tablet Formulation of Deferasirox Is Well Tolerated in Patients with Thalassemia or MDS: Results of the Randomized, Phase II E.C.L.I.P.S.E. Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1285-1285 ◽  
Author(s):  
Ali T. Taher ◽  
Raffaella Origa ◽  
Silverio Perrotta ◽  
Alexandra Kouraklis ◽  
Giovan Battista Ruffo ◽  
...  
Keyword(s):  
Phase Ii ◽  
Research Funding ◽  
Iron Chelation ◽  
Laboratory Evaluation ◽  
Lauryl Sulfate ◽  
Open Label ◽  
End Of Treatment ◽  
Starting Dose ◽  
Coated Tablet ◽  
Open Label Phase

Abstract Background : Patients (pts) compliant with iron chelation therapy (ICT) experience improved organ function and survival (Delea et al. Transfusion 2007;47:1919-29). Once-daily deferasirox (DFX) dispersible tablets (DT) have a well-defined safety and efficacy profile and, compared with parenteral deferoxamine, provide greater adherence, pt satisfaction, and quality of life (Cappellini et al. Clin Ther 2007;29:909-17). However, barriers exist to pt adherence to DFX DT, including GI tolerability and palatability, leading to development of a film-coated tablet (FCT) that can be taken with or without a light meal. The FCT contains the same active substance as DT but different excipients (lactose and sodium lauryl sulfate removed). Here we present results of the randomized, open-label, Phase II ECLIPSE study that evaluated safety of DFX FCT and DT formulations in pts with transfusion-dependent thalassemia (TDT) or IPSS-R very low-, low- or intermediate-risk MDS. Methods : ICT-naïve or pre-treatedpts aged ≥10 yrs, requiring ICT at DFX DT ≥30 mg/kg/day (TDT) or ≥20 mg/kg/day (MDS), with serum ferritin (SF) >1000 ng/mL, were enrolled. Exclusion criteria: creatinine clearance below contraindication limit per local label (<60 mL/min or <40 mL/min), serum creatinine >1.5xULN, alanine aminotransferase >5×ULN, urine protein/urine creatinine ratio (UPCR) >0.5 mg/mg, or impaired GI function. ICT-naïve pts received DFX DT 20 mg/kg/day or DFX FCT 14 mg/kg/day. ICT pre-treated pts received a DT or FCT dose equivalent to their pre-washout dose. FCT doses are 30% lower than DT doses due to improved bioavailability, conversion factor 1.43. Dose was adjusted based on SF and investigator's judgment after wk 4 for ICT-naïve pts and after 3 months for ICT pre-treated pts (DT ±5-10 mg/kg/day, max 40 mg/kg/day; FCT ±3.5-7 mg/kg/day, max 28 mg/kg/day); dose adjustments for safety reasons were permitted at any time. Primary endpoint was overall safety, measured by frequency and severity of AEs and changes in laboratory values from baseline (BL) over 24 wks. A secondary endpoint was evaluation of selected GI AEs. Results: 173 pts were randomized 1:1 to DT or FCT (Table 1). Mean actual daily DFX dose ± SD over 24 wks was 27.5 ± 7.7 mg/kg/day (DT) and 20.8 ± 5.4 mg/kg/day (FCT). More FCT pts were started on a dose higher than the protocol-specified dose than DT pts (26.4% vs 9.3%). Mean/median duration of exposure was 155/168 days with DT and 163/169 days with FCT. 73 (84.9%; DT) and 77 (88.5%; FCT) pts completed 24 wks. Relative consumed tablet count was high, but lower with DT (85.3%) than FCT (92.9%). Absolute median (range) change in SF at end of treatment was -85.5 (-2146 to 8250) ng/mL (from 2485 [915-8250] ng/mL at BL) with DT, and -350 (-4440 to 3572) ng/mL (from 2983 [939-8250] ng/mL at BL) with FCT, corresponding to a median relative change of -4.1% (DT) and -14.0% (FCT) at end of treatment. AEs regardless of causality were reported in similar proportions of pts for each formulation (Table 2). Fewer severe AEs were observed in FCT pts. The most common AEs with either formulation were consistent with the known DFX safety profile. Notable laboratory evaluation frequencies were similar with both formulations (Table 3). 61.6% (95% CI, 50.5-71.9%) of DT pts and 58.6% (95% CI, 47.6-69.1%) of FCT pts reported ≥1 GI AEs. Similar proportions of pts had diarrhea, nausea, and abdominal pain. Fewer FCT pts had constipation and vomiting than pts receiving DT. Fewer pts had severe GI AEs with FCT than with DT. In pts receiving DT prior to study entry, fewer FCT pts had GI AEs (53.5%, FCT; 60.3%, DT), particularly diarrhea, vomiting and constipation. Increased UPCR was reported in more FCT pts (12.8%, DT; 20.7%, FCT), which could be attributed to more FCT pts receiving a higher than recommended starting dose. Renal event frequency was similar when patients were started on a correct starting dose (30.9%, DT; 33.3%, FCT). 23 pts discontinued, 10 because of AEs (n=6, DT; n=4, FCT). Conclusions: These results in pts with TDT or very low-, low- or int-risk MDS demonstrate comparable FCT and DT safety profiles, consistent with the known DFX profile. In patients with prior DT exposure, fewer GI AEs were seen with FCT than DT. Pts receiving FCT had better compliance, continued longer on treatment and experienced greater SF reduction. DFX FCT may improve pt experience with ICT resulting in greater compliance and reduced frequency and severity of iron overload-related complications. Disclosures Taher: Novartis: Honoraria, Research Funding; Celgene: Research Funding. Origa:Novartis: Honoraria; Apopharma: Honoraria. Kouraklis:Gilead: Consultancy; Janssen: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Roche: Consultancy; Celegene: Consultancy. Kattamis:Novartis: Honoraria, Research Funding; ApoPharma: Honoraria. Cortoos:Novartis: Employment. Huang:Novartis: Employment. Weill:Novartis: Employment. Herranz:Novartis: Employment. Porter:Novartis: Consultancy, Honoraria, Research Funding; Celegene: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Bluebird Bio: Consultancy.

scholarly journals Successful Treatment of MYC rearrangement Positive Large B Cell Lymphoma Patients with R-CHOP21 Plus Lenalidomide: Results of a Multicenter Phase II HOVON Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 786-786 ◽  
Author(s):  
Martine E.D. Chamuleau ◽  
Marcel Nijland ◽  
Josée M Zijlstra ◽  
Rogier Mous ◽  
P.J. Lugtenburg ◽  
...  
Keyword(s):  
Ct Scan ◽  
Board Of Directors ◽  
Phase Ii ◽  
Primary Endpoint ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Pet Ct ◽  
Grade 3 ◽  
Pet Ct Scan

Abstract Background: Patients with MYC rearrangement positive large B cell lymphoma other than Burkitt lymphoma (MYC+ LBCL), have a dismal prognosis following standard first line therapy with R-CHOP. Retrospective studies report complete remission rates < 50% and 2-year overall survival (OS) of approximately 35%. Lenalidomide is an immunomodulatory drug and is able to down-regulate MYC and its target genes and proteins in B cells that harbor a MYC rearrangement. We report data of a prospective phase II study evaluating the efficacy of lenalidomide in combination with R-CHOP (R2CHOP) in newly diagnosed MYC+ LBCL patients. Methods: A national screening program for MYC rearrangement by fluorescence in situ hybridization (FISH) was performed in newly diagnosed LBCL patients. Patients with a proven MYC rearrangement, ≥ 18 year, Ann Arbor stage II-IV, were offered participation in a single arm phase II study. Treatment consisted of 6 cycles R-CHOP21 plus lenalidomide 15 mg on day 1-14, followed by two additional rituximab administrations. Use of G-CSF was mandatory. All patients received intrathecal methotrexate prophylaxis. 18F-FDG PET-CT (PET-CT) scans were performed at baseline, midterm (after 3 cycles) and end-of-treatment (EOT). Diagnostic lymphoma samples were centrally reviewed including immunohistochemical (IHC) work-up and complementary BCL2 and BCL6 FISH analysis. Cell of origin classification was determined by IHC (Hans) and by gene expression profiling (Lymph2Cx). The primary endpoint was complete metabolic response rate (CMR) on EOT PET-CT scan, according to the Deauville criteria and assessed by 2 independent nuclear medicine physicians performing central review. In case of discordance, a third adjudicator reviewed. Confirmation of bone marrow (BM) negativity at EOT for patients with positive BM at diagnosis was not required for CMR. Secondary endpoints included disease free survival (DFS), progression free survival (PFS), OS and predictive value of midterm PET-CT for EOT PET-CT scan. Data cut-off was July 4th 2018. Results: From April 2015 to February 2018, 85 patients were included at 20 hospitals. Planned interim analysis (after 26 consecutive patients completed treatment) revealed no safety concerns. At data cut-off, central data management, pathology and imaging review processes were completed for the first 60 patients. The remaining patients (60 to 85) are still on treatment or have recently finished treatment. Among the first 60 patients, 2 were declared ineligible, leaving 58 patients for this analysis (demographics and disease characteristics in table 1). Central pathology review confirmed diagnosis of MYC+ LBCL in all patients. Additional FISH analysis revealed that 41/58 patients (71%) had MYC and BCL2 and/or BCL6 rearrangements (double hit or triple hit), 11/58 (19%) had a single MYC rearrangement, 6/58 (10%) had a MYC rearrangement but no information on BCL2 and BCL6. At EOT PET-CT scan (primary endpoint), 36/58 patients (62%) were in CMR (95% confidence interval (CI) 50%-71%). 2/58 patients (3%) reached a partial metabolic response (PMR), and 20/58 patients (34%) had progressive disease (PD). At midterm PET-CT, 39/58 patients (67%) were in CMR; of these 29 were still in CMR and 10 showed PD at EOT PET-CT. 18/58 patients (31%) were in PMR at midterm; 7 of them converted to CMR, 2 remained in PMR, 9 showed PD at EOT. One patient went off protocol after two cycles due to progression. With a median follow-up of 17.2 months, 1-year estimates for OS were 79% (CI 66%-88%), for DFS 74% (CI 59%-85%), and for PFS 60% (CI 47%-72%). Grade 3 and 4 adverse events (AE) were seen in 26 (43%) respectively 9 patients (15%). Most common grade 3-4 AEs were gastrointestinal disorders, infections, and neutropenia. 55 serious AEs were reported in 27 patients (all hospitalization). 1 patient went off protocol due to grade 3 diarrhea. Univariate regression analyses revealed no significant prognostic factors for achieving CMR or prolonged survival yet. Conclusion: These data represent the first prospective trial worldwide for newly diagnosed MYC rearrangement positive LBCL patients. Treatment with R2CHOP demonstrates acceptable toxicity and promising efficacy with 62% CMR on centrally reviewed PET-CT scan and a 1-year OS rate of 79%. In December 2018, all 85 registered patients will have finished treatment and complete analysis of the primary endpoint and additional biological studies will be available. Disclosures Chamuleau: Gilead: Research Funding; celgene: Research Funding; Genmab: Research Funding; BMS: Research Funding. Mous:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; JANSSEN CILAG: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; sandoz: Membership on an entity's Board of Directors or advisory committees. Lugtenburg:takeda: Consultancy, Research Funding; servier: Consultancy, Research Funding; roche: Consultancy; BMS: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; GenMab: Research Funding. Kersten:celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; roche: Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Oral Rilzabrutinib, a Bruton Tyrosine Kinase Inhibitor, Showed Clinically Active and Durable Platelet Responses and Was Well-Tolerated in Patients with Heavily Pretreated Immune Thrombocytopenia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
David J. Kuter ◽  
Merlin Efraim ◽  
Jiri Mayer ◽  
Vickie McDonald ◽  
Robert J. Bird ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Median Duration ◽  
Primary Endpoint ◽  
Clinical Studies ◽  
Research Funding ◽  
Immune Thrombocytopenia ◽  
Publicly Traded ◽  
Platelet Counts ◽  
Bruton Tyrosine Kinase ◽  
Heavily Pretreated

Introduction: Rilzabrutinib is an oral, reversible, covalent inhibitor of Bruton tyrosine kinase (BTK) that targets underlying disease mechanisms of platelet destruction without inhibiting platelet aggregation (common with ibrutinib). The mechanisms of BTK inhibition provide a new approach for treating patients with immune thrombocytopenia (ITP). Completion of dose-escalation study phase determined that the minimally-effective dose was rilzabrutinib 400 mg given twice daily (BID; Kuter. ASH 2019). Methods: This open-label phase I/II study evaluated rilzabrutinib in adults with relapsed ITP who had at least two platelet counts &lt;30×109/L in the 14 days prior to the first dose of rilzabrutinib, and included patients who had inadequate response to prior corticosteroids (CS)/thrombopoietin receptor agonists (TPO-RA) but were allowed to continue receiving stable doses of these medications. The primary endpoint was ≥2 consecutive platelet counts of ≥50×109/L and an increase of ≥20×109/L from baseline without requiring rescue medication. Subgroup analyses included assessing the impact of select prior therapies on reaching the primary endpoint, as well as the ability of rilzabrutinib to maintain durable responses and safety in the long-term extension (LTE) period. Results: As of May 5, 2020, 32 patients initiated treatment with rilzabrutinib 400 mg BID. The median baseline age was 50 years (range, 21-74) and 97% were classified as having primary ITP. Patients had a median baseline platelet count of 13×109/L, had ITP for a median duration of 7.3 y (range, 0.4-52.5), and were heavily pretreated with a median of 6 prior therapies (range, 1-53; 28% prior splenectomy). Median duration of rilzabrutinib 400 mg BID treatment was 18.0 wk (range, 1.4-24.6). Overall, 14/32 patients (44%) achieved the primary endpoint, and responders maintained platelet counts ≥50×109/L for a median of 71% (range, 33%-100%) of weekly counts. Primary endpoint responses were achieved despite prior splenectomy or lack of response to prior ITP therapies (Table). Independent of the primary response, 67% of all patients were able to achieve clinically meaningful benefit of platelet counts ≥30×109/L. Nine patients continued rilzabrutinib 400 mg BID into the LTE period for an additional median of 20 wk (range, 4-36) of treatment. Four of these LTE patients were on rilzabrutinib monotherapy and 5 on rilzabrutinib with concomitant ITP therapy (n=3 corticosteroids, n=2 romiplostim). Baseline characteristics for the 9 LTE patients were a median duration of ITP of 2.6 y (1.2-14.3) and a median of 5 prior therapies (range, 1-8; 1 patient had a prior splenectomy). Platelet counts of ≥50×109/L in the LTE period were maintained for a median of 100% (range, 36%-100%) of weekly counts (Figure). Treatment-related, treatment-emergent adverse events (TEAEs) were all grade 1/2 in patients initiating rilzabrutinib 400 mg BID; 1 patient each experienced grade 1 diarrhea and grade 1 hypophosphatemia in the LTE period. Conclusions: Oral rilzabrutinib treatment achieved clinically significant platelet responses (≥50×109/L) in patients with heavily pretreated ITP irrespective of splenectomy or lack of response to prior ITP therapy, and maintained responses for the majority of time. In addition, most patients (67%) achieved a clinically meaningful response (platelet counts ≥30×109/L). In patients treated beyond 6 months in the LTE, responses remained consistently reliable (median 100% of weeks). Rilzabrutinib was well tolerated with only grade 1/2 treatment-related TEAEs overall, with only 2 related grade 1 events observed in the LTE period. Continued study is warranted to further demonstrate the magnitude and durability of rilzabrutinib's clinical benefit. Disclosures Kuter: Zafgen: Consultancy, Honoraria; Takeda (Bioverativ): Consultancy, Honoraria, Other, Research Funding; Merck Sharp Dohme: Consultancy, Honoraria; Kyowa-Kirin: Consultancy, Honoraria; UCB: Consultancy, Honoraria; Platelet Disorder Support Association: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Shionogi: Consultancy, Honoraria; Dova: Consultancy, Honoraria; Shire: Consultancy, Honoraria; Sanofi (Genzyme): Consultancy, Honoraria; Protalix Biotherapeutics: Consultancy; Up-To-Date: Consultancy, Honoraria, Patents & Royalties; Protalex: Consultancy, Honoraria, Research Funding; Shionogi: Consultancy; Genzyme: Consultancy, Honoraria; Immunovant: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Actelion (Syntimmune): Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Protalex: Consultancy, Honoraria, Other, Research Funding; Rigel: Consultancy, Honoraria, Other, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Agios: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Caremark: Consultancy, Honoraria; CRICO: Consultancy, Honoraria; Kezar Life Sciences, Inc: Other, Research Funding; Principia Biopharma: Consultancy, Honoraria, Other, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Alnylam: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Immunovant: Other: Travel Expenses, Research Funding; Principia: Consultancy, Research Funding; Momenta: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Argenx: Consultancy, Honoraria, Other: Travel Expenses, Research Funding; Novartis: Consultancy, Honoraria. Efraim:UMHAT"ST.MARINA": Consultancy, Current Employment, Current equity holder in private company. Mayer:AbbVie: Research Funding; Principia Biopharma: Research Funding. McDonald:Bayer: Consultancy, Honoraria; Rigel: Research Funding; Novartis: Consultancy, Honoraria, Other: Travel Expenses; Amgen: Consultancy, Honoraria, Other: Travel Expenses. Bird:Sanofi: Consultancy, Other: (pls note personal honoraria declined for ad board); Principia Biopharma: Other: investigator in clinical studies; Amgen: Consultancy, Other: (pls note personal honoraria declined for all), Speakers Bureau; Novartis: Consultancy, Other: (pls note personal honoraria declined for all), Speakers Bureau; Rigel: Other: investigator in clinical studies; CSL-Behring: Other: investigator in clinical studies; Bristol-Myers Squibb Company: Other: investigator in clinical studies; Ablynx: Other: investigator in clinical studies. Regenbogen:Roche: Current equity holder in publicly-traded company; Gilead: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Moderna: Current equity holder in publicly-traded company; AbbVie: Current equity holder in publicly-traded company. Garg:Takeda: Consultancy. Kaplan:Celgene: Honoraria; Novartis: Honoraria. Bandman:Principia Biopharma: Current Employment. Burns:Principia Biopharma: Current Employment. Neale:Principia Biopharma: Current Employment. Thomas:Principia Biopharma: Current Employment, Current equity holder in publicly-traded company. Cooper:Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Rigel: Consultancy, Honoraria; Principia: Consultancy, Honoraria. OffLabel Disclosure: Rilzabrutinib is an investigational therapy being evaluated in a clinical study for the treatment of patients with immune thrombocytopenia.

scholarly journals Real-World Experience with Fostamatinib in Patients with Immune Thrombocytopenia at an Academic Medical Center

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4912-4912 ◽  
Author(s):  
David Hughes ◽  
Frances Blevins ◽  
Bhavesh Shah ◽  
Shayna Sarosiek ◽  
Adam Lerner ◽  
...  
Keyword(s):  
Platelet Count ◽  
Immune Thrombocytopenia ◽  
Medical Center ◽  
Rescue Therapy ◽  
Academic Medical Center ◽  
Baseline Platelet Count ◽  
Platelet Counts ◽  
Therapy Initiation ◽  
Academic Medical ◽  
Insufficient Response

Introduction Fostamatinib is a first in its class oral inhibitor of spleen tyrosine kinase (Syk) pathway for treatment of adults with immune thrombocytopenia (ITP) with insufficient response to previous treatment. Choice of treatment for relapsed ITP varies greatly according to clinician and patient preference. It is common for patients to switch between available thrombopoietin (TPO) agonists and now fostamatinib. Titration of these agents is often cumbersome and labor intensive; romiplostim in particular requires weekly visits with lab draws and consumes nurse, pharmacy and provider effort. Here we present real world experience with fostamatinib use in an academic medical center. Methods. We retrospectively identified four patients who were prescribed fostamatinib within the past nine months at Boston Medical Center Health System. All patients had a diagnosis of chronic ITP and were previously treated with corticosteroids, intravenous immunoglobulin (IVIG), and rituximab. With respect to previous TPO receptor use, two of four patients had received both eltrombopag and romiplostim. Patients were started on fostamatinib at a dose of 100 mg by mouth twice daily and titrated up to 150 mg by mouth twice daily if platelet counts were <50 10x9 /L after 4 weeks of therapy. All patients were seen by a pharmacist and provider for initiation of the drug and seen in clinic weekly for the first month on therapy to assess toxicity and efficacy. The duration of follow up for the patients is between 2 and 9 months on therapy. Results. Three of four patients initiated on fostamatinib had a baseline platelet count 100K or greater and the fourth patient had ITP refractory to multiple lines of therapy with a baseline platelet count of 7K at therapy initiation. Three patients sought alternative therapy given side effects from TPO agonists or inconvenience of romiplostim. Three patients had platelets counts >50K at 4 weeks and one patient had a platelet count <30K. Recent platelet counts of the two patients that have been on therapy for 7 and 8 months were 123K and 108K, respectively. The third patient that responded initially discontinued therapy due to lack of stable response. Both of the patients with stable responses were well controlled on previous therapy with romiplostim. One patient required rescue therapy with IVIG and romiplostim due to petechiae 15 days after therapy initiation but continued on therapy thereafter. Two patients that discontinued therapy had platelet counts of 10K and 88K upon discontinuation due to inadequate response and toxicity, respectively. One patient was romiplostim naïve and the other patient had not received romiplostim for four years prior. Two patients developed diarrhea that was managed with loperamide and one led to treatment discontinuation (in combination with insufficient response). One patient experienced hypertension that was managed accordingly. Conclusion. The ideal place in therapy for fostamatinib in ITP therapy is not yet clear. However, the availability as an oral option for patients with refractory disease is appealing. One of our patients required rescue therapy which should be considered when transitioning patients to fostamatinib from TPO agonists. Additionally, side effect management with anti-hypertensives and anti-diarrheal agents may be required to continue therapy. Effectiveness of romiplostim may predict responsiveness to fostamatinib, although additional data are needed. Table Disclosures Shah: Rigel Pharmaceutical: Consultancy, Speakers Bureau. Sarosiek:Acrotech: Research Funding. Sloan:Merck: Other: endpoint review commitee; Abbvie: Other: Endpoint Review Committee; Stemline: Consultancy.

Interim Results of A Randomized Phase II Trial of Azacitidine (AZA) +/− Epo In Lower Risk Myelodysplastic Syndrome (MDS) Resistant to An Erythropoietic Stimulating Agent (ESA) Alone

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1880-1880 ◽  
Author(s):  
Simone Boehrer ◽  
Odile Beyne-Rauzy ◽  
Thomas Prebet ◽  
Sophie Park ◽  
Agnès Guerci ◽  
...  
Keyword(s):  
Phase Ii ◽  
Primary Endpoint ◽  
Interim Analysis ◽  
Lower Risk ◽  
Research Funding ◽  
Phase Ii Trial ◽  
Response Duration ◽  
Prolonged Treatment ◽  
Median Response ◽  
Randomized Phase Ii

Abstract Abstract 1880 Background: Red blood cell (RBC) cell transfusion dependency (TD) is an indicator of poor prognosis in IPSS low and int-1 (lower risk) MDS. In addition, median response duration to ESAs is only about 2 years (Park, Blood, 2008). AZA can lead to RBC transfusion independence (RBC-TI) in 30–40% of lower risk MDS (Lyons, JCO, 2009), but it has not been systematically evaluated in ESA-resistant lower risk MDS and it remains unknown if the combination of AZA and ESA would be useful in such patients (pts). Methods: In this randomized phase-II trial (GFMAzaEpo-2008-1 trial, NCT01015352), we compared AZA 75mg/m2/d for 5 days every 28 days for 6 cycles (AZA arm) to the same treatment plus epoetin beta 60000 U/week (AZA+EPO arm) in lower risk MDS. Inclusion criteria were: IPSS low or int-1 MDS resistant to ESA (i.e having received at least 12 weeks of EPO ≥60000 U/w or darbepoetin ≥250 μg/w or having relapsed after response to ESA), and with RBC-TD of at least 4 RBC units in the 8 weeks prior to enrollment. Responders in both arms were eligible for maintenance up to 12 monthly cycles, unless progression or loss of erythroid response occurred. The primary endpoint was major erythroid responses (HI-E major) after 6 courses, according to IWG 2000 criteria. Secondary endpoints included overall IWG 2000 HI-E, including major and minor, after 4 and 6 courses, response duration, IPSS progression, survival and toxicity. An interim analysis was planned after 49 of 98 planned patients were evaluable for response after 6 courses. Results: From Feb 09 to first of Jul 10, 96 pts were included (M/F=2:1); median age 72y (45-85); 3 pts did not receive any study drug and were excluded from the analysis (one consent withdrawal, one pancreatic cancer and one fatal cardiac event); 93 pts are the subject of this analysis (RARS=40, RCMD-RS=16, RCMD=12, RA=5, RAEB1=12, CMML=7, Unclassified=1). IPSS cytogenetics was favorable in 73, intermediate in 18, adverse in 1 (this pt was not excluded from the present analysis) and failed in 1 cases, with no imbalance for all these characteristics between arms. Overall, 68% of the pts were resistant to ESAs and 32% had lost response to ESA (after a median response duration of 32 weeks, range: 4–120). Median RBC-TD was 6 units (range: 4–16) in the 8 weeks prior to enrollment. Fifteen pts were too early for evaluation of response, 78 were evaluable for toxicity and 72 and 52 pts were evaluable for response after 4 and 6 courses, respectively, as 6 and 22 patients went off-study before 4 and 6 courses, respectively, due to toxicity or progression. Although overall HI-E rates were similar in the AZA and AZA+EPO arms, (40 and 36.5 % respectively, P=0.51), there was a trend for more frequent HI-E major after 6 courses (ie the primary endpoint of the study), in the AZA+EPO arm (7/22,32%), compared to the AZA arm (4/30,13%, P=0.17). Furthermore, in responding patients, the proportion of HI-E major was significantly greater in the AZA+EPO arm (87.5%) compared to the AZA arm (30%, P=0.03). Finally, a significant increase in HI-E major between 4 and 6 cycles was noted only in the AZA+EPO arm (P=0.016). Seventeen responding patients entered the maintenance phase. Of the 78 pts evaluable for toxicity, 22 (28%) had to be hospitalized at least once for an anemia-related event (N=6) and/or a clinical infection/febrile neutropenia (N= 16). Interestingly, only 6 pts had to be hospitalized in the AZA+EPO arm, compared to 16 in the AZA arm, (P=0.o4). Conclusions: In this first randomized study comparing AZA and AZA+ EPO in highly transfusion-dependent lower-risk MDS, this planned interim analysis shows a promising trend for more major HI-E in the AZA+EPO arm, suggesting that addition of EPO to AZA increases the frequency of major erythroid responses in those patients, and may also significantly decrease the hospitalization rate due to infectious and non-infectious complications, allowing more patients to receive prolonged treatment with azacitidine. Updated results will be presented at the meeting. Disclosures: Récher: Celgene: Consultancy, Honoraria, Research Funding. Vey:Celgene: Consultancy, Honoraria, Research Funding. Fenaux:Celgene: Consultancy, Honoraria, Research Funding. Gardin:Celgene: Consultancy, Honoraria, Research Funding.

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