The Prospective Analysis Of Clinical Efficacy and Adverse Events In Chronic Myeloid Leukemia In Chronic Phase (CML-CP) Patients With Imatinib Resistance Or Intolerance, Evaluated By European Leukemia Net (ELN) 2013 Criteria

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4027-4027
Author(s):  
Kazunori Murai ◽  
Tomoaki Akagi ◽  
Kenji Shimosegawa ◽  
Kenichi Ishizawa ◽  
Tomohiro Sugawara ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
First Line ◽  
Imatinib Resistance ◽  
Grade 3 ◽  
Dasatinib Treatment

Abstract Background Dasatinib is a highly potent BCR-ABL inhibitor, with a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance or intolerance to imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in Japanese patients with imatinib resistance or intolerance CML. Methods Fifty- five CML-CP patients from 2009 to 2011 with resistance (n=40) or intolerance (n=26) to imatinib were registered to dasatinib administration (100mg once daily). Eleven among 26 patients with intolerance also showed resistance to imatinib at the registration. Imatinib resistance was defined as a lack of partial cytogenetical response at 3 months, a lack of complete cytogenetic response at 6 months or a lack of a major molecular response at 12 months of imatinib treatment. This criteria was identical to the criteria in ELN 2013 recommendation for first line. In another words, the resistance in this study means non-optimal criteria (warning and failure) of definition of the response to TKIs, first line, in ELN 2013 recommendation. Efficacy and safety were assessed using rates of major molecular response (MMR)/ MR4.5 (either (i) detectable disease with<0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) at 12 months and drug-related adverse events (AEs) respectively. All analyses were based on the modified to intension-to treat. Results One patient was withdrawal before dasatinib administration. The median duration of imatinib therapy was 545 days. The overall incidence of MMR (primary endopoint) and MR4.5 at 12 months was 67.2% (95% confidence interval, 53.3-81.1%), and 20.2 % (95% CI, 8.4–32.0 %), respectively. Forty patients with resistance to imatinib, who were warning and failure patients judged by ELN 2013 criteria, were reassessed. Cumulative MMR and MR4.5 rate were 63.4% (95% CI: 46.3-80.6) and 18.0% (95% CI: 4.9-31.1) respectively at 12 months. Eleven patients, who showed more than 1% IS at 3 months of dasatinib treatment, did not reach to MMR at 12 months or discontinued dasatinib due to insufficient efficacy in this resistance cohort. However, progression to the accelerated or blastic phase had not been observed. When imatinib were changed to dasatinib, 5 patients showed the mutations, which were effective in dasatinib therapy. New mutations have not been observed during the treatment of dasatinib. Among 54 patients, most non-hematological AEs were in grade 1/2. including diarrhea (12.7%), rash (7.3%), myalgia (5.5%) and vomiting (3.6%). Grade 3/4 non-hematological AEs were infrequent, including decreased potassium (3.6%), and increased creatinine (3.6%). Grade 1/2 fluid retention AEs were shown in 9.1% of patients, including edema (3.6%). Pleural effusion, which was only in Grade 1/2, was shown in 32.7% of patients. Grade 3/4 hematological toxicities included anemia (7.3%) and thrombocytopenia (3.6 %). Only 3 patients have permanently discontinued dasatinib treatment due to AEs. Conclusions The patients with non-optimal responses (warning and failure) judged by ELN 2013 criteria should have early intervention to dasatinib, which is less toxicity in CML-CP patients. This intervention might induce good prognosis. The BCR-ABL1 IS less than 1% at 3 months of dasatinib administration will be the valuable landmark for outcome. Disclosures: No relevant conflicts of interest to declare.

Efficacy and Safety of Dasatinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) with Imatinib Resistance or Intolerance

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4444-4444
Author(s):  
Tomoaki Akagi ◽  
Kazunori Murai ◽  
Kenji Shimosegawa ◽  
Kenichi Ishizawa ◽  
Tomohiro Sugawara ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Imatinib Resistance ◽  
Once Daily ◽  
Grade 3 ◽  
Complete Molecular Response

Abstract Abstract 4444 Background: Dasatinib is highly potent BCR-ABL inhibitor, with 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. Across a series of phase II and III trials with more than 2 years of follow-up, dasatinib has demonstrated durable efficacy in patients with CML following resistance or intolerance to imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with imatinib resistance or intolerance in the Japanese population. Methods: 54 CML- CP patients (median age 63.5 years) with resistance, intolerance or a suboptimal response to imatinib were submitted to dasatinib 100mg once daily. Efficacy and safety were assessed using rates of major molecular response (MMR)/ complete molecular response (CMR) or drug-related adverse events (AEs) respectively. All analyses were based on the intension-treat principle. Results: Until now, the results of 32 patients, who passed more than 12 months, have been analysed. The median time since of prior imatinib therapy was 19.2 months with 57.4 % being imatinib-resistant and 42.6 % imatinib-intolerant. The incidence of MMR (primary endopoint) and complete molecular response at 12 months was 59.3 % (95% confidence interval, 45.0 – 72.4 %), and 24.1 % patients, respectively. Progression to the accelerated or blastic phase had not been observed. All patients with baseline samples tested for mutations, and different mutations were not observed. Non-hematological AEs were mostly grade 1/2. Grade 3/4 non-hematological AEs were infrequent, including increased AST (1.9%), and increased creatinine (1.9%), respectively. Grade 1/2 fluid retention adverse events were shown in 10 patients, including 2 patients with edema, and 9 patients with pleural effusion. Grade 3/4 hematological toxicities including anemia (1.9%), neutropenia (14.8%), and thrombocytopenia (9.3 %) were shown, and 13 patients have permanently discontinued treatment due to adverse effects. Conclusions: Dasatinib treatment results in high rate of molecular response in CML-CP patients with resistance or intolerance to imatinib, and approximately 60% of evaluated patients who switched to dasatinib achieved MMR at 12 months. Importantly, among all patients who achieved molecular response, 24.1 % patients achieved CMR. Dasatinib at a dose of 100 mg once daily was generally well-tolerated, and had better efficacy for patients with CML-CP post imatinib failure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals First-Line Dasatinib Treatment of CML-CP Leads to Earlier Achievement of MMR and MR4.5 with High Safety

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3102-3102
Author(s):  
Kazunori Murai ◽  
Kohei Yamaguchi ◽  
Shigeki Ito ◽  
Takuto Miyagishima ◽  
Motohiro Shindo ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Odds Ratio ◽  
Phase Ii Study ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
First Line ◽  
Dasatinib Treatment

Abstract (INTRODUCTION) Several clinical studies have revealed that dasatinib demonstrated deep and fast responses. We report a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan (IMIDAS PART2 study). (PATIRNTS AND METHODS) Between July 2011 and June 2013, a total of 79 consecutive patients with CML-CP received 100 mg dasatinib daily as a first-line therapy. Treatment was continued until disease progression or until toxicity became unacceptable. The primary end-point was the rate of major molecular response by 12 months. Secondary end-points included the rate of complete cytogenetic response, rate of molecular responses with a 4.5 log reduction (MR4.5) by 12 months, and adverse events. The median age was 62 years, ranging from 27 to 80 years. Patients older than 65 years comprised 41.7% of all patients. Two-thirds of patients (68.4%) were male. Nearly all patients were ECOG performance status 0. Most patients (83.6%) had low and intermediate Sokal scores. The BCR-ABL1 International Scale (BCR-ABL1 IS) in the peripheral blood was measured by the central laboratory center (BML, Tokyo, Japan). (RESULTS) The median BCR-ABL1 IS before therapy was 54.0% (7.8-230.2). Seventy patients (88.6%) received dasatinib therapy for 12 months. The median BCR-ABL1 ISs were 0.25 % at 3 months (range 0.0002-52.2 %, n =77), 0.03 % at 6 months (range not detected-29.2 %, n = 75) and 0.008 % at 12 months (not detected -0.86 %, n = 70). MMR rate was 77.2% (95% CI, 67.9-86.5 %) by 12 months. The rates of CCyR and MR4.5 by 12 months were 88.6% (95% CI; 81.5-95.7 %) and 35.4% (95% CI; 24.8-46.1 %), respectively (Figure 1). Multivariate analysis of MMR or MR4.5 by 12 months showed that female sex (odds ratio 1.1, P = 0.92, odds ratio 1.7, P = 0.35, respectively), low and intermediate Sokal score (odds ratio 0.9, P = 0.90, odds ratio 3.2, P =0.23, respectively), and BCR-ABL1 IS less than 54% at diagnosis (RR =odds ratio 0.8, P = 0.74, odds ratio 0.7, P = 0.55, respectively) were not significantly correlated with MMR by 12 months nor MR4.5 by 12 months (Table 1). However, patients who were more than 62 years old were significantly correlated with MR4.0 and MR4.5 by 12 months (odds ratio 2.8, P =0.04, odds ratio 3.5, P =0.01). Treatment-related all AEs were reported in 98.7% patients (78 of 79). Grade 3/4 non-hematologic AEs were observed in only a few cases. Lymphocytosis (more than 4x 109/L) was observed in 34.1% of patients, which was within grade 2. Only 9 patients withdrew the study because of adverse events (4 patients), ineffectiveness (3 patients), and others (2 patients). (DISCUSSION AND CONCLUSION) The incidence of lymphocyte predominance may depend on a history of previous cytomegalovirus (CMV) infection in CML-CP patients (Leukemia. 2011 25(10): 1587-97). Although the frequency of CMV-positive patients was unknown in this study, that of blood donors in Japan was almost positive in the ages with 60s or older. The median age of CML-CP patients in this study was 62 years. Therefore, we assumed that some immunological effects induced by dasatinib might have improved the clinical efficacy in Japanese CML-CP patients compared to those worldwide. Our phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed CML-CP in Japan revealed that the first-line dasatinib treatment of CML-CP leads to earlier achievement of MMR and MR4.5 with high safety. Elder age patients (>62 years) were significantly associated with achievement of MR4.5. Disclosures Shindo: Sysmex Corporation: Research Funding. Sakamoto:Yakult: Other: Remuneration; Takeda Pharmaceutical: Consultancy.

Efficacy and Safety of Bosutinib (SKI-606) in Patients with Chronic Phase (CP) Ph+ Chronic Myelogenous Leukemia (CML) with Resistance or Intolerance to Imatinib.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1098-1098 ◽  
Author(s):  
Jorge Cortes ◽  
Hagop M Kantarjian ◽  
Dong- Wook Kim ◽  
H. Jean Khoury ◽  
Anna G. Turkina ◽  
...  
Keyword(s):  
Adverse Events ◽  
Tyrosine Kinase ◽  
Cytogenetic Response ◽  
Fluid Retention ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Bosutinib (SKI-606) is an orally bioavailable dual Src/Abl inhibitor demonstrating inhibitory activity against BCR-Abl phosphorylation, and is 200 times more potent than imatinib but with minimal inhibition of platelet-derived growth factor receptor (PDGFR) or c-kit. The phase I portion of this study identified a treatment dose of 500 mg daily and showed evidence of clinical efficacy. The phase II portion of the study to investigate the efficacy and safety of bosutinib in patients (pts) with CP Ph+ CML who have failed imatinib therapy is ongoing. Preliminary data for 283 treated pts, median age 54 yrs (range 18 – 91 yrs) and 52% male are reported. A subset of pts received treatment in addition to imatinib, including interferon (91 pts), dasatinib (71 pts), nilotinib (7 pts) and stem cell transplant (13 pts). Among pts who failed imatinib (and received no other tyrosine kinase inhibitor treatment), 137 were imatinib-resistant (all received imatinib ≥600mg) and 64 pts were imatinib-intolerant; median duration of bosutinib treatment to date is 7.7 mos (range 0.2 – 28.2 mos) and 4.5 mos (range 0.5 – 21.5 mos), respectively. Among 67 imatinibresistant pts evaluable for hematological response, 53 (79%) had complete hematological response (CHR). Of 84 imatinib-resistant pts evaluable for cytogenetic response, 34 (40%), achieved a major cytogenetic response (MCyR), including 24 (29%) with a complete cytogenetic response (CCyR). Of 34 pts with MCyR, 31 have maintained their response to date. Of 60 evaluable imatinib-resistant pts, 20 (33%) achieved major molecular response, 10 (17%) of which were complete. Among imatinib-intolerant pts, 22 of 29 evaluable (76%) achieved CHR, and 13 of 22 evaluable (59%) achieved MCyR, including 11 (50%) with CCyR. Of 25 evaluable imatinib-intolerant pts, 7 (28%) achieved major molecular response, 5 (20%) of which were complete. Of 105 pts with baseline samples tested for mutations, 17 different mutations were found in 45 pts (43%). CHR occurred in 5/6 pts (83%) with P-loop mutations and 13/17 (76%) with non-P-loop mutations; MCyR occurred in 3/6 pts (50%) and 11/24 pts (46%), with P-loop and non-P-loop mutations, respectively. Treatment was generally well tolerated. The most common adverse events among treated pts (n=283) were gastrointestinal (nausea, vomiting, diarrhea), these were usually grade 1 – 2, manageable and transient, diminishing in frequency and severity after the first 3 – 4 weeks of treatment. Grade 3 – 4 non-hematologic toxicity occurring in ≥5% of pts were diarrhea (8%), rash (8%) and increased ALT (5%). 27 pts (10%) reported grade 1/2 fluid retention adverse events, including 21 pts with edema, and 6 pts with effusions: 4 pleural, 1 pericardial, and 1 pleural and pericardial. A single patient experienced grade 3 pleural effusion possibly related to bosutinib with concomitant pneumonia and a pre-treatment history of recurrent pleural effusions. Grade 3 – 4 hematologic laboratory abnormalities included thrombocytopenia in 65 pts (23%), neutropenia in 37 pts (13%) and anemia in 17 pts (6%). 124 pts (44%) had at least 1 temporary treatment interruption and 85 pts (30%) had at least 1 dose reduction due to toxicity. 37 pts (13%) have permanently discontinued treatment due to adverse event. Bosutinib is effective in pts with CP CML with resistance or intolerance to imatinib across a range of mutations. Unlike other tyrosine kinase inhibitors, bosutinib does not significantly inhibit PDGFR or c-kit, and this may be responsible for the relatively favorable toxicity profile with few pts experiencing hematologic toxicity or fluid retention.

scholarly journals Comparative efficacy and safety of first-line treatments for advanced non-small cell lung cancer with ALK-rearranged: a meta-analysis of clinical trials

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Hao-chuan Ma ◽  
Yi-hong Liu ◽  
Kai-lin Ding ◽  
Yu-feng Liu ◽  
Wen-jie Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Treatment Options ◽  
Small Cell ◽  
Efficacy And Safety ◽  
Small Cell Lung ◽  
First Line ◽  
Grade 3

Abstract Background Whereas there are many pharmacological interventions prescribed for patients with advanced anaplastic lymphoma kinase (ALK)- rearranged non-small cell lung cancer (NSCLC), comparative data between novel generation ALK-tyrosine kinase inhibitors (TKIs) remain scant. Here, we indirectly compared the efficacy and safety of first-line systemic therapeutic options used for the treatment of ALK-rearranged NSCLC. Methods We included all phase 2 and 3 randomised controlled trials (RCTs) comparing any two or three treatment options. Eligible studies reported at least one of the following outcomes: progression free survival (PFS), overall survival (OS), objective response rate (ORR), or adverse events of grade 3 or higher (Grade ≥ 3 AEs). Subgroup analysis was conducted according to central nervous system (CNS) metastases. Results A total of 9 RCTs consisting of 2484 patients with 8 treatment options were included in the systematic review. Our analysis showed that alectinib (300 mg and 600 mg), brigatinib, lorlatinib and ensartinib yielded the most favorable PFS. Whereas there was no significant OS or ORR difference among the ALK-TKIs. According to Bayesian ranking profiles, lorlatinib, alectinib 600 mg and alectinib 300 mg had the best PFS (63.7%), OS (35.9%) and ORR (37%), respectively. On the other hand, ceritinib showed the highest rate of severe adverse events (60%). Conclusion Our analysis indicated that alectinib and lorlatinib might be associated with the best therapeutic efficacy in first-line treatment for major population of advanced NSCLC patients with ALK-rearrangement. However, since there is little comparative evidence on the treatment options, there is need for relative trials to fully determine the best treatment options as well as the rapidly evolving treatment landscape.

Efficacy and safety of approved first-line tyrosine kinase inhibitor (TKI) treatment in patients with metastatic renal cell carcinoma (mRCC): A network meta-analysis based on phase II/III randomised clinical trials (RCTs).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16074-e16074
Author(s):  
Kirsi Manz ◽  
Klaus Fenchel ◽  
Andreas Eilers ◽  
Jon Morgan ◽  
Kirsten Wittling ◽  
...  
Keyword(s):  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Meta Analysis ◽  
Cochrane Central Register ◽  
Line Treatment ◽  
Efficacy And Safety ◽  
First Line ◽  
Manual Search ◽  
Grade 3 ◽  
First Line Treatment

e16074 Background: During the last decade several novel treatment options including TKIs and immune checkpoint inhibitors have been developed for the treatment of mRCC patients. However, results from direct comparisons (head-to-head RCTs) to determine the optimal treatment are lacking for most of these agents. In this network meta-analysis we attempted to indirectly compare efficacy and safety of first-line TKIs in patients with mRCC. Methods: PubMed, Embase, Medline, the Cochrane Central Register of Controlled Trials were searched (English language only). Abstracts of conferences of relevant medical societies were also included from database inception (January 1, 2007) to January 15, 2019. A systematic manual search (including data requests from the publication authors) was also performed. For the purpose of this network meta-analysis only phase II/III RCTs assessing approved first-line TKI therapy for mRCC were analysed. The analysis was done using the software R with the netmeta package. Progression-free survival (PFS) was the primary endpoint; grade 3 and 4 adverse events (AEs) were secondary endpoints. Results: A database search identified 12 studies meeting the eligibility criteria reporting on 4,460 patients. For PFS cabozantinib and sunitinib were found to be superior to sorafenib, however, when compared to tivozanib, PFS did not significantly differ between the TKIs. Furthermore, tivozanib was found to have the highest probability of being the safest drug as first-line treatment in terms of grade 3 and 4 AEs (ranking safety, p score 0.9344). Conclusions: No significant PFS differences for all TKIs currently used for first-line treatment of mRCC have been found when compared with tivozanib. Compared with all approved TKIs tivozanib appears to be the best choice for first-line treatment of these patients because it has demonstrated the most favourable safety profile. These results may provide guidance to oncologists when making treatment decisions for mRCC patients.

IMPACT study: A phase II-III clinical study with the immunomodulator MGN1703 in patients with advanced colorectal carcincoma.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 633-633 ◽  
Author(s):  
Marina Tschaika ◽  
Hans-Joachim Schmoll ◽  
Jorge Riera-Knorrenschild ◽  
Dieter Nitsche ◽  
Jorg Trojan ◽  
...  
Keyword(s):  
Clinical Study ◽  
Adverse Events ◽  
Disease Control ◽  
Phase Ii ◽  
Impact Study ◽  
Efficacy And Safety ◽  
First Line ◽  
First Line Therapy ◽  
Line Therapy ◽  
The Impact

633 Background: The synthetic DNA-based immunomodulator MGN1703 acts as an agonist of toll-like receptor 9. Based on promising data from a phase I study in patients with metastatic solid tumors including those with CRC, a phase II-III study was initiated in patients with advanced CRC having disease control after first-line therapy. The objective of the study is to assess efficacy and safety of the MGN1703 treatment in comparison to placebo. Methods: The IMPACT study is designed as a randomized double-blind placebo-controlled phase II-III study, which is conducted in patients with advanced CRC showing disease control after first-line therapy with standard chemotherapy regimen. The treatment is administered subcutaneously twice weekly in a ratio 2:1 (60 mg MGN1703 or placebo). The study is conducted in Germany, Austria, France, UK, Czech Republic and Russia, and 129 patients will be recruited into the study. The efficacy and safety of the study treatment will be evaluated based on extensive immunological tests, radiological assessment, safety laboratory results and assessments of the quality of life. The study treatment will be continued until tumor progression, intolerable toxicity, exclusion criteria or withdrawal of consent. Results: The majority of adverse events were assessed as not drug-related by the investigator. The remaining AEs include mild night sweat (not assessable), mild fever (at three occasions, possible related), and mild arthralgia (certain related) in one patient each. Three SAE have been reported so far of which one was assessed as probably drug-related – atypical pneumonia. Only in single patients local reactions such as mild redness and swelling at injection site were reported. No laboratory or clinical signs of autoimmunity or dose-limiting toxicities were reported, so far. Conclusions: With these preliminary safety results of the ongoing clinical study in patients with advanced CRC it could be shown that ttreatment with MGN1703 at the dosage of 60 mg is well tolerated and safe. Reported adverse events assessed as possibly drug-related belong to expected study drug reactions known for immune modulating drugs. These events were not accompanied by any signs of autoimmunity.

Efficacy of Dasatinib in Patients with Chronic Phase Philadelphia Chromosome-Positive CML Resistant or Intolerant to Imatinib: First Results of the CA180013 ‘START-C’ Phase II Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 41-41 ◽  
Author(s):  
Andreas Hochhaus ◽  
M. Baccarani ◽  
C. Sawyers ◽  
A. Nagler ◽  
T. Facon ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
White Blood Cells ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Imatinib Resistance ◽  
Biomarker Analysis ◽  
Grade 3

Abstract After 3 years of imatinib (IM) therapy, hematologic relapse occurred in 7% of newly diagnosed chronic myeloid leukemia (CML) pts, and 20% of chronic phase (CP)-CML pts after failure to interferon alpha (IFN), which was mostly associated with BCR-ABL mutations and/or clonal evolution. Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases. Dasatinib has been shown to have 325-fold greater potency compared with imatinib in cells transduced with BCR-ABL and is active against 18/19 BCR-ABL mutants tested that confer imatinib resistance. A Phase I dose-escalating study provided early evidence for the safety and efficacy of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients in CP-CML, which was followed by ‘START-C’ (CA180013), the first Phase II open-label study in dasatinib in CP IM-R or IM-I CML pts. Between February-May 2005, 186 pts (86 male, median age 60 yrs [range 25–82]) were recruited from 40 institutions. Data from 30 pts accrued prior to March 20, 2005, are available for the initial analysis. The definition of IM-R required a failure of IM doses &gt;600 mg/d or the occurrence of BCR-ABL mutations associated with virtual insensitivity to IM. Dasatinib was administered at 70 mg twice daily (BID), based on phase I data and optimal inhibition of BCR-ABL activity from biomarker analysis. Dose escalation to 90 mg BID was permitted in pts lacking response, and dose reductions to 50 and 40 mg BID were allowed in the event of intolerance. Complete blood counts were obtained weekly for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. In the group of 30 evaluable pts, median age was 59 yrs (range 25–78), 50% were male. Median time from diagnosis of CML was 70.8 months (range 7.9–202.1). Prior therapy included IFN in 77% and stem cell transplantation in 10% of pts. 60% of pts were considered IM-R, with the maximum prior IM dose of &gt;600 mg in 60% of pts. 60% of pts received IM for &gt;3 yrs. Best response to prior IM therapy was a complete hematologic response in 83%, and complete (CCyR) and partial (PCyR) cytogenetic responses in 17% and 13% of pts, respectively. Median (range) baseline hematologic parameters were: white blood cells 16.1/nl (4.3–84.3); platelets 437/nl (173–960). IM-R BCR-ABL mutations were documented in 6/12 pts with currently available data. Within the first 3 months, 2 pts required dose escalations and 6 had a dose reduction, mostly due to thrombocytopenia. Hematologic responses were documented in 21/24 pts with available data. From 16 pts evaluable for 3-month cytogenetic analysis, 7 cytogenetic responses were observed, including CCyR (n=4) and PCyR (n=1). Analysis of molecular response is in progress. Grade 3/4 neutropenia or thrombocytopenia were reported in 6 pts each. Most common non-hematologic toxicities were diarrhea (6 pts, 1 grade 3), rash (5 pts, all grade 1), edema (3 pts, all grade 1) and pleural effusion (1 pt, grade 2). In conclusion, despite the short follow up, major hematologic and cytogenetic responses were seen in a group of pretreated CP-CML pts, which further supports the activity of dasatinib in this disease. An updated analysis based on 186 pts with 6-month follow up will be presented.

Efficacy of Dasatinib in Patients (pts) with Previously Untreated Chronic Myelogenous Leukemia (CML) in Early Chronic Phase (CML-CP).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 338-338 ◽  
Author(s):  
Jorge Cortes ◽  
Gautam Borthakur ◽  
Susan O'Brien ◽  
Dan Jones ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Grade 3

Abstract Abstract 338 Dasatinib, a potent inhibitor of ABL and SRC, is approximately 300 times more potent than imatinib in vitro and has significant activity in pts with CML-CP resistant or intolerant of imatinib (IM). We initiated a phase II trial to study efficacy and safety of dasatinib in pts with previously untreated CML-CP. Aims: To investigate the efficacy and safety of dasatinib as initial therapy for patients with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response at 12 months (mo). Pts with previously untreated CML-CP within 6 months from diagnosis were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Sixty-two pts have been enrolled (31 on the QD schedule, 31 BID). Median age was 47 years (yrs) (range 18–76 yrs). Median follow-up is 24 months (mo) (range, 1 to 39 mo). All 45 pts who were not in CHR at the start of therapy achieved CHR. Among 50 pts followed for at least 3 months, 49 (98%) achieved complete cytogenetic response (CCyR). Major molecular response has been achieved in 35 (70%), including 5 (10%) with complete molecular response. The CCyR rate at different timepoints (intention-to-treat) compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily: Major molecular response was achieved by 45% by 12 mo and 71% by 24 mo (corresponding rates with imatinib 400mg 34% and 55%, and with imatinib 800mg 58% and 66%, respectively). There was a trend for higher MMR rate with the QD schedule: overall 75% vs 65% (p=0.54), and by 12 months 52% and 38% (p=0.54). Grade 3-4 non-hematologic toxicity (regardless of causality) included fatigue (6%), pain (muscle or joint) (6%), dyspnea, neuropathy and memory impairment (5% each). Pleural effusion occurred in 13% evaluable pts (grade 3-4 in 2%). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 10%, neutropenia 21%, and anemia 6%. Thirty (48%) of 62 pts required transient treatment interruptions. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3-4 toxicity by treatment schedule but there was a trend for less pleural effusion with QD (3%) vs BID (10%; p=0.26). Three pts lost CCyR: 2 because of non-compliance, 1 due to treatment interruption because of pleural effusion. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 88%. All patients are alive. Conclusion: Rapid CCyR occurs in nearly all patients with previously untreated CML-CP treated with frontline dasatinib therapy; the MMR rate at 18 months was 71%, with a favorable toxicity profile. Because of favorable trends in response and toxicity, only QD arm will continue accrual. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of dasatinib as initial therapy for CML, and indication for which dasatinib is not approved.. Borthakur:BMS: Speakers Bureau. O'Brien:BMS: Research Funding. Jabbour:BMS: Speakers Bureau; Novartis: Speakers Bureau. Ravandi:BMS: Consultancy, Honoraria, Research Funding. Kantarjian:Genzyme: Research Funding; BMS: Research Funding; MGI Pharma (Eisai): Research Funding; Novartis: Research Funding.

scholarly journals Open Label Non-Randomized Phase II Study Exploring «Chemo-Free » Treatment Association with Idelalisib + Obinutuzumab in Patients with Relapsed/Refractory (R/R) Waldenstrom's Macroglobulinemia (MW), a Filo Trial: Results of the Intermediary Analysis of the Induction Phase

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 346-346 ◽  
Author(s):  
Cecile Tomowiak ◽  
Kristell Desseaux ◽  
Stéphanie Poulain ◽  
Charles Herbaux ◽  
Aurore Perrot ◽  
...  
Keyword(s):  
Adverse Events ◽  
Board Of Directors ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Fixed Dose ◽  
Induction Phase ◽  
Efficacy And Safety ◽  
Advisory Committees ◽  
Grade 3

Background The treatment algorithm is still limited in WM as very few drugs were approved based on studies dedicated to WM patients. In 2015, the Bruton tyrosine kinase (BTK) inhibitor ibrutinib became the first drug approved to treat WM (Treon et al, 2015). However, a subset of patients (pts) relapses due to acquired resistance. Therefore there is a great medical need to develop chemo-free approaches based on a better understanding of the biology of the disease to increase all survival endpoints. MYD88L265P also promotes activation of the phosphatidylinositol-3-kinase (PI3K) pathway Gopal et al. reported 80% ORR in 10 patients with WM, refractory to anti-CD20 and alkylating agents, treated with idelalisib (a PI3K inhibitor) (NEJM, 2014). A previous study was stopped because of high incidence of hepatotoxicity (Castillo, Leuk lymphoma, 2017). So we design our trial with a Bayesian analysis of adverse events. Aims We initiated a prospective, single-arm phase II study to evaluate efficacy and safety of idelalisib in combination with obinutuzumab in pts with R/R WM in need of treatment. (NCT02962401). Methods During the induction phase, idelalisib was given continuously 150 mg BID PO in association with IV obinutuzumab 100mg day 1, 900mg day 2 then 1000mg fixed dose day 8, 15 of cycle 1 and every day 1 of cycles 2 to 6 (28-days cycle). Then during the maintenance phase, idelalisib was given alone for a maximum of 2 years. Pts were closely monitored for infusion related reactions (IRR). Adverse events were graded per CTCAE v.4.0. Response was assessed based on IWWM6 criteria. The analyses of PFS, primary endpoint of this study, were based on the intent-to-treat population. The safety analysis was designed according to Bayesian estimation of the probability of grade 3 or more adverse events. Roche and Gilead provide drugs and funding. Results Fifty pts were enrolled between February 2017 and July 2018 but 49 pts were analyzed (1 screen failure). We present the results of early efficacy and safety, assessed after the induction phase. At time of analysis, median follow-up was 18.3 months (range 14.9-23 months). Median age was 71 years (range 50-83 years) and 36 pts (73%) were men. MYD88 mutation was present in 47 pts (96%). Indications to treat were anemia (31%), anemia + thombocytopenia (11%), constitutional symptoms (11%), rapid evolution of monoclonal component (11%), hyperviscosity syndrome (9%), thrombocytopenia (6%), extramedullary disease (8%) and neuropathy (6%) (data not available for 2 pts). Median number of previous lines of therapy was 1 (range 1-3), and only 1 patient was previously exposed to BTK inhibitors. At baseline, median serum IgM was 2.193 mg/dl (range 0.19-9.2), median bone marrow involvement was 55% (range 10-90, n=25) and median hemoglobin was 10 g/dl (range 6.5-13.8). Thirty-four pts responded, 13 after 3 cycles and 21 after 6 cycles. The overall response rate (ORR) was 90% and the major response rate (MRR) was 76% (no CR, VGPR: 8%, PR: 68%, MR: 14%, SD: 8%, and progression: 3%). The correlation between responses and genomic status using ultra deep next generation sequencing will be communicated later. Median PFS was 25.2 months. The1-year and 2-year PFS were 90% [IC95%: 80; 100] and 70% [IC95%: 53; 93] respectively. The1-year and 2-year OS were 98% [IC95%: 94; 100] and 85% [IC95%: 69; 100] respectively. Three pts died (1 before starting treatment, 1 from macrophage activation syndrome, 1 after stopping treatment). Median duration of response was 21.8 months. No flare, no IRR grade ≥ 2, no tumor lysis syndrome were observed. Thirty-five pts experienced at least one grade ≥ 3 adverse events (AE) or serious adverse events (SAE), with an estimated probability of 72.5% (95% credibility interval, 59.5-83.9) and a probability of 1 that more than 30% of pts experience at least 1 grade 3 AE. Events that occurred most frequently included hepatotoxicity (23 AE, 5 SAE, 20%), diarrhea (4 AE, 10 SAE; 10%), skin (3 AE, 3 SAE, 4%), infections (0 AE, 5 SAE, 4%), neutropenia (41 AE, 29%), anemia (7 AE, 5%), thrombopenia (6 AE, 4%). This trial is ongoing with 29 pts who started idelalisib maintenance. Conclusion This is the first study evaluating combination with idelalisib + obinutuzumab and the first chemo-free fixed-duration association in R/R WM pts. The combination has clinical activity with 90% ORR and 76% MRR. Median PFS was 25 months. Most of grade ≥ 3 AE or SAE are hepatotoxicity, diarrhea and neutropenia as expected with idelalisib. Figure Disclosures Tomowiak: Abbvie: Honoraria; Janssen: Honoraria. Perrot:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Amgen: Honoraria; takeda: Honoraria; jannsen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Leblond:Gilead: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Speakers Bureau.

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