Temporal characteristics of treatment-emergent adverse events and dose modifications with tivozanib and sorafenib in the phase 3 TIVO-3 study of relapsed or refractory mRCC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4567-4567
Author(s):  
Sumanta K. Pal ◽  
David F. McDermott ◽  
Bernard Escudier ◽  
Thomas E. Hutson ◽  
Camillo Porta ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Reduction ◽  
Phase 3 ◽  
Temporal Characteristics ◽  
Dose Modifications ◽  
Time To Onset ◽  
Improve Patient ◽  
Insight Into ◽  
Dose Reductions ◽  
Clinical Trial Information

4567 Background: The randomized phase 3 TIVO-3 study met the primary endpoint of improved PFS with tivozanib (TIVO) vs sorafenib (SOR) in patients with relapsed/refractory mRCC with fewer dose reductions, interruptions and discontinuations despite a longer time on therapy. Greater insight into temporal characteristics of treatment-emergent adverse events (TEAEs) may enable proactive supportive care strategies and improve patient experience. Methods: Updated safety from the previously reported TIVO-3 study with a data cutoff August 15, 2019, was analyzed by treatment arm for time-to-onset (TTO, days [d]) of the most commonly reported TEAEs, and TTO of first dose reduction, interruption, and discontinuation occurring with TIVO and SOR. Duration of TEAE (median d and IQ range), and rate of dose reduction, interruption, or discontinuation due to the TEAE was calculated for each arm. Results: Patients in the safety analysis randomly assigned to TIVO (n = 173) or SOR (n = 170) received 11.9 and 6.7 cycles, or 336 and 192 mean days of treatment exposure, respectively. Incidence of any Gr, Gr >3, and TTO of any Gr TEAE of special interest occurring with >20% frequency in either arm is shown in Table 1. While TIVO was associated with less Gr>3 diarrhea, rash and PPE and more HTN than SOR, there were few differences in the TTO or duration of these TEAEs. Overall, dose reductions, interruptions, and discontinuations due to TEAEs were less frequent with TIVO than SOR, and TTO of first dose reduction (85 vs 45 d), interruption (81 vs 50 d), and discontinuation (114 vs 49 d) was longer for TIVO than SOR. Among those experiencing the same TEAE in either arm, resulting dose modifications were less frequent with TIVO than SOR. Conclusions: TIVO-3 demonstrated improved PFS with TIVO compared to SOR in mRCC, with longer duration of TIVO exposure, but fewer all Gr and Gr >3 TEAEs. Temporal characteristics of TEAEs were similar, but time to dose modifications was longer with TIVO than SOR. Among those with the same TEAEs, unmodified treatment was continued more often with TIVO than SOR. Clinical trial information: NCT02627963. [Table: see text]

Effect of dose modifications on response to duvelisib in patients with relapsed/refractory (R/R) CLL/SLL in the DUO trial.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7523-7523
Author(s):  
Ian Flinn ◽  
Marco Montillo ◽  
Árpád Illés ◽  
Gabriel Etienne ◽  
Julio Delgado ◽  
...  
Keyword(s):  
Median Time ◽  
Median Duration ◽  
Effective Management ◽  
Phase 3 ◽  
Dose Modification ◽  
First Response ◽  
Duration Of Response ◽  
Dose Modifications ◽  
Time To Onset ◽  
Clinical Trial Information

7523 Background: Duvelisib (DUV), a first-in-class oral dual PI3K-δ,γ inhibitor, is approved for treatment (tx) of R/R CLL/SLL after ≥ 2 prior therapies. In the phase 3 DUO trial, DUV 25 mg BID significantly improved efficacy vs ofatumumab (OFA; mPFS, 13.3 vs 9.9 mo; HR, 0.52 [ P < .0001]; ORR, 74% vs 45% [ P < .0001]) in pts with R/R CLL/SLL. Tx-emergent AEs (TEAEs) of special interest (AESIs) such as infections, diarrhea, colitis, neutropenia, rash, ALT/AST elevation, and pneumonitis, were moderate and manageable with early intervention and dose modification. We examined dose-modification patterns and their impact on response to DUV in the DUO trial. Methods: Dose interruptions (DI) or reductions (DR) to 15, 10, or 5 mg BID were permitted per study protocol to manage TEAEs. Responses were assessed by IRC. Results: Among 158 DUV-treated pts, median duration of DUV exposure was 11.6 mo (vs 5.3 mo, OFA). DI and DR occurred in 80% (126/158) and 27% (43/158) of pts, respectively. The most common cause of DI was diarrhea (23%), followed by neutropenia (12%) and pneumonia or colitis (11% each). Among responders (n = 118), median time to first response on DUV was 1.9 mo and estimated median duration of response was 11.1 mo. Median time to first DI was 3.9 mo and median duration of DI was 15 d (range, 1-133 d). Response to DUV was improved or maintained in most pts evaluated for response who had ≥ 1 DI for > 1 wk (84% [42/50]) or > 2 wk (82% [31/38]) followed by ≥ 3 wk on DUV. In a landmark analysis, median PFS was similar in pts with DI and those without DI for > 1 wk (17.8 vs 16.3 mo) or > 2 wk (17.8 vs 16.3 mo) within the first 3 mo. The median time to DR after CR/PR was 5.6 mo (n = 25) and median duration was 3.4 mo. Median time to onset across AESIs after starting DUV ranged from 2.2 to 4.3 mo; median time to resolution was within 4 wk across AESIs. Proportions of pts experiencing AESIs were stable or decreased over time after 3-6 mo: 0-3 mo, 64% (101/158); > 3-6 mo, 63% (86/137); > 6-9 mo, 47% (54/114); > 9-12 mo, 52% (52/100), and seldom led to discontinuation of DUV (≤ 10%). Conclusions: DI/DR can contribute to the effective management of TEAEs with DUV. These findings suggest that DI of > 1-2 weeks or more do not appear to significantly impact response to DUV or PFS. Clinical trial information: NCT02004522.

Impact of bevacizumab dose reduction on clinical outcomes for patients treated on the Eastern Cooperative Oncology Group’s Study E3200

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3538-3538 ◽  
Author(s):  
B. J. Giantonio ◽  
P. J. Catalano ◽  
P. J. O’Dwyer ◽  
N. J. Meropol ◽  
A. B. Benson
Keyword(s):  
Dose Reduction ◽  
Progression Free Survival ◽  
Free Survival ◽  
Hazard Ratios ◽  
Previously Treated ◽  
Grade 3 ◽  
Number Of Cycles ◽  
Colorectal Cancer Patients ◽  
Dose Modifications ◽  
Dose Reductions

3538 Background: E3200 demonstrated improved survival (OS) for previously treated metastatic colorectal cancer patients who received second-line therapy with bevacizumab (10 mg/kg) in combination with FOLFOX4. Dose reductions of bevacizumab to 5 mg/kg were allowed for: hypertension, bleeding and thrombosis of ≤ grade 2; proteinuria of > 2 grams/24 that resolved to <0.5 grams/24hrs; liver function abnormalities ≥ grade 3 that resolved to ≤ grade 1. Methods: Data on dose modifications of bevacizumab were obtained from a post-study survey of participating institutions for all participants. Median OS and progression-free survival (PFS) were determined based upon a dose reduction any time during treatment. Hazard ratios (HR) for OS and PFS were stratified by number of cycles (1–5, 6–10, 11+) to adjust for the time-varying nature of dose reductions. Results: Surveys were received on 84% of E3200 patients treated with bevacizumab. Dose reductions of bevacizumab were performed in 134 of 240 (55.8%) patients treated with FOLFOX + bevacizumab (Arm A) and 77 of 205 (37.6%) patients treated with bevacizumab alone (Arm C). The average number of cycles of bevacizumab administered at a dose reduction for Arm A is 42% and for Arm C is 52%. Conclusions: OS and PFS on E3200 were not compromised for patients who underwent dose reductions of bevacizumab. [Table: see text] [Table: see text]

Time to grade ≥3 adverse events in pts receiving trifluridine/tipiracil (TAS-102).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 788-788 ◽  
Author(s):  
Eric Van Cutsem ◽  
Atsushi Ohtsu ◽  
Natividad Lopez Busto ◽  
Akira Kanehisa ◽  
Ronan Fougeray ◽  
...  
Keyword(s):  
Adverse Events ◽  
Rest Period ◽  
Outpatient Setting ◽  
Phase 3 ◽  
Serious Adverse Events ◽  
Safety Population ◽  
End Of Treatment ◽  
Grade 3 ◽  
Post Hoc ◽  
Clinical Trial Information

788 Background: The phase 3 RECOURSE showed that treatment with trifluridine/tipiracil in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved survival versus placebo (7.1 versus 5.3 months, respectively; HR for death 0.68, 95% CI 0.58–0.81, p < 0.001), with few serious adverse events. Trifluridine/tipiracil is administered in 4-week cycles comprising 2 weeks with 5 days at 35 mg/m2 bid followed by 2 rest days, and then a 2-week rest period. Exploration of timing for AEs, particularly within the first cycle of treatment, is important for pt monitoring in the outpatient setting. Methods: We performed a post hoc analysis of the RECOURSE safety population (533 trifluridine/tipiracil; 265 placebo) to explore timing of hematological and nonhematological AEs. Results: Grade ≥ 3 adverse events (AEs) were more frequent with trifluridine/tipiracil than placebo for both hematological AEs (38% vs 0% neutropenia; 4% vs 0% febrile neutropenia; 18% vs 3% anemia; and 5% vs < 1% thrombocytopenia) and nonhematological AEs (2% vs 1% nausea; 2% vs < 1% vomiting; and 3% vs < 1% diarrhea). The median time to nadir in cycle 1 for hematological events was 28 days (17–31) for grade ≥ 3 neutropenia, 22 days (9–39) for grade ≥ 3 anemia, and 18 days (9–33) for grade ≥ 3 thrombocytopenia; similar values were obtained in subsequent cycles. The median times to nadir and values at nadir over the whole treatment duration (all cycles) are presented in the table for hematological and nonhematological AEs. Conclusions: Hematological and nonhematological AEs with trifluridine/tipiracil appear to be most intense towards the end of treatment cycles, which is reassuring for its use in the outpatient setting. Clinical trial information: NCT01607957. [Table: see text]

Analysis of hematologic adverse events (HeAEs) in trifluridine/tipiracil (FTD/TPI)-treated patients (pts) with or without renal/hepatic impairment (RI/HI): Pooled safety analyses from TAGS and RECOURSE.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 145-145
Author(s):  
Ben George ◽  
Eric Van Cutsem ◽  
Howard S. Hochster ◽  
Robert J. Mayer ◽  
Atsushi Ohtsu ◽  
...  
Keyword(s):  
Median Time ◽  
Total Bilirubin ◽  
Gastroesophageal Junction ◽  
Hepatic Function ◽  
Pooled Analysis ◽  
Phase 3 ◽  
Gastroesophageal Junction Cancer ◽  
Normal Hepatic Function ◽  
Time To Onset ◽  
Clinical Trial Information

145 Background: FTD/TPI has shown clinical benefit and consistent safety in pretreated pts with metastatic colorectal cancer (mCRC) and metastatic gastric or gastroesophageal junction cancer (mGC/GEJC) in the phase 3 RECOURSE and TAGS trials, respectively. HeAEs were the most frequent AEs with FTD/TPI treatment. Methods: Pts in this analysis received ≥1 FTD/TPI dose in the TAGS and RECOURSE trials. Subgroups included pts with normal renal function (nRF; CrCl ≥90 mL/min), mild RI (CrCl 60–89 mL/min), moderate (mod) RI (CrCl 30–59 mL/min), normal hepatic function (nHF) and mild HI (total bilirubin <1.5 X ULN, or AST >ULN). Results: FTD/TPI was administered to 868 pts in the overall pooled population (OPP; n=335, TAGS [mGC/GEJC]; n=533, RECOURSE [mCRC]); 52%, 36%, and 11% had nRF, mild and moderate RI, and 66% and 33% had nHF and mild HI, respectively. Frequencies of any-cause grade (gr) ≥3 HeAEs were similar across subgroups and the OPP, except for gr ≥3 anemia and gr ≥3 leukopenia, which were higher with mod RI (table). In the OPP, most gr 3/4 neutropenia events occurred within the first 2 cycles (median time to onset [mTTO], 49 d). Median time to resolution (mTTR) was 8 d. Gr 3/4 neutropenia TTO and TTR in most subgroups were consistent with the OPP, except with mod RI (mTTO, 29 d). HeAE management and correlative efficacy analyses will be presented. Conclusions: In this pooled analysis of pts with mCRC and mGC/GEJC, HeAEs with FTD/TPI in pts with mild to mod RI and mild HI were manageable and not largely different from those in the OPP. Clinical trial information: NCT02500043 and NCT01607957. [Table: see text]

scholarly journals Dose Modifications of Ribociclib and Endocrine Therapy for Treatment of ER+ HER2- metastatic Breast Cancer 

2021 ◽  
Author(s):  
Kristoffer Bøss Kristensen ◽  
Ida Marie Nedergaard Thomsen ◽  
Tobias Berg ◽  
Annette R. Kodahl ◽  
Anders B. Jensen
Keyword(s):  
Breast Cancer ◽  
Dose Reduction ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Lymph Node Involvement ◽  
Treatment Information ◽  
Estrogen Receptor Positive ◽  
Node Involvement ◽  
Dose Modifications ◽  
Dose Reductions

Abstract Purpose: Treatment for estrogen receptor positive (ER+), human epidermal receptor 2 negative (HER2-) metastatic breast cancer (MBC) has improved with the approval of CDK 4/6 inhibitors. Clinical trials with the CDK4/6 inhibitor ribociclib, suggest that between 35% to 57.5% of the patients experience a dose reduction during treatment. Information on the possible consequences of dose reduction concerning efficacy is needed. Methods: A retrospective cohort study on patients with ER+ HER2- MBC from three Danish oncology departments. Data on tolerability and progression-free survival were collected from electronic health records. Results: 128 patients with ER+ HER2- MBC who initiated ribociclib treatment between 1st January 2018 to 31st March 2020 were included in our analysis. Of these patients, 48.4% required one or more dose reductions. Overall median PFS was 19.2 months (CI-95%: 14.3-NR). Patients with one or more dose reductions did not have decreased median PFS (19.2 months, CI-95%: 14.3-NR compared to 12.2 months, CI-95%: 7.3-NR. p=0.078). Frequency of adverse events were as previously reported, with grade III and IV neutropenia occurring in 45.3% and 7% of patients, respectively. Patients treated with fulvestrant versus an aromatase inhibitor and patients with lymph node involvement at baseline had lower odds of requiring dose reduction (ORa = 0.30, CI-95%: 0.18-0.89 & ORa = 0.41, CI-95%: 0.12-0.73, respectively). Conclusion: Our results indicate that dose reduction of ribociclib is safe and do not compromise the efficacy of the treatment. Furthermore, the study supports translation of results from the MONALEESA trials to patients treated in real-world clinical settings.

scholarly journals SAT0157 NINTEDANIB DOSE ADJUSTMENTS AND ADVERSE EVENTS IN PATIENTS WITH PROGRESSIVE AUTOIMMUNE DISEASE-RELATED INTERSTITIAL LUNG DISEASES IN THE INBUILD TRIAL

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1019.1-1019
Author(s):  
E. Volkmann ◽  
I. Castellví ◽  
S. Johnson ◽  
E. Matteson ◽  
J. Distler ◽  
...  
Keyword(s):  
Placebo Group ◽  
Autoimmune Disease ◽  
Adverse Events ◽  
Dose Reduction ◽  
Treatment Interruption ◽  
Treatment Discontinuation ◽  
Research Support ◽  
Treatment Interruptions ◽  
Trial Drug ◽  
Dose Reductions

Background:In the INBUILD trial in patients with progressive fibrosing ILDs, the adverse event (AE) profile of nintedanib was characterised predominantly by gastrointestinal AEs. Dose adjustments were used to manage AEs.Objectives:Assess AEs and dose adjustments in patients with autoimmune disease-related ILDs in the INBUILD trial.Methods:Patients with progressive fibrosing ILDs other than idiopathic pulmonary fibrosis were randomised to nintedanib 150 mg bid or placebo. Dose reductions to 100 mg bid and treatment interruptions were permitted to manage AEs. AEs over 52 weeks of treatment (or 28 days after last trial drug intake for patients who discontinued drug before week 52) were assessed in patients who received ≥1 dose of trial drug.Results:Of 663 patients in the INBUILD trial, 170 (82 nintedanib, 88 placebo) had autoimmune disease-related ILDs (89 RA-ILD, 39 SSc-ILD, 19 MCTD-ILD, 23 other autoimmune ILDs). In the nintedanib and placebo groups of patients with autoimmune disease-related ILDs, respectively, over 52 weeks, the proportions of patients with ≥1 dose reduction were 28.0% and 3.4%, with ≥1 treatment interruption were 31.7% and 10.2%, and with ≥1 dose reduction and/or treatment interruption were 40.2% and 12.5% (Table). Dose intensity (amount of drug administered divided by amount that would have been received had 150 mg bid been administered over 52 weeks or until permanent treatment discontinuation) was >90% in 80.5% of patients in the nintedanib group and 95.5% in the placebo group. AEs led to permanent treatment discontinuation in 17.1% and 10.2% of patients treated with nintedanib and placebo, respectively. Diarrhoea was the most common AE, reported in 63.4% and 27.3% of patients in the nintedanib and placebo groups, respectively. Diarrhoea AEs led to dose reduction, treatment interruption and permanent treatment discontinuation in 7.3%, 9.8% and 4.9% of patients in the nintedanib group, compared with 0%, 1.1% and 1.1% of patients in the placebo group, respectively. Of the nintedanib-treated patients who experienced ≥1 diarrhoea AE, 80.8% experienced 1 or 2 events and 76.9% experienced events that were mild at worst (Common Terminology Criteria for Adverse Events [CTCAE] grade 1).Conclusion:In the INBUILD trial, management of AEs via dose adjustments enabled most patients with autoimmune disease-related ILDs to remain on treatment for 52 weeks. Diarrhoea was the AE that most commonly led to dose adjustment.TableNintedanib(n=82)Placebo (n=88)Patients with ≥1 dose reduction or treatment interruption33 (40.2)11 (12.5)Patients with ≥1 dose reduction23 (28.0)3 (3.4)Total number of dose reductions253Patients with ≥1 dose re-escalation after dose reduction5 (6.1)2 (2.3)Patients with ≥1 treatment interruption26 (31.7)9 (10.2)Total number of treatment interruptions3211Total duration of treatment interruptions, days, mean (SD)20.1 (15.1)19.3 (20.7)Data are n (%) of patients unless otherwise indicated.Disclosure of Interests:Elizabeth Volkmann Grant/research support from: Forbius, Corbus Pharmaceuticals, Consultant of: Boehringer Ingelheim, Forbius, Speakers bureau: Boehringer Ingelheim, Ivan Castellví Consultant of: Boehringer Ingelheim, Actelion, Kern Pharma, Speakers bureau: Boehringer Ingelheim, Actelion, Bristol-Myers Squibb, Roche, Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Eric Matteson Grant/research support from: Pfizer, Consultant of: Boehringer Ingelheim, Gilead, TympoBio, Arena Pharmaceuticals, Speakers bureau: Simply Speaking, Jörg Distler Grant/research support from: Boehringer Ingelheim, Consultant of: Boehringer Ingelheim, Paid instructor for: Boehringer Ingelheim, Speakers bureau: Boehringer Ingelheim, James Seibold Shareholder of: BriaCell, Pacific Therapeutics, Consultant of: Atlantic, Blade Therapeutics, Eicos Sciences, Eiger Biopharmaceuticals, Indalo Therapeutics, Mitsubishi Tanabe Pharma, Bayer, Xenikos, Boehringer Ingelheim, Camurus, Corbus Pharmaceuticals, EMD Serono, Speakers bureau: Boehringer Ingelheim, Ulrich Costabel Consultant of: Boehringer Ingelheim, Roche, Fibrogen, Global Blood Therapeutics, Speakers bureau: Boehringer Ingelheim, Roche, AstraZeneca, Alexandra James Employee of: Employee of Boehringer Ingelheim, Carl Coeck Employee of: Employee of Boehringer Ingelheim, Manuel Quaresma Employee of: Employee of Boehringer Ingelheim, Vincent Cottin Grant/research support from: Boehringer Ingelheim, Roche, Consultant of: Boehringer Ingelheim, Roche, Actelion, Bayer, Gilead Sciences, Novartis, Promedior, Celgene, Galapagos, Galecto. He was a member of the INBUILD trial Steering Committee., Speakers bureau: Actelion, Boehringer Ingelheim, Novartis, Roche, Sanofi

scholarly journals Dose Reductions in Ibrutinib Therapy Are Not Associated with Inferior Outcomes in Patients with Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5567-5567 ◽  
Author(s):  
Othman S. Akhtar ◽  
Kris Attwood ◽  
Ian Lund ◽  
Ryan Hare ◽  
Francisco J. Hernandez-Ilizaliturri ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Treatment Initiation ◽  
Standard Dose ◽  
Comprehensive Cancer Center ◽  
Fixed Dose ◽  
Significant Difference ◽  
Baseline Characteristics ◽  
Dose Modifications ◽  
Dose Reductions

Abstract Introduction: Ibrutinib is a first-in-class small molecule inhibitor that binds irreversibly to Bruton's Tyrosine Kinase (BTK) and has shown remarkable efficacy in the treatment of CLL. Current guidelines recommend life-long therapy with administration at a fixed daily dose of 420 mg. However, lower doses of ibrutinib have been demonstrated to adequately abrogate kinase function. Limited clinical data suggests that dose reductions are not associated with inferior outcomes. Hypothetically, judicious dose reductions to manage toxicities could result in improved tolerance and decreased discontinuation rates. Our objective was to study the impact of dose reductions on outcomes in CLL patients treated with ibrutinib in a real-world setting. Methods: We conducted a retrospective chart review of all CLL patients treated with ibrutinib at Roswell Park Comprehensive Cancer Center between January 2014 and June 2017. Patients who underwent ibrutinib dose reduction were identified. Baseline characteristics and outcomes were compared between patients who underwent dose reductions vs those who did not. Reason and timing of dose reduction was also elucidated. Mann-Whitney U and Fisher's Chi Square test were used to compare groups, Kaplan Meier methods were used for time to event analysis, and Cox regression was used to obtain hazard ratios (HR). Overall survival (OS) was calculated as time from start of ibrutinib until death or last follow-up, freedom from progression (PFS) was taken as time from start of ibrutinib until progression or last follow-up. All analyses were performed in SAS v9.4 (Cary, NC). Results: A total of 70 CLL patients treated with ibrutinib were followed for a median period of 21.9 months. Most patients had RR disease (n = 63) and 7 received ibrutinib as frontline therapy. All patients received a fixed dose regimen with the standard dose of 420 mg once daily. Twenty-three (31.3%) patients required dose reductions and received ibrutinib at a median dose of 140 mg . Eleven (47.8%) of these had dose reductions within 3 months of treatment initiation. There was no statistically significant difference in baseline characteristics including age, number of prior lines of treatment, WBC count, hemoglobin or LDH level in the dose reduced group (DRG) and standard dose group (SDG). Patients in the DRG had a lower median platelet count at initiation of ibrutinib than patients in the SDG (86 x 103/mm3 vs 145 x 103/mm3, p<0.05). The most frequent reasons for dose reductions included cytopenia (n=8), fatigue (n=5), infections (n=4) and atrial fibrillation (n=3) with 2 patients requiring dose reduction due to simultaneous CYP inhibitor administration. There was no statistically significant difference in the overall response rate (ORR) (p=0.25) and clinical benefit rate (CBR) (p=1.00) between the DRG (ORR- 65.2%, CBR- 91.4%) and SDG (ORR 78.7%, CBR 91.5%). Median PFS and OS was not reached in both groups. PFS at 12 months was 86% (95% CI 63-95%) and 87% (95% CI 71- 94%) in the DRG and SDG respectively (p=0.92). OS at 12 months was 83% (95% CI 60-93%) and 84% (95% CI 69-92%) in the DRG and SDG respectively (p=0.53). We noticed no statistically significant difference in the median PFS and OS between the two groups (Figure 1). In a subgroup analysis, we compared outcomes in patients in the SDG with those who had dose modifications within 3 months of initiating therapy or later and found no statistically significant differences in OS and PFS between the groups (p=0.15 and p=0.46 respectively). Of the 23 patients requiring dose modifications, 11 (47.8%) had to eventually discontinue therapy as compared to 17 (36.2%) patients in the SDG and we noticed similar 1-year discontinuation rates in the DRG and SDG groups (22% vs 21% respectively, p=0.91). Conclusion: In CLL patients treated with ibrutinib, reductions in the dose of ibrutinib were not associated with worse outcomes. These results extended to all patients with dose modifications, irrespective of whether the modification was made within 3 months of treatment initiation, or later in the course of treatment. Disclosures No relevant conflicts of interest to declare.

scholarly journals Real-world ibrutinib dose reductions, holds and discontinuations in chronic lymphocytic leukemia

2021 ◽  
Author(s):  
Jing-Zhou Hou ◽  
Kellie Ryan ◽  
Senxi Du ◽  
Bruno Fang ◽  
Stanley Marks ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Chronic Lymphocytic Leukemia ◽  
Adverse Events ◽  
Dose Reduction ◽  
Chart Review ◽  
Retrospective Chart Review ◽  
Routine Clinical Practice ◽  
Lymphocytic Leukemia ◽  
First Line ◽  
Dose Reductions

Aim: A retrospective chart review of ibrutinib-treated patients with chronic lymphocytic leukemia (CLL) was conducted. Patients & methods: Adults with CLL who initiated ibrutinib were followed for ≥6 months (n = 180). Results: Twenty-five percent of first-line ibrutinib patients experienced ≥1 dose reduction, mainly due to adverse events (AEs; 79%). Treatment discontinuations and dose holds occurred in 20 and 34% of patients, respectively, most commonly due to AEs (73 and 74%). Approximately one-quarter of relapsed/refractory ibrutinib patients experienced ≥1 dose reduction, mainly due to AEs (88%). Treatment discontinuation and dose holds occurred in 40% of patients (58 and 76% due to AEs, respectively). Conclusion: Dose reductions, holds and discontinuations were frequent in patients with CLL receiving ibrutinib in routine clinical practice.

Impact of Dose Reductions and Interruptions Due to Adverse Events (AEs) on Efficacy in Newly Diagnosed Chronic Myeloid Leukemia in ChronicPhase (CML-CP) Patients (pts) Receiving Either Dasatinib (D) or Imatinib(IM): Analysis of the DASISION Trial

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2768-2768 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Francois Guilhot ◽  
Chao Zhu ◽  
...  
Keyword(s):  
Adverse Events ◽  
Dose Reduction ◽  
Research Funding ◽  
Response Rates ◽  
Similar Response ◽  
Medical Procedure ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Equity Ownership ◽  
Dose Reductions

Abstract Abstract 2768 Background: 24-month follow-up of pts with newly diagnosed CML-CP in the DASISION trial demonstrated both a high rate of complete cytogenetic response (CCyR) with dasatinib (D) and higher and faster rates of major molecular response (MMR) with D over imatinib (IM), supporting the use of D 100 mg once daily as a first-line treatment option for newly diagnosed CML-CP. Discontinuations due to adverse events (AEs) occurred in 7% with D and 5% with IM. Median dose intensity for D and IM were 99.5 mg/day and 400 mg/day, respectively (Kantarjian JCO 2011:29;Abs 6510). A retrospective analysis of pts from DASISION was performed to evaluate the impact of dose reductions and interruptions due to AEs on efficacy of D or IM in newly diagnosed CML-CP. Methods: Pts with newly diagnosed CML-CP received D 100 mg QD (N=258) or IM 400 mg QD (N=258). The primary endpoint was confirmed CCyR by 12 months. In DASISION, up to two dose reductions were permitted for AEs; dose reduction levels were 80 mg/50 mg for D and 300 mg/200 mg for IM. Dose interruptions were permitted for management of AEs. Upon resolution or improvement of AEs to ≤ Grade 1, pts could resume therapy at an appropriate dose based on initial severity of the AE. Efficacy was evaluated for pts with or without dose reductions and/or interruptions due to AEs at any time. Efficacy was also evaluated for pts with first dose interruption and/or reduction due to AEs within ≤6 or >6 months of their first dose who remained on treatment for at least 6 months, in order to reduce selection bias of pts with longer duration of therapy. Pts with dose reduction and/or interruption for reasons other than AEs (dosing error, medical procedure) were excluded from all analyses. Results: 134 D pts (52%) and 92 IM pts (36%) had dose reduction and/or interruption for AE management at the DASISION 24-month update. First dose reduction and/or interruption due to non-hematologic AEs occurred in 59 (23%) D and 40 (16%) IM pts and hematologic AEs in 75 (29%) D and 52 (20%) IM pts. Pts with dose reduction and/or interruption for reasons other than AE management were excluded, including 21 (8%) D pts and 19 (7%) IM pts. The median duration of first dose interruption due to AEs was approximately 2 weeks on both arms. CCyR and MMR rates with D were comparable whether pts did or did not have their dose reduced and/or interrupted at any time (Table). D pts who had dose reduction and/or interruption had generally higher rates of responses than IM pts overall and in those without an IM dose reduction and/or interruption. The timing of dose reduction and/or interruption appeared to have a potential impact as response rates were higher when dose reduction and/or interruption occurred >6 months after the first dose of either drug (Table). CCyR and MMR rates with D remained higher than with IM when dose reduction and/or interruption occurred ≤6 months from first dose. Similarly, both CCyR and MMR were higher for D than with IM if dose reduction and/or interruption occurred >6 months from the first dose. Conclusions: Results of this analysis suggest that CML-CP pts receiving dasatinib achieved similar response rates despite dose modification for the management of AEs. Data for pts with and without dose reduction and/or interruption due to AEs are consistent with DASISION 24-months results, showing higher rates of response with dasatinib than with imatinib. Disclosures: Kantarjian: Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Quintas-Cardama:Bristol-Myers Squibb: Honoraria. Guilhot:Novartis: Honoraria; Bristol-Myers Squib: Honoraria; Pfizer: Honoraria; Celgene: Honoraria. Zhu:Bristol-Myers Squibb: Employment. Hong:Bristol-Myers Squibb: Employment, Equity Ownership. Cain:Bristol-Myers Squibb: Employment, Equity Ownership. Cortes:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Outcomes based on age in the phase 3 METEOR trial of cabozantinib (cabo) vs everolimus (eve) in patients with advanced renal cell carcinoma (RCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4578-4578 ◽  
Author(s):  
Frede Donskov ◽  
Robert J. Motzer ◽  
Eric Voog ◽  
Elizabeth J. Hovey ◽  
Carsten Grüllich ◽  
...  
Keyword(s):  
Adverse Events ◽  
Older Patients ◽  
Objective Response ◽  
Age Groups ◽  
Progression Free Survival ◽  
Phase 3 ◽  
Free Survival ◽  
Previously Treated ◽  
Grade 3 ◽  
Dose Reductions

4578 Background: The incidence of RCC increases with age with the highest incidence at ~75 years of age (Znaor, Eur Urol 2015). The Phase 3 METEOR trial (NCT01865747) showed a significant improvement in progression-free survival (PFS; HR 0.58, 95% CI 0.45–0.74; P < 0.0001), overall survival (OS; HR 0.66, 95% CI 0.53–0.83, P = 0.0003), and objective response rate (ORR; 17% vs 3%; P < 0.0001) for cabo compared with eve in patients with advanced RCC previously treated with VEGFR TKIs (Choueiri, NEJM 2015, Lancet Oncol 2016). Here we present outcomes by 3 categories of age for the METEOR trial. Methods: 658 patients were randomized 1:1 to cabo (60 mg qd) or eve (10 mg qd). Stratification factors were MSKCC risk group and number of prior VEGFR TKIs. Endpoints included PFS, OS, and ORR. Subgroup analyses by age ( < 65, 65 to 74, and ≥75 years) are presented. Results: At baseline, 60% of patients were < 65 years old, 31% were 65 to 74 years old, and 10% were ≥75 years old. Subgroups by age generally had similar baseline characteristics in both arms. The HRs for PFS favored cabo for all age groups (HR 0.53, 95% CI 0.41–0.68 for < 65 years old; 0.53, 95% CI 0.37–0.77 for 65 to 74 years old; and 0.38, 95% CI 0.18–0.79 for ≥75 years old). ORR per independent radiology committee for cabo vs eve was 15% vs 5% for < 65 years old, 21% vs 2% for 65 to 74 years old, and 19% vs 0% for ≥75 years old. HRs for OS also favored cabo (HR 0.72, 95% CI 0.54–0.95 for < 65 years old; 0.66, 95% CI 0.44–0.99 for 65 to 74 years old; and 0.57, 95% CI 0.28–1.14 for ≥75 years old). Median OS for cabo vs eve was 21.4 mo vs 17.1 mo for < 65 years old, not reached vs 18.0 mo for 65 to 74 years old, and 18.4 mo vs 14.0 mo for ≥75 years old. Older patients more frequently had dose reductions (60% with cabo and 22% with eve for < 65 years old vs 85% with cabo and 36% with eve for ≥75 years old). Grade 3 or 4 adverse events were generally consistent with the safety profiles in the overall population although some events such as fatigue and hypertension occurred at a higher rate in older patients. Conclusions: Treatment with cabo improved PFS, ORR, and OS compared with eve in patients with advanced RCC irrespective of age. Adverse events in older patients were more frequently managed with dose reductions. Clinical trial information: NCT01865747.

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