Interim analysis (IA) of OPTIC: A dose-ranging study of three ponatinib (PON) starting doses.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 7502-7502 ◽  
Author(s):  
Jorge E. Cortes ◽  
Elza Lomaia ◽  
Anna Turkina ◽  
Beatriz Moiraghi ◽  
Maria Undurraga Sutton ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Final Analysis ◽  
Molecular Response ◽  
Efficacy And Safety ◽  
Phase 2 Trial ◽  
Heavily Pretreated ◽  
Long Term Follow Up ◽  
Grade 3 ◽  
Dose Reductions

7502 Background: In PACE (NCT01207440) heavily pretreated patients (pts) with chronic-phase CML (CP-CML) had deep, lasting responses to PON; long-term follow-up showed increasing rates of arterial occlusive events (AOEs). We present IA results from OPTIC (NCT02467270), evaluating the association between PON exposure, efficacy, and safety, and response-based dose reduction in pts with CP-CML. Methods: This ongoing, multicenter, randomized phase 2 trial enrolled pts with CP-CML resistant or intolerant to ≥2 TKIs or with a T315I mutation to receive PON at a starting dose of 45 mg (cohort A), 30 mg (B), and 15 mg (C) qd. Doses were reduced to 15 mg qd on achievement of ≤1% BCR-ABL1IS in A/B. Primary endpoint: 12 mo ≤1% BCR-ABL1IS; secondary endpoints include cytogenetic and molecular response and AOE, VTE, and TEAE rates. Results are descriptive at this IA and will be inferential by adjusting multiplicity across 3 cohorts at final analysis. Results: 283 pts were randomized (A/B/C: n = 94/95/94); median age 48 y (18‒81 y). 26% had hypertension history; 2/43/55% received 1/2/≥3 TKIs; 40% had ≥1 baseline (BL) mutations, with 23% T315I. At IA data cutoff (20 Jul 2019), 162 pts (57%; n = 57/51/54) remained on study treatment. Among 282 pts in the safety population, median duration of exposure was ≈1 y (A/B/C, 12.9/11.2/11.0 mo). At 12 mo, 39% (95% CI, 27.6, 50.6), 27% (17.6, 39.1), and 26% (16.5, 38.6) in A, B, and C, respectively, achieved ≤1% BCR-ABL1IS. Additional efficacy in Table. Dose reductions due to efficacy (A/B): 35/21%. Most common TEAEs (any grade/≥3): thrombocytopenia 39/27%, neutropenia 25/17%. AOEs/serious AOEs were reported by (A, B, C) 5%/2%, 4%/3%, and 1%/0%. Dose reductions due to TEAEs: (A/B/C): 44/31/28%; discontinuations due to TEAEs: 18/15/14%. There were 4 (1.4%) on-study deaths; A, sudden death, n = 2; C, pneumonia, n = 2; no deaths were due to AOEs. Clinical trial information: NCT01207440 . Conclusions: OPTIC IA shows a trend toward dose-dependent efficacy and safety and may provide a refined understanding of the PON benefit:risk profile and its relation to dose. Data from longer follow-up may support an alternate dosing regimen for pts with CP-CML. [Table: see text]

Dasatinib in patients with chronic phase chronic myeloid leukemia (CP-CML) who are resistant or intolerant to imatinib: Results of the CA180013 ’START-C’ Study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6508-6508 ◽  
Author(s):  
A. Hochhaus ◽  
H. Kantarjian ◽  
M. Baccarani ◽  
F. Cervantes ◽  
T. Facon ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Response Analysis ◽  
Clinical Activity ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3 ◽  
Dose Reductions

6508 Background: Dasatinib (BMS-354825) is a novel, oral, multi-targeted kinase inhibitor of BCR-ABL and SRC kinases with proven preclinical and clinical activity against imatinib resistant BCR-ABL mutations. Methods: CA180013 is an open-label Phase II study of dasatinib in imatinib-resistant (IM-R) or -intolerant (IM-I) patients (pts) with CP-CML. Between February-August 2005, 424 pts were recruited from 75 centers worldwide. Dasatinib was given at 70 mg twice daily (BID) with dose escalation to 90 mg BID in pts lacking response, and dose reductions to 50 and 40 mg BID for toxicity. Evaluations were weekly blood counts for the first 12 weeks; bone marrow cytology and cytogenetics every 3 months. The primary endpoint was rate of major cytogenetic response (MCyR; ≤35% Philadelphia pos. metaphases) in IM-R pts. Results: Data are currently available from the first 186 pts (127 IM-R, 59 IM-I) accrued prior to May 12, 2005. Median age was 59 yrs (range 24–79); 46% were male. Median time from diagnosis of CML was 64 months. Of the IM-R pts, 72% received IM >3 yrs, and 72% had >600 mg/day of IM. Overall, 70% had received prior interferon alpha. 62 (33%) pts achieved a prior MCyR to IM. With ≥6 months of follow up, 168 (90%) pts had a complete hematologic response (CHR). MCyR were achieved in 83 (45%) pts including 40 (31%) of IM-R pts, and 43 (73%) of IM-I pts. Mutations in the BCR-ABL domain were found in 65/176 (37%) pts; 57 (88%) achieved CHR, and 24 (37%) MCyR. Molecular response analysis is ongoing. 160 (86%) pts remain on study without progression. Grade 3/4 neutropenia or thrombocytopenia was reported in 83 (45%) pts and 85 (46%) pts with onset after 4–8 weeks of therapy in most pts. Temporary dose interruptions occurred in 146 (78%), and dose reductions in 96 (52%) pts with a median daily of 108 (range 19–169) mg. Non-hematologic toxicity consisted mainly of Grade 1/2 diarrhea, headache, superficial edema, and pleural effusion, with ≤2% Grade 3/4. There was no cross-intolerance between dasatinib and IM. Conclusions: Dasatinib demonstrated substantial hematologic and cytogenetic activity in IM-R and IM-I pts with CP-CML. An updated analysis of 424 pts with ≥6 months of follow up will be presented. [Table: see text]

Efficacy and safety of pembrolizumab (pembro) alone or in combination with chemotherapy (chemo) in patients (pts) with advanced gastric or gastroesophageal (G/GEJ) cancer: Long-term follow up from KEYNOTE-059.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4009-4009 ◽  
Author(s):  
Zev A. Wainberg ◽  
Harry H. Yoon ◽  
Daniel V.T. Catenacci ◽  
Shadia Ibrahim Jalal ◽  
Kei Muro ◽  
...  
Keyword(s):  
Safety Data ◽  
Efficacy And Safety ◽  
First Line ◽  
Meaningful Activity ◽  
Heavily Pretreated ◽  
Long Term Follow Up ◽  
Combined Positive Score ◽  
Grade 3

4009 Background: Interim analysis of a global, phase 2 KEYNOTE-059 study (NCT02335411) reported manageable safety and promising antitumor activity for pembro alone or pembro + chemo in pts with G/GEJ cancer. Here we report long-term efficacy and safety data of all cohorts. Methods: Pts with recurrent or metastatic G/GEJ adenocarcinoma were enrolled in 3 cohorts. Cohort 1 pts (PD-L1–positive or –negative) received pembro alone after ≥2 prior lines of therapy. Cohort 2 pts (PD-L1–positive or –negative) received pembro + cisplatin (80 mg/m2 day 1) + 5-fluorouracil (800 mg/m2 days 1-5 Q3W) or capecitabine (in Japan only, 1000 mg/m2 twice daily) as first-line. Cohort 3 pts (PD-L1–positive, combined positive score ≥1% using the PD-L1 IHC 22C3 pharmDx assay) received pembro alone as first-line. All pts received pembro 200 mg Q3W for up to 2 years. End points included safety, ORR, DOR, and OS. Results: At data cutoff (Aug 8, 2018), median (range) follow-up was 6 (1-38), 14 (2-40), and 21 (2-36) months for cohorts 1 (n = 259), 2 (n = 25), and 3 (n = 31), respectively. In cohort 1, confirmed ORR (95% CI) was 11.6% (8-16) overall, 15.5% (10-22) in PD-L1–positive, and 6.4% (3-13) in PD-L1–negative tumors. In cohort 2, confirmed ORR was 60.0% (39-79) overall, 73.3% (45-92) in PD-L1–positive, and 37.5% (9-76) in PD-L1–negative tumors. In cohort 3, confirmed ORR was 25.8% (12-45). Median (range) DOR in months was 16.1 (2-35+), 4.6 (3-37+), and not reached (2.1-32.5+) in cohorts 1, 2, and 3, respectively. OS at 1 year/2 years was 24.6%/12.5%, 52%/32%, and 63.6%/40.1% in cohorts 1, 2, and 3, respectively. In cohorts 1, 2, and 3, grade 3-5 treatment-related adverse event (TRAE) incidence was 46 (18%), 20 (80%), and 8 (26%) respectively. TRAEs led to discontinuation in 6 (2%) and 3 (12%) pts in cohorts 1 and 2, respectively, and to death in 2 (1%) pts in cohort 1. No TRAEs led to discontinuation or death in cohort 3. Conclusions: These updated results demonstrate manageable safety, durable clinically meaningful activity of pembro in heavily pretreated pts, and promising efficacy of first-line pembro (alone or + chemo) in pts with advanced G/GEJ cancer. Clinical trial information: NCT02335411.

Occurrence, Management, and Outcomes In Patients with Pleural Effusion During Dasatinib Treatment for Chronic-Phase Chronic Myeloid Leukemia (CML-CP) In the First-Line Setting: Analysis of the DASISION Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2282-2282 ◽  
Author(s):  
Kimmo Porkka ◽  
Michele Baccarani ◽  
Andreas Hochhaus ◽  
Hagop Kantarjian ◽  
Satu Mustjoki ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Research Funding ◽  
Chronic Phase ◽  
Risk Scores ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Once Daily ◽  
Management Interventions ◽  
Grade 3

Abstract Abstract 2282 Background: The Phase 3 DASISION trial comparing dasatinib 100 mg once daily with imatinib 400 mg once daily as initial treatment in patients (pts) with newly diagnosed CML-CP has demonstrated superior efficacy and favorable safety of dasatinib after a minimum of 12 months of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260). While fluid retention was more frequent with imatinib than with dasatinib, pleural effusion was seen only with dasatinib. Here, we provide a detailed analysis of pts experiencing pleural effusion, a clinically relevant adverse drug reaction. Methods: 519 pts with newly diagnosed, treatment-naive CML-CP (median disease duration of 1 month) were randomly assigned to either dasatinib 100 mg once daily (259 pts) or imatinib 400 mg one daily (260 pts). Key endpoints included complete cytogenetic response (CCyR), major molecular response (MMR) and safety. All pts were assessed by chest x-ray at baseline and at 6 months after randomization, or more frequently, if indicated clinically. Pts with pleural effusion at baseline were excluded. Pleural effusion was graded according to CTCAE version 3 (grade 1, asymptomatic; grade 2, symptomatic, up to 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, < 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability). Results: After a minimum follow-up of 12 months with median treatment duration of 14.3 months (range, 0.3–25.8), 26 (10%, median age, 60 years) of the 258 dasatinib-treated pts (median age, 46 years) experienced pleural effusion. Of the pts with pleural effusion, 6 (23%) had low, 17 (65%) had intermediate and 3 (12%) had high Hasford risk scores. There were no grade 3 or 4 pleural effusion events. All events were grade 1(2%) or grade 2 (8%). Most events (n = 22, 85%) occurred more than 8 weeks after the start of study drug. In pts who had a pleural effusion, the median time to the event was 28 weeks (range, 4–88). Lymphocytosis (defined as peripheral blood lymphocyte count > 3.6 × 109/L) was noted in 11 (42%) of the 26 pts with pleural effusion, as compared to 46 (20%) of 232 pts with no pleural effusion. Pleural effusion was managed by dose modification and/or medical intervention. Therapy was interrupted in 19 pts, and the dose of dasatinib was reduced in 8 pts (4 pts, to 80 mg; 1 pt, to 70 mg; 3 pts, to 50 mg). Twelve pts received diuretics, 7 received corticosteroids, and only 1 pt underwent therapeutic thoracentesis. Only 3 pts (1.2%) discontinued therapy due to pleural effusion (grade 2). Eleven pts who continued dasatinib had resolution of their pleural effusion. Five pts had recurrent effusions. Of the 26 pts with pleural effusion, 24 (92%) achieved a CCyR and 17 (65%) achieved a MMR by 12 months of treatment; the corresponding CCyR and MMR rates in the total pt population were 83% and 46%, respectively Seven of the 8 pts with pleural effusion who reduced their dose achieved CCyR and MMR. Conclusion: In pts with newly diagnosed CML-CP treated with dasatinib as initial therapy, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR. These findings are in line with data reported previously for second-line dasatinib in CML pts resistant or intolerant to imatinib (Porkka, K, et al. Cancer 2010;116:377). Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated antitumor activity of dasatinib. Disclosures: Porkka: BMS, Novartis: Consultancy, Honoraria, Research Funding. Baccarani: Novartis, Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Mustjoki: BMS, Novartis: Honoraria. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Zhu: Bristol-Myers Squibb: Employment. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria.

Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted 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. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of 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) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

High-dose imatinib mesylate treatment in patients (Pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6535-6535 ◽  
Author(s):  
E. Aoki ◽  
H. Kantarjian ◽  
S. O’Brien ◽  
M. Talpaz ◽  
F. Giles ◽  
...  
Keyword(s):  
Standard Dose ◽  
Chronic Phase ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Molecular Responses ◽  
Pre Treatment ◽  
Grade 3

6535 Background: The standard dose (SD) of imatinib for CP CML is currently 400 mg daily, but higher doses (HD) may be more effective. We conducted 2 consecutive trials using HD imatinib (i.e., 400mg twice daily) in previously untreated early CP CML pts. This is an updated analysis of the longer follow-up. Methods: A total of 175 previously untreated pts received HD imatinib. We compared the results with a previous study using SD imatinib (400mg/day) in untreated pts with early CP CML (N=50). Results: Cytogenetic and molecular responses were evaluable in 222 pts (N=49 at SD, 173 at HD) and 217 pts (N=46 at SD, 171 at HD), respectively. In HD group, Sokal risk classification was good in 69%, intermediate in 29%, and poor in 11% of pts. There were no differences in pre-treatment characteristics between two groups. The median age was 48 years in both groups. Median follow-up is 53 months for SD and 30 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (90% vs 78% with SD, p=0.03) and these occurred earlier, with 69% achieving this response after 6 months of therapy vs 45% with SD (p=0.001). The cumulative incidence of major molecular response was significantly better in HD group (p=0.03), and this response was also observed earlier in HD group: at 12 months 54% in HD and 24% in SD group had achieved this response (p=0.001). At 24 months, 19/70 (27%) evaluable pts with HD versus 3/31 (10%) of pts in SD group achieved complete molecular remission. Four pts (2%) in HD group and 4 pts (8%) in SD group have progressed to advanced phases (p=0.05). There was a trend in favor of the HD group for transformation-free-survival but it was not statistically significant (p=0.07). Overall survival is excellent in both groups (24 month survival, 99% with HD vs 98% with SD; p=0.24). Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in two groups. The median actual dose in HD group was 800 mg at 12 months, with 39% patients requiring dose reduction at some point. Conclusions: High-dose imatinib provides higher rates of complete cytogenetic responses and earlier molecular responses with some increase myelosupression. The long-term benefit of earlier responses remains to be demonstrated. [Table: see text]

Long-term follow-up of previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) treated with ofatumumab (OFA) and chlorambucil (CHL): Final analysis of the phase 3 COMPLEMENT 1 trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7528-7528
Author(s):  
Fritz Offner ◽  
Tadeusz Robak ◽  
Ann Janssens ◽  
Govind Babu Kanakasetty ◽  
Janusz Kloczko ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Primary Analysis ◽  
Free Survival ◽  
Anti Cancer ◽  
Long Term Follow Up ◽  
Grade 3

7528 Background: Previously in the COMPLEMENT 1 study, treatment with OFA and CHL in pts with untreated CLL had shown a significant improvement in the progression-free survival (PFS) compared with CHL alone, and was well tolerated. Here, we report the final overall survival (OS) analysis of the 5-year (y) follow-up, updated investigator-assessed PFS and safety from the study. Methods: Untreated pts, not fit for fludarabine-based therapy (due to advanced age or co-morbidities) were randomized 1:1 to OFA+CHL or CHL alone. Pts in OFA+CHL arm received OFA (Cycle 1: 300 mg day (d) 1, 1000 mg d8; subsequent cycles: 1000 mg d1) in addition to CHL (10 mg/m2, d1-7) for 3 to 12 cycles of 28 d each. Pts in CHL arm received CHL only. Results: Overall, 447 pts were randomized to OFA+CHL (n = 221) or CHL (n = 226); 168 (76%) and 164 (73%) pts completed the scheduled treatments, respectively. Baseline characteristics were similar in both arms. The investigator-assessed median PFS was 23.4 months (mos) in the OFA+CHL arm and 14.7 mos in the CHL arm (HR: 0.61 [95% CI 0.49, 0.76], p < 0.001). Median OS could not be estimated for the OFA+CHL arm and was 84.7 mos for the CHL arm (HR: 0.88 [95% CI 0.65, 1.17], p = 0.363). Estimated OS rate (95% CI) at 5 y was 68.5% (61.5%, 74.5%) in the OFA+CHL arm, and 65.7% (58.6%, 71.9%) in the CHL arm. Post-treatment anti-cancer therapy after discontinuation was received by a greater proportion of pts in the CHL (66%) vs. OFA+CHL (56%), and started earlier in the CHL arm (486 d) vs. OFA+CHL (743 d) arm. Overall, 84 (39%) pts in the OFA+CHL, and 99 (44%) pts in the CHL arms died during the study with 5 on-treatment deaths in each group. Grade ≥3 adverse events were seen in 64% and 48% of pts in the OFA+CHL vs. CHL arms, respectively, most common being (≥5% in either arm) neutropenia (26% vs. 15%), thrombocytopenia (5% vs. 10%), pneumonia (9% vs. 5%), and anemia (5% vs. 5%). Conclusions: This 5-y survival follow-up analysis supported the results from primary analysis with an estimated 12% (not significant) and 39% risk reduction in OS and PFS, respectively, in the OFA+CHL arm compared with the CHL arm. No new safety concerns were observed in the OFA+CHL arm. Clinical trial information: NCT00748189.

Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6504-6504 ◽  
Author(s):  
Andreas Hochhaus ◽  
Neil P. Shah ◽  
Jorge E. Cortes ◽  
Michele Baccarani ◽  
M. Brigid Bradley-Garelik ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Cytogenetic Response ◽  
Transformation Rate ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Intent To Treat

6504 Background: In the phase 3 DASISION trial of dasatinib v IM in patients (pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates of complete cytogenetic response (CCyR) and major molecular response (MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P=0.001, meeting the primary endpoint. Methods: Pts were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Results: Minimum 24-month follow-up (median 26.6 months) is reported here. 24-month molecular response rates were higher for dasatinib v IM: MMR (BCR-ABL ≤0.1%) 64% v 46%, P<0.0001; MR4 (BCR-ABL ≤0.01%) 29% v 19%, P=0.0053; MR4.5 (BCR-ABL ≤0.0032%) 17% v 8%, P=0.0032. MMR rates were higher for dasatinib in all Hasford risk groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had maintained their MMR at 24 months, respectively. Pts receiving dasatinib v IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts receiving dasatinib (n=9; 3.5%) transformed to accelerated/blast phase v IM (n=15; 5.8%) on study or during follow-up after discontinuation. 24-month overall and progression-free survival were similar for dasatinib v IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few additional adverse events (AEs) were reported between 12 and 24 months in both arms, with grade 3/4 nonhematologic AE rates ≤1%. In each arm, 10 pts had a BCR-ABL mutation detected at time of discontinuation. For dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs (7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v <1%), death (2% v <1%), and other (4% v 8%). Few pts discontinued between 12 and 24 months for dasatinib (n=19; 7%) and IM (n=16; 6%). Conclusions: Updated data with minimum 36-month follow-up will be presented, including mutation analyses in pts who discontinued, progressed, or had suboptimal response. Pts receiving dasatinib had a lower transformation rate and higher molecular responses v pts receiving IM, supporting the use of dasatinib in newly diagnosed CML-CP.

BELA trial update: Bosutinib (BOS) versus imatinib (IM) in patients (pts) with newly diagnosed chronic phase chronic myeloid leukemia (CP CML) after 30 months of follow-up.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6512-6512 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Jeffrey Howard Lipton ◽  
Goh Yeow Tee ◽  
Luis Felipe Casado ◽  
Andrey Zaritskey ◽  
...  
Keyword(s):  
Overall Survival ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Geographic Region ◽  
Molecular Response ◽  
Primary Reason ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
Grade 3

6512 Background: The BELA study compared the efficacy and safety of BOS (dual Src/Abl kinase inhibitor) with IM in newly diagnosed CP CML. Methods: 502 pts with newly diagnosed CP CML were randomized to BOS 500 mg/d (n = 250) or IM 400 mg/d (n = 252) and stratified by Sokal risk group and geographic region. Efficacy analyses included all randomized pts (ITT); safety analyses included all treated pts (BOS, n = 248; IM, n = 251). Data described below are for ≥24 mo of follow-up; updated data for ≥30 mo of follow-up will be presented. Results: Median treatment duration was 27.5 mo in both cohorts; 63% of BOS pts and 71% of IM pts were still receiving treatment. The primary reason for BOS discontinuation was a treatment-emergent adverse event (TEAE; 24% vs 7% with IM); the primary reason for IM discontinuation was disease progression (13% vs 4% with BOS). Cumulative complete cytogenetic response (CCyR) rates by 24 mo were 79% for BOS and 80% for IM. Cumulative major molecular response (MMR) rates by 24 mo were 59% for BOS and 49% for IM (P = 0.019), including 16% and 12% of pts with complete molecular response (4.0-log sensitivity). On-treatment transformation to accelerated/blast phase occurred in 4 (2%) BOS pts and 13 (5%) IM pts. Deaths were reported for 7 BOS pts (6 due to CML progression) and 13 IM pts (10 due to CML progression); 24-mo Kaplan-Meier overall survival estimates were 97% (BOS) and 95% (IM). BOS was associated with higher incidences of gastrointestinal events than IM (diarrhea [70% vs 25%], vomiting [32% vs 16%]; primarily transient), but lower incidences of edema (13% vs 40%) and musculoskeletal events (cramps [4% vs 22%], bone pain [4% vs 10%]). Grade ≥3 TEAEs in ≥2% of BOS or IM pts were diarrhea (12% vs 1%), vomiting (3% vs 0%), and rash (2% vs 1%). Grade ≥3 lab abnormalities (≥15% of pts) with BOS and IM were neutropenia (10% vs 24%), thrombocytopenia (14% vs 15%), elevated alanine aminotransferase (23% vs 4%), and hypophosphatemia (6% vs 20%). Conclusions: BOS was effective for newly diagnosed CP CML and had a distinct toxicity profile. With continued follow-up both on-treatment transformation to accelerated/blast phase and overall survival continue to favor BOS versus IM.

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

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 182-182 ◽  
Author(s):  
Jorge Cortes ◽  
Susan O’Brien ◽  
Gautam Borthakur ◽  
Dan Jones ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Treatment Schedule ◽  
Molecular Response ◽  
Significant Activity ◽  
Efficacy And Safety ◽  
Significant Difference ◽  
Grade 3

Abstract Background: Dasatinib (BMS-354825) is a multi-targeted kinase inhibitor of BCRABL and SRC with significant activity in pts with CML-CP resistant to 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 (MMR) at 12 months (mo). Pts with previously untreated CML-CP were eligible and received dasatinib 100 mg/day, randomized to either 50 mg-twice-daily (BID) or a 100 mg-once-daily (QD). Results: Fifty pts have been enrolled (25 on the QD schedule, 25 BID). Median age was 45 years (yrs) (range 18–76 yrs); 75% are Sokal low risk. Median follow-up is 24 months (mo). Overall, 44/45 (98%) evaluable patients achieved complete cytogenetic response [CCyR]. The CCyR rate at 3, 6 and 12 mo compares favorably to that observed in historical controls treated with imatinib 400mg or 800 mg daily: Percent with CCyR (No. evaluable) Mo on therapy Dasatinib Imatinib 400mg Imatinib 800mg P value 3 78 (45) 37 (49) 62 (202) 0.0003 6 93 (41) 54 (48) 82 (199) &lt;0.0001 12 97 (35) 65 (48) 86 (197) 0.0001 18 88 (33) 68 (38) 89 (179) 0.004 24 80 (25) 70 (40) 88 (173) 0.006 MMR was achieved in 12/35 (34%) at 12 mo and 12/25 (48%) at 18 mo. One of 46 (2%) evaluable pts have achieved confirmed complete molecular response, and 1 other unconfirmed (ie, only achieved on their last assessment). Grade 3–4 non-hematologic toxicity (regardless of causality) included pruritus (13%), fatigue (6%), neuropathy (4%), and memory impairment (4%). Pleural effusion occurred in 21% evaluable pts (grade 3–4 in 2%). Grade 3–4 hematologic toxicity (transient) was thrombocytopenia in 11%, neutropenia in 21%, and anemia in 9%. Twenty-seven (54%) pts required transient treatment interruption. The actual median daily dose for all pts was 100mg. There is no significant difference in grade 3–4 toxicity by treatment schedule. Four pts came off study: 1 pts choice after 1 dose, 1 for toxicity (pleural effusion, QD schedule), and 2 lost response after multiple treatment interruptions (1 myelosuppression, 1 pleural effusion, both BID schedule). Two other pts have lost response because of non-compliance. 24 month EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 81%. Conclusion: Rapid CCyR occurs in most patients with previously untreated CML-CP treated with dasatinib frontline therapy with a favorable toxicity profile. Accrual to this trial continues.

Outcomes of Patients with Chronic Phase CML Who Discontinued Ponatinib in the Frontline Setting

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1580-1580
Author(s):  
Preetesh Jain ◽  
Hagop M Kantarjian ◽  
Elias Jabbour ◽  
Zeev Estrov ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Median Time ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
The Other ◽  
Molecular Response ◽  
Vascular Events ◽  
Grade 3

Abstract Background: Ponatinib is a novel TKI efficacious in relapsed refractory patients (pts) with CML and in those with T315I mutation. Despite the achievement of deep early responses in most pts observed in the frontline setting, the concern for arterio-thrombotic events led to the discontinuation (DC) of ponatinib frontline clinical trial. In this study, we have assessed the outcomes after DC of ponatinib of pts in a clinical trial of frontline ponatinib in CML-CP. Methods: Fifty one pts with CML-CP were treated with frontline ponatinib in a single-arm, clinical trial between May 2012 and September 2013. Initial dose of ponatinib was 45 mg orally daily in 43 pts and, after amendment, 30 mg in 8 pts. All pts DC ponatinib therapy after June 2014 and were switched to another TKI. Patients were assessed for cause of DC, treatment received after ponatinib DC, response achieved/maintained on subsequent TKI, adverse events (AE) and survival after ponatinib DC. Survival was calculated from the time of ponatinib DC to the time of last follow up. Results: All 51 patients DC ponatinib: 38 per FDA recommendation and 13 due to AE. Median duration of ponatinib therapy was 13.2 months (range-2.1-25.4). At the time of DC, 47/51 (92%) pts were in complete cytogenetic response (CCyR) and 4 (8%) in partial cytogenetic response (PCyR); 1 pt DC before 3-mo evaluation. Forty (78%) pts were in MMR and 26 (51%) in molecular response 4.5-log (MR4.5). Thirty-six (70%) pts were switched to dasatinib, 7 (14%) to imatinib, and 4 (8%) each to nilotinib and bosutinib. After switching to another TKI, with a median of 13 months (range, 0.2 to 26.3) of follow-up, 2 pts have lost their cytogenetic response (both PCyR on ponatinib), 1 pt improved from PCyR to CCyR and one maintained PCyR; all 47 (92%) pts with CCyR on ponatinib maintained this response. Molecular responses improved in some pts: 6 improved from no MMR to MMR; 1 to MR4.5 (median time on ponatinib 4 months; median time on subsequent TKI 17 months); 11 from MMR to MR4.5 (median time on ponatinib 13 months; median time on subsequent TKI 17 months). One pt (treated with imatinib 400) lost MR4.5 to no MMR after 2 months. At last follow-up 37 pts (72%) had MR4.5 and 45 (90%) MMR. Two pts died after ponatinib DC. One pt was treated with imatinib 400 and developed grade-3 edema and recurrent lung cancer; the second was switched to dasatinib and had recurrent progressive peripheral arterial disease (PAD). Four pts had events (2 deaths, 1 secondary MDS with -7 and 1 pt lost major CyR). Median post ponatinib survival (Figure-1) and median post ponatinib event free survival (not shown) was not reached (1-year OS 98% and EFS 95%). Forty five pts continued on their first post-ponatinib TKIs, 5 required 2 post-ponatinib TKI and 1 pt received 3 different TKIs after DC. The most common cause for post-ponatinib TKI switch was toxicity (n=6). Of the 36 pts switched to dasatinib, 5 discontinued: 4 due to pleural effusion and 1 with acute renal failure. 29/36 pts (81%) were in MMR before switch and all maintained MMR; 4 pts achieved MMR after switch to dasatinib. Four pts developed grade 3-4 non hematological vascular AEs (3 among pts with such events while on ponatinib and 1 new vascular event within 3 months of ponatinib DC). Of the 4 pts switched to nilotinib, 1 DC within 3 months due to grade-3 pancreatitis and also developed grade-1 pulmonary hypertension with 1 month of discontinuing ponatinib. This pt was then switched to bosutinib. The other 3 pts maintained MMR and had no vascular events. Of the 4 pts switched to bosutinib, one developed MDS, one was switched back to ponatinib off protocol (patient's choice), 1 lost cytogenetic response and one DC therapy after 1 month and maintains MR4.5 (this pt had TIA while on ponatinib, developed cerebral infarct within 1 month post ponatinib). Seven pts switched to imatinib. One developed a new PAD within 3 months of ponatinib DC (history of MI while on ponatinib). The other 6 pts maintained MMR on imatinib. Overall, 15 pts who had aggravated hypertension on ponatinib were under control after DC of ponatinib. Conclusion: Treatment with 2nd generation TKIs and imatinib was effective and safe in pts who DC ponatinib, and most pts were able to maintain/improve the responses achieved on ponatinib. Ponatinib-associated hypertension was usually reversible after DC and most vascular events with subsequent TKIs occurred in patients with prior such events while on ponatinib. Figure 1. Post ponatinib survival in patients Figure 1. Post ponatinib survival in patients Disclosures Jabbour: pfizer: Research Funding; ariad: Research Funding; teva: Consultancy; teva: Research Funding; pfizer: Consultancy; bms: Consultancy; ariad: Consultancy. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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