Effect of fixed-duration venetoclax plus obinutuzumab (VenG) on progression-free survival (PFS), and rates and duration of minimal residual disease negativity (MRD–) in previously untreated patients (pts) with chronic lymphocytic leukemia (CLL) and comorbidities.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 7502-7502
Author(s):  
Kirsten Fischer ◽  
Othman Al-Sawaf ◽  
Jasmin Bahlo ◽  
Anna-Maria Fink ◽  
Maneesh Tandon ◽  
...  
Keyword(s):  
Residual Disease ◽  
Progression Free Survival ◽  
Treatment Completion ◽  
Lymphocytic Leukemia ◽  
Fixed Duration ◽  
Open Label ◽  
Open Label Phase ◽  
Allele Specific ◽  
Intent To Treat ◽  
Next Generation Sequencing Ngs

7502 Background: The multinational, open-label, phase 3 CLL14 trial compared fixed-duration targeted VenG treatment with chlorambucil-obinutuzumab (ClbG) in previously untreated pts with CLL and comorbidities. Here we present endpoint analyses with particular emphasis on MRD− and PFS. Methods: Pts with a CIRS score >6 and/or an estimated creatinine clearance <70 mL/min were randomized 1:1 to receive equal duration treatment with 12 cycles (C) of standard Clb or Ven 400 mg daily in combination with G for first 6 C. Primary endpoint was PFS. MRD− in peripheral blood (PB) or bone marrow (BM) 3 months (mo) after treatment completion was a key secondary endpoint. MRD was analyzed serially from C4 every 3 mo by an allele-specific oligonucleotide polymerase chain reaction assay (ASO-PCR; cut-off, 10-4) and by next generation sequencing (NGS; cut-offs, 10-4, 10-5,10-6). Results: 432 pts were enrolled; 216 in each treatment group (intent-to-treat population). After 29 mo median follow-up, superior PFS was observed with VenG vs ClbG (HR 0.35; 95% CI 0.23–0.53; P<0.0001). MRD− by ASO-PCR was significantly higher with VenG vs ClbG in both PB (76% vs 35% [P<0.0001]) and BM (57% vs 17% [P<0.0001]) 3 mo after treatment completion. Overall, 75% of VenG MRD-negative pts in PB were also MRD-negative in BM vs 49% in the ClbG group. Landmark analysis for this timepoint by PB MRD status showed that MRD− was associated with longer PFS. Higher MRD− rates were achieved early and were more sustainable with VenG: 81% (VenG) vs 27% (ClbG) of pts were MRD-negative 12 mo after treatment completion; HR for MRD conversion 0.19; 95% CI 0.12–0.30 (median time off-treatment: 19 mo). MRD− rates by NGS confirmed these results; 78% (VenG) vs 34% (ClbG) of pts had MRD− at <10-4, 31% vs 4% at <10-6 and 35% vs 15% at ≥10-6–<10-5, respectively. Conclusions: Fixed-duration VenG induced deep (<10-6 in 1/3 of pts), high, and long lasting MRD− rates (with a low rate of conversion to MRD+ status 1 year after treatment) in previously untreated pts with CLL and comorbidities, translating into improved PFS. Clinical trial information: NCT02242942.

scholarly journals Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study

Leukemia ◽  
2020 ◽  
Vol 34 (7) ◽  
pp. 1875-1884 ◽  
Author(s):  
Nizar J. Bahlis ◽  
Meletios A. Dimopoulos ◽  
Darrell J. White ◽  
Lotfi Benboubker ◽  
Gordon Cook ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Refractory Multiple Myeloma ◽  
Open Label Phase ◽  
Intent To Treat ◽  
Line Of Therapy

Abstract In POLLUX, daratumumab (D) plus lenalidomide/dexamethasone (Rd) reduced the risk of disease progression or death by 63% and increased the overall response rate (ORR) versus Rd in relapsed/refractory multiple myeloma (RRMM). Updated efficacy and safety after >3 years of follow-up are presented. Patients (N = 569) with ≥1 prior line received Rd (lenalidomide, 25 mg, on Days 1–21 of each 28-day cycle; dexamethasone, 40 mg, weekly) ± daratumumab at the approved dosing schedule. Minimal residual disease (MRD) was assessed by next-generation sequencing. After 44.3 months median follow-up, D-Rd prolonged progression-free survival (PFS) in the intent-to-treat population (median 44.5 vs 17.5 months; HR, 0.44; 95% CI, 0.35–0.55; P < 0.0001) and in patient subgroups. D-Rd demonstrated higher ORR (92.9 vs 76.4%; P < 0.0001) and deeper responses, including complete response or better (56.6 vs 23.2%; P < 0.0001) and MRD negativity (10–5; 30.4 vs 5.3%; P < 0.0001). Median time to next therapy was prolonged with D-Rd (50.6 vs 23.1 months; HR, 0.39; 95% CI, 0.31–0.50; P < 0.0001). Median PFS on subsequent line of therapy (PFS2) was not reached with D-Rd versus 31.7 months with Rd (HR, 0.53; 95% CI, 0.42–0.68; P < 0.0001). No new safety concerns were reported. These data support using D-Rd in patients with RRMM after first relapse.

4-Jahres-Update der Murano-Studie bestätigt den Stellenwert von Venetoclax in der 2. Therapielinie der CLL

2021 ◽  
pp. 77-79
Author(s):  
Maximilian Schmutz ◽  
Sebastian Sommer
Keyword(s):  
Response Rate ◽  
Residual Disease ◽  
Gene Mutations ◽  
Progression Free Survival ◽  
Lymphocytic Leukemia ◽  
Fixed Duration ◽  
Genetic Characteristics ◽  
Genomic Complexity ◽  
End Of Treatment

<b>Purpose:</b> In previous analyses of the MURANO study, fixed-duration venetoclax plus rituximab (VenR) resulted in improved progression-free survival (PFS) compared with bendamustine plus rituximab (BR) in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). At the 4-year follow-up, we report long-term outcomes, response to subsequent therapies, and the predictive value of molecular and genetic characteristics. <b>Patients and methods:</b> Patients with CLL were randomly assigned to 2 years of venetoclax (VenR for the first six cycles) or six cycles of BR. PFS, overall survival (OS), peripheral-blood minimal residual disease (MRD) status, genomic complexity (GC), and gene mutations were assessed. <b>Results:</b> Of 389 patients, 194 were assigned to VenR and 195 to BR. Four-year PFS and OS rates were higher with VenR than BR, at 57.3% and 4.6% (hazard ratio [HR], 0.19; 95% CI, 0.14 to 0.25), and 85.3% and 66.8% (HR, 0.41; 95% CI, 0.26 to 0.65), respectively. Undetectable MRD (uMRD) at end of combination therapy (EOCT) was associated with superior PFS compared with low MRD positivity (HR, 0.50) and high MRD positivity (HR, 0.15). Patients in the VenR arm who received ibrutinib as their first therapy after progression (n = 12) had a reported response rate of 100% (10 of 10 evaluable patients); patients subsequently treated with a venetoclax-based regimen (n = 14) had a reported response rate of 55% (six of 11 evaluable patients). With VenR, the uMRD rate at end of treatment (EOT) was lower in patients with GC than in those without GC (<i>P</i> = 0.042); higher GC was associated with shorter PFS. Higher MRD positivity rates were seen with <i>BIRC3</i> and <i>BRAF</i> mutations at EOCT and with <i>TP53, NOTCH1, XPO1,</i> and <i>BRAF</i> mutations at EOT. <b>Conclusion:</b> Efficacy benefits with fixed-duration VenR are sustained and particularly durable in patients who achieve uMRD. Salvage therapy with ibrutinib after VenR achieved high response rates. Genetic mutations and GC affected MRD rates and PFS. <b>Trial registration:</b> ClinicalTrials.gov NCT02005471.

scholarly journals Randomised, open-label, phase II study of gemcitabine with and without IMM-101 for advanced pancreatic cancer

2016 ◽  
Vol 115 (7) ◽  
pp. 789-796 ◽  
Author(s):  
Angus G Dalgleish ◽  
Justin Stebbing ◽  
Douglas JA Adamson ◽  
Seema Safia Arif ◽  
Paolo Bidoli ◽  
...  
Keyword(s):  
Phase Ii ◽  
Immune Modulation ◽  
Advanced Pancreatic Cancer ◽  
Progression Free Survival ◽  
Similar Rate ◽  
Adverse Event Reporting ◽  
Ductal Adenocarcinoma ◽  
Open Label ◽  
Open Label Phase ◽  
Intent To Treat

Abstract Background: Immune Modulation and Gemcitabine Evaluation-1, a randomised, open-label, phase II, first-line, proof of concept study (NCT01303172), explored safety and tolerability of IMM-101 (heat-killed Mycobacterium obuense; NCTC 13365) with gemcitabine (GEM) in advanced pancreatic ductal adenocarcinoma. Methods: Patients were randomised (2 : 1) to IMM-101 (10 mg ml−l intradermally)+GEM (1000 mg m−2 intravenously; n=75), or GEM alone (n=35). Safety was assessed on frequency and incidence of adverse events (AEs). Overall survival (OS), progression-free survival (PFS) and overall response rate (ORR) were collected. Results: IMM-101 was well tolerated with a similar rate of AE and serious adverse event reporting in both groups after allowance for exposure. Median OS in the intent-to-treat population was 6.7 months for IMM-101+GEM v 5.6 months for GEM; while not significant, the hazard ratio (HR) numerically favoured IMM-101+GEM (HR, 0.68 (95% CI, 0.44–1.04, P=0.074). In a pre-defined metastatic subgroup (84%), OS was significantly improved from 4.4 to 7.0 months in favour of IMM-101+GEM (HR, 0.54, 95% CI 0.33–0.87, P=0.01). Conclusions: IMM-101 with GEM was as safe and well tolerated as GEM alone, and there was a suggestion of a beneficial effect on survival in patients with metastatic disease. This warrants further evaluation in an adequately powered confirmatory study.

Translational research (TR) results from pointbreak: A randomized, open-label, phase III study of pemetrexed (Pem)+carboplatin (Cb)+bevacizumab (Bev) followed by maintenance pem+bev (Pem Arm) versus paclitaxel (Pac)+cb+bev followed by maintenance bev (Pac Arm) in patients (pts) with stage IIIB or IV nonsquamous non-small cell lung cancer (ns-NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8086-8086 ◽  
Author(s):  
Edward B. Garon ◽  
Jyoti D. Patel ◽  
Scott Myrand ◽  
Tuan Nguyen ◽  
Craig H. Reynolds ◽  
...  
Keyword(s):  
Folate Receptor ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Egfr Mutations ◽  
Open Label ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Open Label Phase ◽  
Intent To Treat

8086 Background: Results of PointBreak were previously reported. Correlative tissue TR results are presented. Methods: Of 939 pts in the intent-to-treat population (ITT), 211 (22.5%) signed TR consent forms and had evaluable samples. Specimens were analyzed for: Epidermal Growth Factor Receptor (EGFR) mutations by polymerase chain reaction (n=132); thyroid transcription factor-1 (TTF-1) (n=205), thymidylate synthase (TS) (n=189), and folate receptor-alpha (FR-α) (n=180) by immunohistochemistry (IHC) (H-scores range, 0-300). H scores were dichotomized based on positive (>0)/negative (=0) cutpoint. Adjusted Cox/logistic regression determined correlations between overall survival (OS), progression-free survival (PFS), response rate (RR), and dichotomous IHC markers. A 2-sided test with α = 0.05 and 0.1 evaluated treatment and interaction effects, respectively. Results: Median (m) OS and mPFS were similar in the ITT and TR populations for both arms. 11/132 (8.3%) pts had activating EGFR mutations. For TS or FR-α, no significant between-arm differences in OS, PFS and RR were seen. 139/205 (67.8%) pts had positive TTF-1 (TTF-1+). TTF-1+ pts, compared with TTF-1-, independent of treatment, had significantly longer mOS (14.9 vs 8.7 mos, HR 0.48, p<0.001), mPFS (6.9 vs 4.5 mos, HR 0.62, p=0.006), and higher RR (38.9% vs 19.7%, OR 2.68, p=0.008). For TTF-1+ pts, compared with Pac arm, Pem arm had longer mOS (17.6 vs 12.8 mos, HR=0.7, p=0.08; interaction p=0.12) and mPFS (7.3 vs 5.8 mos, HR=0.78, p=0.20; interaction p=0.261); although not statistically significant. Conclusions: The number of pts with EGFR mutations was too small to draw conclusions. No significant between-arm differences for TS and FR-α were seen. Longer survival in TTF-1+ pts suggests TTF-1 expression is prognostic. Additional studies will be needed to better understand trends favoring pem for survival among TTF-1+ pts and other prognostic and/or predictive relationships of these markers. Clinical trial information: NCT00762034.

scholarly journals Consolidation Therapy With Subcutaneous Alemtuzumab After Fludarabine and Rituximab Induction Therapy for Previously Untreated Chronic Lymphocytic Leukemia: Final Analysis of CALGB 10101

2010 ◽  
Vol 28 (29) ◽  
pp. 4500-4506 ◽  
Author(s):  
Thomas S. Lin ◽  
Kathleen A. Donohue ◽  
John C. Byrd ◽  
Margaret S. Lucas ◽  
Eva E. Hoke ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Serious Infections ◽  
Listeria Meningitis ◽  
Intent To Treat

PurposeTo determine if alemtuzumab consolidation improves response rate and progression-free survival (PFS) after induction chemoimmunotherapy in previously untreated symptomatic patients with chronic lymphocytic leukemia.Patients and MethodsPatients (n = 102) received fludarabine 25 mg/m2intravenously days 1 to 5 and rituximab 50 mg/m2day 1, 325 mg/m2day 3, and 375 mg/m2day 5 of cycle 1 and then 375 mg/m2day 1 of cycles 2 to 6; fludarabine plus rituximab (FR) administration was repeated every 28 days for six cycles. Three months after completion of FR, patients with stable disease or better response received subcutaneous alemtuzumab 3 mg day 1, 10 mg day 3, and 30 mg day 5 and then 30 mg three times per week for 5 weeks.ResultsOverall response (OR), complete response (CR), and partial response (PR) rates were 90%, 29%, and 61% after FR, respectively; 15% of patients were minimal residual disease (MRD) negative. Of 102 patients, 58 received alemtuzumab; 28 (61%) of 46 patients achieving PR after FR attained CR after alemtuzumab. By intent to treat (n = 102), OR and CR rates were 90% and 57% after alemtuzumab, respectively; 42% of patients became MRD negative. With median follow-up of 36 months, median PFS was 36 months, 2-year PFS was 72%, and 2-year OS was 86%. In patients achieving CR after FR, alemtuzumab was associated with five deaths resulting from infection (viral and Listeria meningitis and Legionella, cytomegalovirus, and Pneumocystis pneumonias), which occurred up to 7 months after last therapy. The study was amended to exclude CR patients from receiving alemtuzumab.ConclusionAlemtuzumab consolidation improved CR and MRD-negative rates after FR induction but caused serious infections in patients who had already achieved CR after induction and did not improve 2-year PFS or survival.

scholarly journals Ibrutinib plus obinutuzumab as frontline therapy for chronic lymphocytic leukemia is associated with a lower rate of infusion-related reactions and with sustained remissions after ibrutinib discontinuation: a single-arm, open-label, phase 1b/2 clinical trial NCT0231576

2021 ◽  
Author(s):  
Januario E. Castro ◽  
Paula A. Lengerke-Diaz ◽  
Juliana Velez-Lujan ◽  
Michale Y. Choi ◽  
Eider F. Moreno-Cortes ◽  
...  
Keyword(s):  
Residual Disease ◽  
Single Agent ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Open Label ◽  
Continuous Administration ◽  
Open Label Phase ◽  
Phase 1B ◽  
Treatment Safety ◽  
Anti Cd20

Abstract Ibrutinib-based therapies are costly and require continuous administration. We hypothesized combining BTK inhibition with anti-CD20 monoclonal antibodies would yield deep remissions allowing discontinuation. We enrolled 32 therapy-naïve CLL patients to receive ibrutinib plus obinutuzumab, followed by single-agent ibrutinib. Patients could discontinue ibrutinib after 36 months with sustained complete response (CR). We evaluated treatment safety, efficacy, and outcomes after ibrutinib discontinuation. The overall response rate was 100%, 28% achieved a CR, and 12.5% achieved bone marrow undetectable minimal residual disease. At a three-year median follow-up, 91% remain in remission with 100% overall survival. Five patients in sustained CR stopped ibrutinib and have not progressed. Eight non-CR patients discontinued for other reasons, with only two progressing. The treatment was safe, with a lower IRR rate. All patients responded to treatment with longer time-to-progression after discontinuation of ibrutinib. Our data support the evaluation of ibrutinib discontinuation strategies in more extensive clinical trials.

scholarly journals Glembatumumab vedotin for patients with metastatic, gpNMB overexpressing, triple-negative breast cancer (“METRIC”): a randomized multicenter study

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Linda T. Vahdat ◽  
Peter Schmid ◽  
Andres Forero-Torres ◽  
Kimberly Blackwell ◽  
Melinda L. Telli ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Primary Endpoint ◽  
Triple Negative ◽  
Progression Free Survival ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Common Grade ◽  
Open Label Phase ◽  
Grade 3

AbstractThe METRIC study (NCT#0199733) explored a novel antibody–drug conjugate, glembatumumab vedotin (GV), targeting gpNMB that is overexpressed in ~40% of patients with triple-negative breast cancer (TNBC) and associated with poor prognosis. The study was a randomized, open-label, phase 2b study that evaluated progression-free survival (PFS) of GV compared with capecitabine in gpNMB-overexpressing TNBC. Patients who had previously received anthracycline and taxane-based therapy were randomized 2:1 to receive, GV (1.88 mg/kg IV q21 days) or capecitabine (2500 mg/m2 PO daily d1–14 q21 days). The primary endpoint was RECIST 1.1 PFS per independent, blinded central review. In all, 327 patients were randomized to GV (213 treated) or capecitabine (92 treated). Median PFS was 2.9 months for GV vs. 2.8 months for capecitabine. The most common grade ≥3 toxicities for GV were neutropenia, rash, and leukopenia, and for capecitabine were fatigue, diarrhea, and palmar-plantar erythrodysesthesia. The study did not meet the primary endpoint of improved PFS over capecitabine or demonstrate a relative risk/benefit improvement over capecitabine.

Daratumumab (DARA) maintenance or observation (OBS) after treatment with bortezomib, thalidomide and dexamethasone (VTd) with or without DARA and autologous stem cell transplant (ASCT) in patients (pts) with newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 2.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 8004-8004
Author(s):  
Philippe Moreau ◽  
Pieter Sonneveld ◽  
Keyword(s):  
Interim Analysis ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Autologous Stem Cell Transplant ◽  
Second Primary ◽  
Cell Transplant ◽  
Open Label ◽  
Depth Of Response

8004 Background: D-VTd plus ASCT was approved for transplant-eligible (TE) NDMM based on part 1 of CASSIOPEIA. We report a prespecified interim analysis of CASSIOPEIA part 2: DARA maintenance vs OBS in pts with ≥partial response (PR) in part 1, regardless of induction/consolidation (ind/cons) treatment. Methods: CASSIOPEIA is a 2-part, randomized, open-label, phase 3 study in TE NDMM. Pts received 4 cycles ind and 2 cycles cons with D-VTd or VTd. 886 pts who achieved ≥PR were rerandomized to DARA 16 mg/kg IV Q8W for up to 2 yr (n = 442) or OBS (n = 444) until progressive disease per IMWG. Pts were stratified by ind (D-VTd vs VTd) and depth of response (minimum residual disease [MRD] status and post cons response ≥PR). Primary endpoint was progression-free survival (PFS) after second randomization. This interim analysis assessed efficacy and safety after 281 PFS events. A preplanned hierarchical procedure tested key secondary endpoints: time to progression (TTP), ≥complete response (CR), MRD negativity rates by NGS and overall survival (OS). Results: At median follow-up of 35.4 mo, median PFS was not reached (NR) with DARA and 46.7 mo with OBS (HR 0.53; 95% CI 0.42–0.68; P <0.0001). PFS advantage for DARA was consistent across most subgroups. However, a prespecified analysis showed significant interaction with ind/cons treatment arm ( P< 0.0001). PFS HR for DARA vs OBS was 0.32 (95% CI 0.23–0.46) in the VTd arm and 1.02 (0.71–1.47) in the D-VTd arm. Median TTP was NR for DARA vs 46.7 mo for OBS (HR 0.49; 95% CI 0.38–0.62; P <0.0001). More pts in the DARA vs OBS arm achieved ≥CR (72.9% vs 60.8%; OR 2.17; 95% CI 1.54–3.07; P <0.0001). MRD negativity (in ≥CR pts at 10-5) was 58.6% with DARA vs 47.1% with OBS (OR 1.80; 95% CI 1.33–2.43; P= 0.0001). Median OS was NR in either arm. Most common (≥2.5%) grade 3/4 adverse events (AEs) with DARA vs OBS were pneumonia (2.5% vs 1.4%), lymphopenia (3.6% vs 1.8%), and hypertension (3.0% vs 1.6%). Serious AEs occurred in 22.7% (DARA) vs 18.9% (OBS) of pts; the most common (≥2.5%) was pneumonia (2.5% vs 1.6%). 13 (3.0%) pts discontinued DARA due to an AE. The rate of infusion-related reactions was 54.5% (DARA-naïve pts) and 2.2% (prior DARA pts); 90% were grade 1/2.Second primary malignancies occurred in 5.5% (DARA) vs 2.7% (OBS) of pts. Conclusions: CASSIOPEIA part 2 demonstrated a clinical benefit of DARA maintenance in TE NDMM pts, with significantly longer PFS for DARA vs OBS. With current follow-up, maintenance PFS benefit appeared only in pts treated with VTd as ind/cons. Pts who received D-VTd ind/cons with or without DARA maintenance achieved similar PFS; longer follow-up is needed for PFS2 and OS. DARA significantly increased deeper response and MRD negativity rates vs OBS, and was well tolerated with no new safety signals. Clinical trial information: NCT02541383.

scholarly journals First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase 3 iLLUMINATE trial

Haematologica ◽  
2022 ◽  
Author(s):  
Carol Moreno ◽  
Richard Greil ◽  
Fatih Demirkan ◽  
Alessandra Tedeschi ◽  
Bertrand Anz ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Final Analysis ◽  
Lymphocytic Leukemia ◽  
Small Lymphocytic Lymphoma ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
First Line Therapy ◽  
Line Therapy ◽  
Open Label Phase

iLLUMINATE is a randomized, open-label phase 3 study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or

Silmitasertib (CX-4945) in combination with gemcitabine and cisplatin as first-line treatment for patients with locally advanced or metastatic cholangiocarcinoma: A phase Ib/II study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 312-312
Author(s):  
Mitesh J. Borad ◽  
Li-Yuan Bai ◽  
Ming-Huang Chen ◽  
Joleen M. Hubbard ◽  
Kabir Mody ◽  
...  
Keyword(s):  
Phase Ii ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Preliminary Evidence ◽  
Phase Iii ◽  
Response To Treatment ◽  
Open Label ◽  
Phase Ib ◽  
Open Label Phase ◽  
Almost All

312 Background: Silmitasertib (CX-4945), an oral small molecule inhibitor of casein kinase 2 (CK2), has exhibited preclinical antitumor activity and strong synergism with gemcitabine + cisplatin. We investigated the safety and efficacy of silmitasertib in combination with gemcitabine + cisplatin in patients with unresectable cholangiocarcinoma (CCA). Methods: S4-13-001 is a multicenter, open-label, phase Ib/II study of silmitasertib in combination with gemcitabine + cisplatin in patients with locally advanced or metastatic CCA. The phase Ib portion included dose-escalation, expansion, and exploratory cohorts of silmitasertib with doses ranging from 200 to 1000 mg bid (6 days for the escalation/expansion cohorts and 10 and 21 days’ continuous dosing for the exploratory cohorts). In the phase II portion patients received silmitasertib 1000 mg bid for 10 days in combination with gemcitabine + cisplatin on days 1 & 8 over a 21-day cycle. In this interim analysis, we present findings from the combined population of patients from the phase Ib and II portions of the study. Response to treatment was assessed by RECIST v1.1 every 6 weeks. Primary efficacy outcome measure was progression-free survival (PFS). ClinicalTrials.gov (NCT02128282). Results: A total of 87 patients were enrolled and received silmitasertib in the phase Ib (n=50) and phase II (n=37) portions of the study. Of these, 55 patients were evaluable for efficacy with details as follows: median PFS 11.1 (95% CI 7.6–14.7) months; median overall survival (OS) 17.4 (95% CI 13.4–25.7) months; overall response rate (ORR) 32.1%; and disease control rate (DCR) 79.3%. Almost all patients (79/87; 90.8%) evaluable for safety reported ≥1 treatment-related adverse event (TEAE). The most common TEAEs (all grades) with silmitasertib were diarrhea (65.5%), nausea (50.6%), vomiting (33.3%), fatigue (31.0%), and anemia (21.8%). The most common grade ≥3 TEAEs were diarrhea (13.8%), neutropenia (11.5%), nausea (9.2%), anemia (8.0%), and thrombocytopenia (8.0%). Eleven patients (12.6%) discontinued treatment due to TEAEs. Conclusions: Silmitasertib in combination with gemcitabine + cisplatin yields promising preliminary evidence of efficacy in patients with locally advanced or metastatic CCA. Based on these data a randomized phase III trial is planned. Clinical trial information: NCT02128282.

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