A retrospective analysis of data from two trials of sunitinib in patients with advanced renal cell carcinoma (RCC): Pitfalls of efficacy subgroup analyses based on dose-reduction status.

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 363-363 ◽  
Author(s):  
Reza Khosravan ◽  
Xin Huang ◽  
Robin Wiltshire ◽  
Mariajose Lechuga ◽  
Robert John Motzer
Keyword(s):  
Dose Reduction ◽  
Progression Free Survival ◽  
Dose Schedule ◽  
Cancer Center ◽  
Phase 2 ◽  
Phase 3 ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Trough Concentrations ◽  
Require Dose

363 Background: Patients requiring sunitinib dose reduction who received a novel dose/schedule modification scheme had longer progression-free survival (PFS) than patients who did not require dose reduction and remained on 50 mg Schedule 4/2 (4 weeks on, 2 weeks off) (Bjarnason 2011). Our analysis compared sunitinib efficacy in advanced RCC patients with/without dose reduction using the label-approved, dose-reduction scheme (ie, 50 mg/37.5 mg/25 mg) and schedule (Schedule 4/2) and explored potential causes of any differences. Methods: Data from a Phase 3 and a Phase 2 trial, sunitinib Schedule 4/2 arms only (N=375 and 146, respectively), were retrospectively analyzed, and pharmacokinetics and baseline characteristics of patients with/without dose reduction compared. Results: In the Phase 3 trial, median (95% CI) PFS was 14.0 (13.1–16.2) months (mos) and 8.1 (6.3–10.6) mos with (n=194) and without (n=181) dose reduction, respectively. In the Phase 2 trial, corresponding PFS values were 13.4 (9.8–19.8) mos and 5.8 (3.9–8.5) mos (n=51 and 95, respectively). In the Phase 2 trial, steady-state mean (SD) total drug trough concentrations were 96.0 (42.2) ng/mL and 85.8 (43.4) ng/mL on Day 29 of Cycle 1 in patients with/without dose reduction, respectively. In both studies, the percent of patients with baseline Memorial Sloan-Kettering Cancer Center risk factors of 0 (favorable), 1–2 (intermediate), and 3 (poor) were 37–47%, 53–57% and 0–6% with dose reduction vs. 25–28%, 65–72%, and 0–10% without dose reduction. The mean (range) time to dose reduction was 7.2 (0.03–40.4) mos in the Phase 3 trial and 4.5 (0.4–22.6) mos in the Phase 2 trial. Conclusions: Patients with dose reduction remaining on Schedule 4/2 appeared to have longer PFS than patients with no dose reduction. The differences were not caused by differences in plasma drug exposures; they appeared to be due, at least in part, to 1) differences in patients’ baseline prognostic factors and 2) patients’ PFS or longevity affecting their dose-reduction status. Thus, efficacy subgroup analysis based on patients’ dose-reduction status appears to be confounded, leading to biased results.

Eribulin and gemcitabine in previously treated patients with advanced liposarcoma or leiomyosarcoma: A multicenter, single-arm, phase 2-trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11516-11516
Author(s):  
Chang Gon Kim ◽  
Jin-Hee Ahn ◽  
Jeong Eun Kim ◽  
Jee Hung Kim ◽  
Min Kyung Jeon ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Alternative Hypothesis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Previously Treated Patients ◽  
Previously Treated ◽  
Histologic Types

11516 Background: Eribulin and gemcitabine have shown encouraging efficacy in soft-tissue sarcoma (STS) as a monotherapy. Here, we evaluated the activity and safety of combined use of eribulin and gemcitabine in two most common histologic types of STS, liposarcoma and leiomyosarcoma. Methods: In this non-randomized, multi-center phase 2 study, patients were included if they had progressive disease after one or two prior chemotherapy including doxorubicin. Patient were given eribulin 1.4 mg/m2 and gemcitabine 1,000 mg/m2 on day1 and day 8 every 3 weeks. The primary endpoint was progression-free survival rate at 12 weeks (PFSR12wks) with null and alternative hypothesis of PFSR12wks≤20.0% and ≥40.0%, respectively. Results: Of 37 patients included, 22 had leiomyosarcoma, and 15 had liposarcoma. At 12-weeks after treatment, 16 and (72.7%) 11 (73.3%) patients in leiomyosarcoma and liposarcoma were progression-free. Overall PFSR12wks was 73.0%, satisfying the primary endpoint. Objective response rate, disease control rate, median progression-free survival, and median overall survival were 16.2%, 78.4%, 23.9 weeks, and 88.9 weeks, without any statistical differences according to histologic subtypes. No new safety signals and treatment-related death were observed. Conclusions: Eribulin and gemcitabine showed promising activity and manageable safety profile in patients with STS of liposarcoma and leiomyosarcoma histology. Updated outcomes for ongoing patients will be presented. Clinical trial information: NCT03810976.

Overall response rate (ORR) in STEAM, a randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab (BEV) vs FOLFOX-BEV for the first-line (1L) treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 492-492 ◽  
Author(s):  
Johanna C. Bendell ◽  
Benjamin R. Tan ◽  
James Andrew Reeves ◽  
Henry Xiong ◽  
Bradley G. Somer ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Tumor Location ◽  
Induction Phase ◽  
Phase 2 ◽  
Open Label ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Disease Rates ◽  
Open Label Phase ◽  
The Impact

492 Background: 3-drug chemotherapy (CT) + BEV (cFOLFOXIRI-BEV) significantly improved efficacy vs FOLFIRI-BEV for 1L mCRC tx, but safety and the impact of subsequent fluoropyrimidine-BEV maintenance tx require further definition. The phase 2 STEAM (NCT01765582) trial assessed efficacy of 1L cFOLFOXIRI-BEV vs FOLFOX-BEV and safety of alternating 2-drug CT (FOLFOX and FOLFIRI) + BEV tx monthly in a sequential sFOLFOXIRI-BEV regimen. Methods: Pts with unresectable, previously untreated mCRC were randomized 1:1:1 to BEV-containing (5 mg/kg) arms (cFOLFOXIRI, sFOLFOXIRI [alternating FOLFOX and FOLFIRI every 4 weeks {q4w}], or FOLFOX q3w) in a 4–6 month induction phase, followed by BEV-containing maintenance tx. Stratification factors included extent of metastatic disease and tumor location. Primary objectives: 1L ORR, 1L progression-free survival (PFS), safety. Secondary objectives: resection and conversion to resectable disease rates, time to 2L PFS, overall survival. ORR was tested with a 1-sided alpha of 5%; tx arms were compared with a stratified 1-sided Cochran-Mantel-Haenszel test. PFS was analyzed descriptively. Results:Among 280 enrolled pts (median age, 57.5 yrs), 186 remainined in the study on July 1, 2015. Efficacy and safety are shown (see Table). Conclusion: While not statistically significant, there was a trend of increased ORR with cFOLFOXIRI-BEV vs FOLFOX-BEV in 1L mCRC tx. Analysis of PFS is ongoing. All 3 regimens were well tolerated. Clinical trial information: NCT01765582. [Table: see text]

Impact of primary tumor side (TS) on outcomes of once-every-2-weeks (q2w) cetuximab + first-line (1L) FOLFOX or FOLFIRI in patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in the phase 2 APEC trial.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 747-747
Author(s):  
Timothy Jay Price ◽  
Lin Shen ◽  
Brigette Ma ◽  
Regina Esser ◽  
Wen-Feng Chen ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Hepatic Flexure ◽  
Asia Pacific ◽  
Phase 2 ◽  
Exon 2 ◽  
Free Survival ◽  
Prognostic Effect ◽  
Phase 2 Trial ◽  
Colon And Rectum ◽  
The Impact

747 Background: In the RAS wt population of APEC, q2w cetuximab combined with 1L FOLFOX or FOLFIRI achieved a best confirmed overall response rate (BORR), median progression-free survival (PFS), and median overall survival (OS) similar to those reported in prior 1L pivotal studies involving weekly (qw) cetuximab. In this hypothesis-generating subgroup analysis, we evaluated the impact of TS in APEC study patients with RAS wt mCRC. Methods: APEC was a nonrandomized phase 2 trial conducted in the Asia-Pacific region, with BORR as the primary endpoint. Patients with KRAS exon 2 wt tumors received q2w cetuximab + investigator’s choice of FOLFOX or FOLFIRI; subsequent analyses considered patients who were RAS wt ( KRAS/ NRAS, exons 2-4). TS was categorized in evaluable patients with RAS wt tumors (left [L]-sided = splenic flexure, descending colon, sigmoid colon, and rectum; right [R]-sided = appendix, cecum, ascending colon, hepatic flexure, and transverse colon). Results: Among 167 patients with RAS wt mCRC, 159 were evaluable for TS; 130 (81.8%) had L-sided and 29 (18.2%) had R-sided mCRC. Baseline characteristics in the TS subgroups reflected the known differences between L- and R-sided mCRC. Efficacy data for the TS subgroups are summarized in the table. Conclusions: Consistent with prior 1L pivotal studies involving qw cetuximab, a prognostic effect of TS in patients receiving 1L q2w cetuximab was confirmed in APEC. BORR remained ≥50% in patients with R-sided mCRC, in line with prior evidence that use of cetuximab may be appropriate when tumor shrinkage/cytoreduction is the goal. These hypothesis-generating data also raise the possibility of synergy between cetuximab and, in particular, irinotecan for PFS and OS in patients with R-sided tumors, although numbers are small. Clinical trial information: NCT00778830. [Table: see text]

Retrospective comparison of modified FOLFIRINOX with full-dose FOLFIRINOX for advanced pancreatic cancer: A Japanese cancer center experience.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 469-469 ◽  
Author(s):  
Akihiro Ohba ◽  
Hideki Ueno ◽  
Yasunari Sakamoto ◽  
Shunsuke Kondo ◽  
Chigusa Morizane ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Dose Reduction ◽  
Advanced Pancreatic Cancer ◽  
Group Versus ◽  
Progression Free Survival ◽  
Cancer Center ◽  
Control Group ◽  
Phase 2 ◽  
Full Dose ◽  
Grade 3

469 Background: Various modified FOLFIRINOX (mFFX) regimens have been reported and widely used in clinical practice. Although there are retrospective studies and single-arm phase 2 studies comparing modified regimens to the full-dose regimen of the historical control group, head-to-head comparisons in the same population are limited. This study aimed to compare mFFX with full-dose FOLFIRINOX (fFFX) in patients with advanced pancreatic cancer (APC). Methods: We reviewed 85 patients with APC who received mFFX (no bolus fluorouracil and irinotecan 150 mg per square) or fFFX as first-line chemotherapy between January 2014 and December 2016. mFFX has been used since January 2016 on the basis of results of a Japanese phase 2 study. The efficacy, safety, and dose reduction pattern were evaluated. Results: A total of 56 eligible patients (26 treated with mFFX and 30 with fFFX) were selected. Baseline characteristics of each group were well-balanced. The median relative dose intensities of oxaliplatin, irinotecan, bolus fluorouracil, and continuous infusion fluorouracil were 68.6%, 78.5%, 0%, and 88.5% in the mFFX group, and 80.5%, 76.5%, 25.6%, and 83.6% in the fFFX group, respectively. Second cycle dose reduction occurred in 38% of the patients in the mFFX group and in 62% of those in the fFFX group. The median overall survival (OS) was 19.0 months in the mFFX group, compared to 13.2 months in the fFFX group (HR 0.60, 95% CI 0.25–1.47, P = 0.27). In a multivariate analysis to adjust for prognostic factors for OS, the hazard ratio for death with mFFX was significant (adjusted HR 0.36, 95% CI 0.14–0.93, P = 0.04). The median progression-free survival was 8.3 months in the mFFX group and 5.9 months in the fFFX group (HR 0.83, 95% CI 0.44–1.54, P = 0.55). The response rate was 35% in the mFFX group versus 30% (P = 0.78) in the fFFX group, respectively. Grade 3 or 4 leucopenia (15% versus 40%), neutropenia (42% versus 70%), febrile neutropenia (8% versus 17%), and nausea (4% versus 13%) were decreased in the mFFX group, but the differences were not statistically significant. Conclusions: mFFX had equivalent or higher efficacy and improved safety compared to fFFX in the same population.

scholarly journals RTID-12. PHASE 2 TRIAL OF TUMOR TREATING FIELDS (TTFIELDS) PLUS RADIATION THERAPY (RT) PLUS TEMOZOLAMIDE (TMZ) COMPARED TO RT PLUS TEMOZOLOMIDE IN NEWLY DIAGNOSED GLIOBLASTOMA (ndGBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii196-ii196
Author(s):  
Rachel Grossman ◽  
Dror Limon ◽  
Felix Bokstein ◽  
Carmit Ben Harosh ◽  
Deborah Blumenthal ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Skin Toxicity ◽  
Phase 2 ◽  
Free Survival ◽  
Tumor Treating Fields ◽  
Phase 2 Trial ◽  
Phase 2 Study ◽  
Newly Diagnosed Glioblastoma ◽  
Early Progressive Disease

Abstract OBJECTIVE In the EF-14 phase 3 trial, TTFields 9200 kHz) added to maintenance TMZ increased median OS to 20.9 months versus 16.0 months with maintenance TMZ (p< 0.001) in ndGBM. Preclinical investigations showed that TTFields/RT have a synergistic effect. A pilot study (N=10) in ndGBM demonstrated the feasibility and safety of TTFields combined with RT/TMZ (Grossman Front Onc 2020). The only TTFields-related adverse event was array-associated skin toxicity. Median PFS was 8.9 months. Based on these encouraging results, this prospective, randomized phase 2 study [NCT03869242] in 60 patients further investigates if the addition of TTFields TMZ/RT treatment in ndGBM patients improves treatment efficacy and delays disease progression. METHODS Following debulking surgery or biopsy, 60 patients (≥18 years) with histologically confirmed GBM, KPS≥70 and life expectancy >3 months will be randomized 1:1 to: i) RT with concomitant TMZ/TTFields (200 kHz) for 6 weeks followed by up to 6 months of maintenance TMZ combined with TTFields (experimental arm) up to 24 months; or ii) RT with concomitant TMZ alone followed by maintenance TMZ combined with TTFields (control arm). Patients with early progressive disease, significant comorbidities precluding maintenance RT or TMZ or with implanted electronic devices will be excluded. The primary endpoint is the rate of progression free survival at 12 months (PFS12). Treatment with TTF will be continued until second progression or 24 months (the earlier of the two). All patients will be followed for survival. All adverse events will graded per CTCAE V5.0. The sample size of 60 patients provides 80% power with two-sided alpha level of 0.05 to detect a PFS12 of 46.5% with RT/TMZ/TTFields compared to 29.4% with RT/TMZ followed, respectively, by maintenance TMZ/TTFields (calculated from the RT/TMZ followed by maintenance TMZ/TTFields arm of the EF-14 trial). Follow-up will continue for >12 months from recruitment of the last patient.

scholarly journals Meta-Analyses of Clinical Trials Comparing the Progression Free Survival and Adverse Events in Treated Versus Observed Patients with Smoldering and Indolent Multiple Myeloma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2196-2196
Author(s):  
Fahrettin Covut ◽  
Tariq Zuheir Kewan ◽  
Apoorva Anandan ◽  
Folashade Otegbeye ◽  
James Driscoll ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Visual Inspection ◽  
Meta Analysis ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Phase 3 ◽  
Free Survival ◽  
Treatment Regimens ◽  
Meta Analyses ◽  
Entire Text

Background: Observation is currently the standard of care for patients with smoldering and indolent multiple myeloma (MM). However, the evidence has been building up recently to support early initiation of treatment. We performed a meta-analysis of previous clinical trials involving smoldering/indolent MM patients who were treated with novel anti-myeloma agents to examine progression free survival (PFS) and safety profile of the treatment regimens. Methods: A systematic literature search was conducted independently by 2 authors (F.C. and T.Z.K.) in PubMed, MEDLINE, EMBASE, Cochrane, and abstracts from major oncology meetings. Keywords used in the search included "myeloma", "smoldering MM", "indolent MM", "asymptomatic MM". The title and abstract of studies identified in the search were reviewed by 2 authors (F.C. and T.Z.K.) independently to exclude studies that were not clinical trials and included patients with MGUS or symptomatic MM. Entire text of the remaining articles, including the references, was examined to identify studies which reported Cox regression analysis for PFS or Kaplan-Meier curve of PFS to be able to extract HR, 95% CI, and P value, as previously described by Tierney JF et al. (Trials, 2007). Historical control arm is extracted from intermediate and high risk patients in an observational clinical trial by Khan R et al. (Haematologica, 2015) and used for the phase 2 clinical trials. The Jadad scale was used to assess the methodological quality of phase 3 trials. The random-effects model was used to synthesize the data. Heterogeneity was assessed using Cochran's Q statistic and I2 statistics, p≤0.1 and I2>50% considered statistically significant, respectively. We examined publication bias quantitatively using the Begg and Mazumdar adjusted rank correlation test and qualitatively by visual inspection of funnel plots of the logarithmic HR versus their standard errors. Results: We reviewed title/abstracts of 3327 studies, identified 31 manuscripts/meeting abstracts to read entire text, and incorporated 9 trials (four phase 3 and five phase 2) in the meta-analysis based on inclusion criteria. These studies cumulatively reported 677 patients with smoldering/indolent MM. Six trials were performed in USA, 2 were multi-country trials, and 1 was in Europe. Median number of patients in the trials was 68 (range: 29 - 181) and median follow-up was ranged between 26 and 121 months. The characteristics of these studies are shown in table 1. Overall response rate and grade ≥3 adverse events for trials with thalidomide vs. lenalidomide vs. monoclonal antibody based treatment arms were 41% and 59% vs. 65% and 32% vs. 36% vs 44%. On meta-analyses of all studies, treatment vs observation of smoldering/indolent MM was statistically significant predictor of PFS (HR 0.41, 95% CI: 0.31 - 0.56, p < 0.001) (Figure 1). The results showed considerable heterogeneity (Cochran's Q test P = 0.037, I2 = 51%). There was no evidence of publication bias both quantitatively (P = 0.30) and on visual inspection of the funnel plot (Figure 2). We performed preplanned stratified analysis of studies based on location, trial phase, and treatment arm (Table 2). Subgroup analyses according to treatment regimens identified the trials with thalidomide based treatment arms as the source of heterogeneity (I2 = 55% vs I2 = 0%, P = 0.027). Trials with lenalidomide and monoclonal antibody based treatment arms showed significantly greater prognostic impact on PFS (HR 0.22, 95% CI: 0.14 - 0.35 and HR 0.41, 95% CI: 0.22 - 0.94, respectively) compared to trials with thalidomide based treatment arms (HR 0.53, 95% CI: 0.33 - 0.83). Conclusion: In this first meta-analysis of patients with smoldering/indolent MM, we found that novel anti-myeloma agents prolongs the PFS with an acceptable toxicity profile. Disclosures Malek: Amgen: Speakers Bureau; Adaptive: Consultancy; Janssen: Speakers Bureau; Medpacto: Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy.

Safety and efficacy of dasatinib in patients with advanced gastrointestinal stromal tumors refractory to imatinib and sunitinib: A single arm, multicenters, phase 2 trial.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 138-138 ◽  
Author(s):  
Jian Li ◽  
Ye Zhou ◽  
Xinhua Zhang ◽  
Xiaojun WU ◽  
Yongjian Zhou ◽  
...  
Keyword(s):  
Day Treatment ◽  
Progression Free Survival ◽  
Phase 2 ◽  
Free Survival ◽  
Intention To Treat ◽  
Phase 2 Trial ◽  
Medical Centers ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ct Dna

138 Background: Regorafenib is recommended to treat advanced gastrointestinal stromal tumor (GIST) refractory to imatinib and sunitinib. However, the efficacy is not satisfied, other active agents need to be explored to advanced patients. Methods: In this single arm, multi-center, phase 2 trial, we enrolled patients aged 18 years and older with advanced GIST who had received previous imatinib and sunitinib treatment. Participants were treated with oral dasatinib 50mg twice a day for 2 weeks. If patients were tolerable, then they received dasatinib 70mg twice a day treatment, to tumor progression or intolerable toxicities. The primary endpoint was RECIST-based progression-free survival (PFS) in the intention-to-treat population. The secondary endpoints included response rate, overall survival (OS) and advent events. ctDNA will be analysis in some patients to explore the sensitive biomarker to dasatinib. Results: From May 2016 to June 2018, 58 patients from nine medical centers were enrolled in this study. Two patients had partial response and disease control rate was 62.0%. The median PFS was 3.0 months (95% CI, 2.6-3.4 months). There was no statistic difference of PFS in both subgroup with different primary mutations and in subgroup with different secondary mutations. The patients with wild type GIST had a trend of longer PFS of 5.5 months. In 4 patients with PDGFRA D842V mutation, two patients had stable disease. The median OS was 14.0 months (95% CI, 10.8-17.2 months). The most frequently observed grade 3 adverse events included anemia (10.3%), diarrhea (1.7%). The analysis of ct DNA is ongoing. Conclusions: Dasatinib is an active treatment for patients with GIST who are refractory to imatinib and sunitnib. This study is registered with ClinicalTrials.gov, NCT02776878 . Clinical trial information: NCT02776878.

scholarly journals Randomized, multicenter, phase 2 study (EVOLUTION) of combinations of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide in previously untreated multiple myeloma

Blood ◽  
2012 ◽  
Vol 119 (19) ◽  
pp. 4375-4382 ◽  
Author(s):  
Shaji Kumar ◽  
Ian Flinn ◽  
Paul G. Richardson ◽  
Parameswaran Hari ◽  
Natalie Callander ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase 2 ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Highly Active ◽  
Phase 2 Study ◽  
Significant Efficacy ◽  
Good Partial Response

Abstract Combinations of bortezomib (V) and dexamethasone (D) with either lenalidomide (R) or cyclophosphamide (C) have shown significant efficacy. This randomized phase 2 trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum 8 cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms) ≥ very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances. All regimens were highly active and well tolerated in previously untreated MM, and, based on this trial, VDR and VCD-mod are preferred for clinical practice and further comparative testing. No substantial advantage was noted with VDCR over the 3-drug combinations. This trial is registered at www.clinicaltrials.gov (NCT00507442).

Phase 2 Study of the Safety and Efficacy of Umbralisib in Patients with CLL Who Are Intolerant to BTK or PI3Kδ Inhibitor Therapy

Blood ◽  
2020 ◽  
Author(s):  
Anthony R. Mato ◽  
Nilanjan Ghosh ◽  
Stephen J Schuster ◽  
Nicole Lamanna ◽  
John M. Pagel ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Inhibitor Therapy ◽  
Pi3k Inhibitor ◽  
Phase 2 ◽  
Free Survival ◽  
Phase 2 Trial ◽  
Buccal Swabs ◽  
Secondary Endpoints ◽  
Grade 3

Purpose: Intolerance is the most common reason for kinase inhibitor (KI) discontinuation in CLL. Umbralisib a novel, highly selective PI3Kδ/CK1ε inhibitor, is active and well tolerated in CLL patients. This phase 2 trial evaluated umbralisib in CLL patients who are intolerant to prior BTK or PI3K inhibitor therapy. Patients and Methods: In this phase 2 trial (NCT02742090), umbralisib was initiated at 800 mg oral daily in CLL patients requiring therapy per investigator discretion who were intolerant to prior BTK or PI3K inhibitor therapy, until progression or toxicity. Primary endpoint was progression-free survival (PFS). Secondary endpoints included time to treatment failure and umbralisib safety profile. DNA isolated from buccal swabs was genotyped for polymorphisms in CYP3A4, CYP3A5 and CYP2D6. Results: Fifty-one patients were enrolled (44 BTKi and 7 PI3Kδi intolerant). Median age was 70 years (range 48-96), median of 2 prior lines of therapy (1-7), 24% had del17p and/or TP53 mutation, and 65% were IGHV unmutated. Most common AEs leading to prior KI discontinuation were rash (27%), arthralgia (18%), and atrial fibrillation (16%). Median progression free survival (PFS) was 23.5 months (95% CI 13.1-not estimable). 58% of patients were on umbralisib for a longer duration than prior KI. Most common (≥5%) grade ≥3 AEs on umbralisib (all causality) were neutropenia (18%), leukocytosis (14%), thrombocytopenia (12%), pneumonia (12%), and diarrhea (8%). Six patients (12%) discontinued umbralisib due to an AE. Eight patients (16%) had dose reductions and were successfully re-challenged. Conclusions: Umbralisib is safe and effective in this BTK and alternate PI3K inhibitor intolerant CLL population. These are the first prospective data to confirm that switching from a BTK or alternate PI3K inhibitor to umbralisib can result in durable, well tolerated responses.

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