Efficacy and safety of epacadostat plus pembrolizumab treatment of NSCLC: Preliminary phase I/II results of ECHO-202/KEYNOTE-037.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9014-9014 ◽  
Author(s):  
Tara C. Gangadhar ◽  
Bryan J. Schneider ◽  
Todd Michael Bauer ◽  
Jeffrey S. Wasser ◽  
Alexander I. Spira ◽  
...  
Keyword(s):  
Phase 1 ◽  
Phase 2 ◽  
Test Results ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase ◽  
History Of ◽  
Grade 3 ◽  
Preliminary Phase ◽  
Clinical Trial Information

9014 Background: ECHO-202/KEYNOTE-037 is an open-label, phase 1/2 study of epacadostat (a potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus pembrolizumab (E + P) in patients (pts) with advanced tumors. We report preliminary efficacy and safety outcomes for the phase 1/2 NSCLC cohort. Methods: Adult pts with prior platinum-based therapy (tx) and no prior checkpoint inhibitor tx were eligible. Phase 1 dose-escalation tx was E (25, 50, 100, 300 mg PO BID) + P (2 mg/kg or 200 mg IV Q3W); MTD was not exceeded. E (100 mg BID) + P (200 mg Q3W) tx doses were selected for phase 2 cohort expansion. Efficacy was evaluated by tumor proportion score (TPS [% viable tumor cells, PD-L1 staining]: < 50% and ≥50%) and by prior lines of tx in RECIST 1.1 evaluable pts. Safety was assessed in pts receiving ≥1 E + P dose. Results: As of 29OCT2016,43 pts (phase 1, n = 12; phase 2, n = 31) were evaluated. Median age was 65 years, 58% of pts were women, 12% were EGFR-positive, and 23% were KRAS-positive. Most pts had a history of smoking (84%), ≤2 prior lines of tx (84%), and no prior TKI tx (93%). For the 40 efficacy-evaluable pts, ORR (CR+PR) and DCR (CR+PR+SD) were 35% (14/40; 14 PR) and 60% (24/40; 10 SD), respectively. PD-L1 TPS test results were available in 28/40 efficacy-evaluable pts. ORR and DCR for pts with TPS ≥50% and ≤2 prior tx were 43% (3/7; all PR) and 57% (4/7; 1 SD), respectively; for pts with TPS < 50% and ≤2 prior tx, ORR and DCR were 35% (6/17; all PR) and 53% (9/17; 3 SD). Among the 40 efficacy-evaluable pts, 12/14 responses were ongoing (range, 1+ to 519 days) at data cutoff. PFS and biomarker analyses are ongoing. Across all 43 pts, most frequent TRAEs were fatigue (19%), arthralgia (9%), and increased AST (9%); 16% of pts had grade ≥3 TRAEs, and increased lipase (asymptomatic) was the only grade ≥3 TRAE that occurred in > 1 pt (n = 2). Two pts discontinued due to TRAEs (grade 3 increased AST, grade 2 increased ALT [n = 1]; grade 2 brain edema [n = 1]). Conclusions: E + P was generally well tolerated and associated with promising responses in pts with NSCLC. A phase 3 NSCLC study is planned. Clinical trial information: NCT02178722.

Epacadostat plus nivolumab in patients with advanced solid tumors: Preliminary phase I/II results of ECHO-204.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3003-3003 ◽  
Author(s):  
Raymond P. Perez ◽  
Matthew John Riese ◽  
Karl D. Lewis ◽  
Mansoor N. Saleh ◽  
Adil Daud ◽  
...  
Keyword(s):  
Phase 1 ◽  
Open Label ◽  
Common Grade ◽  
Open Label Phase ◽  
Study Population ◽  
N Dose ◽  
Grade 3 ◽  
Tumor Types ◽  
Preliminary Phase ◽  
Clinical Trial Information

3003 Background: ECHO-204 is an ongoing, open-label, phase 1/2 (P1/2) study of epacadostat (E; potent and selective oral inhibitor of the immunosuppressive enzyme indoleamine 2,3-dioxygenase 1) plus PD-1 inhibitor nivolumab (N) in patients (pts) with advanced cancers (NSCLC, MEL, OVC, CRC, SCCHN, B-cell NHL [including DLBCL], GBM). Preliminary P1/2 safety and tolerability outcomes for the overall study population and P2 response for select tumor types (SCCHN, MEL, OVC, CRC) are reported. Methods: In P1 dose escalation, pts received E (25, 50, 100, 300 mg BID) + N (3 mg/kg Q2W); in P2 cohort expansion, pts received E (100 or 300 mg BID) + N (240 mg Q2W). Safety/tolerability was assessed in pts receiving ≥1 E + N dose. Response was assessed in RECIST v1.1 evaluable pts; for recently enrolled pt subgroups, only preliminary DCR (CR+PR+SD) is presented. Results: As of 29OCT2016,241 pts (P1, n = 36; P2, n = 205) were enrolled. No DLT was observed in P1. Most common TRAEs (≥15%) in pts treated with E 100 mg (n = 70) and E 300 mg (n = 135) were rash (33% and 22%, respectively), fatigue (26% and 31%), and nausea (24% and 19%). Rash was the most common grade ≥3 TRAE in E 100 mg and E 300 mg subgroups (10% and 12%). TRAEs led to discontinuation in 7% (E 100 mg) and 13% (E 300 mg) of pts. There were no TR-deaths. For the 23 recently enrolled, efficacy-evaluable SCCHN pts treated with E 300 mg, preliminary DCR was 70% (n = 16). Of 30 MEL pts, 8 were treated with E 100 mg and 22 were more recently enrolled and treated with E 300 mg. ORR (CR+PR) and DCR in MEL pts treated with E 100 mg were 75% (n = 6; all PR) and 100% (n = 8; 2 SD), respectively. Preliminary DCR in MEL pts treated with E 300 mg was 64% (n = 14). Of 29 OVC pts, 18 were treated with E 100 mg and 11 with E 300 mg.ORR and DCR for OVC pts treated with E 100 mg were 11% (n = 2; 2 PR) and 28% (n = 5; 3 SD); for 11 OVC pts treated with E 300 mg, ORR and DCR were 18% (n = 2; 2 PR) and 36% (n = 4; 2 SD).For 25 CRC pts (all E 100 mg), ORR and DCR were 4% (n = 1; PR) and 24% (n = 6; 5 SD).Safety/efficacy evaluations are ongoing for all cohorts. Conclusions: E + N was generally well tolerated up to the maximum E 300-mg dose. P2 ORR/DCR outcomes are promising, particularly in SCCHN and MEL pts. Updated data will be presented at the meeting. Clinical trial information: NCT02327078.

Efficacy/safety of epacadostat plus pembrolizumab in triple-negative breast cancer and ovarian cancer: Phase I/II ECHO-202 study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1103-1103 ◽  
Author(s):  
Alexander I. Spira ◽  
Omid Hamid ◽  
Todd Michael Bauer ◽  
Virginia F. Borges ◽  
Jeffrey S. Wasser ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Phase 1 ◽  
Open Label ◽  
Biomarker Analysis ◽  
Open Label Phase ◽  
Grade 3 ◽  
Clinical Trial Information

1103 Background: Epacadostat is an oral, potent, and selective inhibitor of indoleamine 2,3-dioxygenase 1, a tryptophan-catabolizing enzyme that induces immune tolerance via T-cell suppression and is associated with poor patient (pt) survival when overexpressed in some cancers. The ongoing, open-label, phase 1/2 (P1/2) ECHO-202/KEYNOTE-037 study is evaluating the efficacy, safety, and tolerability of epacadostat plus PD-1 inhibitor pembrolizumab (E + P) in pts with advanced/recurrent cancers. We report P1/2 study outcomes for triple-negative breast cancer (TNBC) pts and P2 outcomes for ovarian cancer (OVC; no P1) pts as of a 29OCT2016 data cutoff. Methods: Eligible pts were ≥18 years old with no prior checkpoint inhibitor treatment (tx); prior platinum/taxane tx was required for OVC pts. As part of P1 dose escalation, TNBC pts received E (300 mg BID) + P (200 mg Q3W). In P2, TNBC and OVC pts received E (100 mg BID) + P (200 mg Q3W). Response (RECIST v1.1) was assessed in evaluable pts. Safety and tolerability were assessed in pts with ≥1 dose of E + P. Results: A total of 39 pts with TNBC and 37 with OVC were enrolled. The majority of TNBC pts (56%, n = 22) and OVC pts (78%, n = 29) received ≥3 prior lines of tx. For TNBC pts, ORR (CR+PR) was 10% (n = 4; all PR) and DCR (CR+PR+SD) was 36% (n = 14; 10 SD); ORR and DCR for pts with ≤2 prior tx were 12% (n = 2) and 29% (n = 5), respectively, and for ≥3 prior tx were 9% (n = 2) and 41% (n = 9). For OVC pts, ORR was 8% (n = 3; all PR) and DCR was 35% (n = 13; 10 SD); ORR and DCR for pts with ≤2 prior tx were 13% (n = 1) and 25% (n = 2), and for ≥3 prior tx were 7% (n = 2) and 38% (n = 11). The most common TRAEs (≥15% of pts) were rash (18%), fatigue (15%), and nausea (15%) in the 39 TNBC pts, and fatigue (19%) in the 37 OVC pts. Grade ≥3 TRAEs occurred in 13% of TNBC pts (n = 5; none in > 1 pt) and 19% of OVC pts (n = 7; only rash occurred in > 1 pt [n = 3]). TRAEs led to discontinuation in 1 TNBC pt (grade 3 ascites) and 1 OVC pt (grade 2 arthralgia). Conclusions: E + P tx was generally well tolerated and showed antitumor activity consistent with previously reported P monotherapy in pts with advanced TNBC or OVC. Biomarker analysis is ongoing to characterize pt populations enrolled in this study. Clinical trial information: NCT02178722.

scholarly journals ACTR-59. A PHASE 1 STUDY OF BPM31510 PLUS VITAMIN K IN SUBJECTS WITH HIGH-GRADE GLIOMA THAT HAS RECURRED ON A BEVACIZUMAB-CONTAINING REGIMEN

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi27-vi27
Author(s):  
Lawrence Recht ◽  
Reena Thomas ◽  
Sophie Bertrand ◽  
Priya Yerballa ◽  
Gordon Li ◽  
...  
Keyword(s):  
Phase I ◽  
Vitamin K ◽  
Phase I Study ◽  
Phase 1 ◽  
High Grade Glioma ◽  
High Grade ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

Abstract BACKGROUND High-grade gliomas (HGG) are characterized by dysregulated metabolism, utilizing glycolysis for energy production to support unrestricted growth. BPM 31510, an ubidecarenone (coenzyme Q10) containing lipid nanodispersion, causes a switch in cancer energy sourcing from glycolysis towards mitochondrial oxidative phosphorylation in vitro, reversing the Warburg effect and suggesting potential as an anti-tumor agent. The current study is a phase I study of BPM31510 + vitamin K in GB with tumor growth after bevacizumab (BEV). METHODS This is an open-label phase I study of BPM31510 continuous infusion with weekly vitamin K (10mg IM) in HGG patients using an mTPI design, starting at 110mg/kg, allowing for a single dose de-escalation and 2 dose-escalations. Patients had received first-line ChemoRadiation and were in recurrence following a BEV containing regimen. RESULTS 9 eligible and evaluable patients completed the 28 day DLT period. 8 patients had primary GB, 1 had anaplastic astrocytoma with confirmed pathologic transformation to GB. Median age was 55 years (27–67) and median KPS 70 (60–90) at enrollment. 4 patients were treated at the highest dose 171mg/kg, where there was a single DLT: Grade 3 AST & ALT. The most common grade 1–2 AEs possibly, probably or definitely related to drug were elevated AST, rash, and fatigue, each occurring in 3 patients. Median OS for 9 eligible/evaluable patients was 128 days (95% CI: 48–209) while PFS was 34 days (CI of mean 8.9). 3 patients are currently alive; 2 patients have survived >1 year. PK/PD data are being processed and will be presented. CONCLUSION This study confirms that BPM 31510 + vitamin K is safe and feasible in treatment-refractory HGG patients. Though this study demonstrates safety at 171mg/kg, the proposed dose for future studies in GB, based on additional pre-clinical and non-GB clinical data is 88mg/kg.

Efficacy and safety of burosumab in children aged 1–4 years with X-linked hypophosphataemia: a multicentre, open-label, phase 2 trial

2019 ◽  
Vol 7 (3) ◽  
pp. 189-199 ◽  
Author(s):  
Michael P Whyte ◽  
Thomas O Carpenter ◽  
Gary S Gottesman ◽  
Meng Mao ◽  
Alison Skrinar ◽  
...  
Keyword(s):  
Phase 2 ◽  
Efficacy And Safety ◽  
Open Label ◽  
Phase 2 Trial ◽  
Open Label Phase

Phase 1/2 Trial Of Lenalidomide In Combination With Cyclophosphamide and Prednisone (REP) In Patients With Lenalidomide-Refractory Multiple Myeloma (REPEAT-study)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 287-287 ◽  
Author(s):  
Inger S. Nijhof ◽  
Sonja Zweegman ◽  
Mark-David Levin ◽  
Harry R. Koene ◽  
Aart Beeker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Dose Level ◽  
Research Funding ◽  
Phase 1 ◽  
Oral Cyclophosphamide ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Grade 3 ◽  
Dose Levels

Abstract Background The outcome of multiple myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide (LEN) and bortezomib (BORT) is very poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012; 26;149-157). We have previously shown in a small retrospective study that the combination of continuous low dose oral cyclophosphamide (endoxan) and prednisone combined with lenalidomide (REP) had remarkable activity in heavily pretreated LEN-refractory multiple myeloma patients (median 6 lines of previous chemotherapy) (vd Donk et al; Br J Haematol 2010;148(2):335-7). To determine the optimal dose of lenalidomide with continuous cyclophosphamide and prednisone, we initiated a prospective study to evaluate the maximum tolerated dose (MTD) of the REP regimen and to assess its efficacy and safety in LEN-refractory MM patients. Here we report safety and efficacy data from the phase 1 dose-escalation part of the REPEAT-study (NCT01352338). Patients and Methods Patients aged ≥ 18 years with LEN-refractory MM, ECOG-performance status 0-3 and adequate kidney, liver and hematologic function were included. Five dose levels were evaluated using a standard 3+3 design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Patients received LEN in doses ranging from 10-25 mg/day on days 1-21 of 28-day cycle, while oral cyclophosphamide (50 or 100 mg) and prednisone (20 mg) were given continuously. Therapy was continued until progression. The MTD for the phase 2 part is defined as the highest dose level with 0 or 1 DLT's observed in 6 patients. Results Up till now, 35 patients were enrolled (22 in phase 1 and 13 in phase 2) from August 2011 to June 2013. The phase 2 part is still recruiting and data are not evaluable yet. One patient in phase 1 was excluded because of study violation and is not included in the analysis. The median age of the 21 evaluable patients in phase 1 was 69 years (range 41-73); 76% were male. The median duration of the disease from diagnosis was 41 months (range 18-96), median number of prior therapies was 3 (range 2-6), and 12 patients (57%) had previously received autologous SCT. All patients were LEN-refractory, 19 (90%) had prior BORT treatment, and 16 (76%) had BORT-refractory MM. Fifty-five % of the patients were considered high risk by FISH. At the time of analysis, 16 of 21 patients in phase 1 have discontinued treatment because of disease progression (13), alternative treatment (allo-SCT) (1), or adverse events (2). The MTD was defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously (dose level 4), based on three patients experiencing a DLT: two developed pneumonia (in dose levels 4 and 5; CTC grade 3), and one patient at dose level 5 experienced CTC grade 3 dyspnea. Neutropenia (18%) and thrombocytopenia (18%) were the most common grade 3 hematological adverse events (AEs), which were managed with growth factor support and/or dose modification. There were no grade 4 hematologic AEs. Grade 3 respiratory tract infections (29%) and grade 2 fatigue (19%) were the most common non-hematological AEs. Venous thromboembolism occurred in 1 patient. Figure 1 shows a waterfall plot of the responses of the patients that participated in the phase 1 part of the study. Overall response rate (≥ PR) was 67% with 6 out of 21 (29%) patients achieving at least VGPR. In addition 2 patients achieved MR (≥ MR: 76%). Median PFS and OS were 6.3 and 15.5 months respectively. Similar results were achieved in the subset of patients with LEN- and BORT-refractory disease. Interestingly, laboratory experiments with purified myeloma cells from these patients suggest synergism between LEN and cyclophosphamide. Conclusions The REP regimen induces high response rates and prolonged PFS and OS in LEN-refractory patients with acceptable toxicity. The MTD is defined as LEN 25 mg days 1-21 of a 28-day cycle, combined with oral cyclophosphamide 50 mg and prednisone 20 mg continuously. Phase 2 is enrolling patients and evaluates efficacy and safety of the REP regimen at the MTD. REP should be considered a valuable salvage option for LEN-refractory MM patients. We will present an updated follow-up at ASH. Disclosures: Sonneveld: Onyx: Research Funding; Millenium: Research Funding; Janssen-Cilag: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Janssen-Cilag: Honoraria; Celgene: Research Funding. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. van de Donk:Celgene: Research Funding.

A Multinational, Open-Label Phase 2 Study Of Ruxolitinib In Asian Patients (Pts) With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (PPV-MF), Or Post–Essential Thrombocythemia MF (PET-MF)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4086-4086
Author(s):  
Chul Won Jung ◽  
Lee-Yung Shih ◽  
Zhijian Xiao ◽  
Jie Jin ◽  
Hsin-An Hou ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Research Funding ◽  
Phase 2 ◽  
Spleen Volume ◽  
Open Label ◽  
Phase 3 ◽  
Phase 2 Study ◽  
Open Label Phase ◽  
Large Phase ◽  
Grade 3

Abstract Background Ruxolitinib is a potent JAK1/JAK2 inhibitor that has demonstrated rapid and durable reductions in splenomegaly, improved MF-related symptoms and quality of life (QoL), and prolonged survival in 2 phase 3 studies comparing ruxolitinib with placebo (COMFORT-I) and best available therapy (COMFORT-II). However, no clinical trial in pts with MF had been conducted in Asian countries, and only a limited number of Asian pts or healthy volunteers had been enrolled in any ruxolitinib study. Methods This study was an open-label phase 2 study evaluating ruxolitinib in Asian pts with PMF, PPV-MF, or PET-MF who had palpable splenomegaly ≥ 5 cm below the costal margin and intermediate-2– or high-risk MF by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria. Pts received starting doses of ruxolitinib 15 or 20 mg twice daily (bid) based on baseline platelet count (100-200 or > 200 × 109/L, respectively); dose adjustments balancing safety and efficacy were allowed to titrate each pt to their most appropriate dose. The primary endpoint was met if the proportion of pts achieving ≥ 35% reduction in spleen volume from baseline at week 24 was ≥ 27.5% as measured by MRI/CT. Symptomatic response was assessed as a secondary endpoint using the 7-day modified MF Symptom Assessment Form (MFSAF) v2.0 total symptom score (TSS) and European Organisation for Research and Treatment of Cancer QoL Questionnaire Core 30 (EORTC QLQ-C30). The study was conducted in China (n = 63), Japan (n = 30), Korea (n = 17), and Taiwan (n = 10). The data cutoff date for this analysis was 7 June 2013. Results Overall, 120 pts were enrolled (PMF, n = 80; PPV-MF, n = 21; PET-MF, n = 19), and their baseline characteristics were as follows: median age, 61 years (range, 25-80 years); 51.7% female; 69.2% intermediate-2 and 30.8% high risk by IWG-MRT criteria; median palpable spleen size, 15 cm (range, 5-45 cm); median spleen volume, 2159 cm3; 55.8% of pts had prior exposure to hydroxyurea. The median follow-up was 8.44 months; 22.5% of pts discontinued treatment, primarily for adverse events (AEs; 9.2%) and disease progression (7.5%). The median duration of treatment was 8.44 months (range, 0.5-21.7 months), and the median daily dose was 20.64 mg/day in the 15 mg bid group (n = 46) and 36.11 mg/day in the 20 mg bid group (n = 74). All pts were evaluable for achievement of the primary endpoint, 101 pts remained on study and were evaluable at week 24, and 96 pts had nonzero scores on the MFSAF-TSS and were evaluable for a reduction from baseline. Most pts who had assessments at week 24 (91% [92/101]) had a reduction from baseline in spleen volume (Figure). The study met the primary endpoint, with 31.7% (38/120) of all pts achieving ≥ 35% reduction from baseline at week 24. Overall, 38.3% (46/120) of pts achieved ≥ 35% reduction from baseline in spleen volume at any time on study. As measured by the 7-day MFSAF, 49% (47/96) of pts achieved ≥ 50% reduction from baseline in TSS (median reduction, 47.2%). Pts experienced an improvement from baseline at week 24 in EORTC global health status/QoL (mean change, 5.2). The most common nonhematologic AEs (≥ 10%) regardless of relationship to study medication included diarrhea (25.8%), upper respiratory tract infection (17.5%), ALT level increased (15.0%), pyrexia (15.0%), AST level increased (13.3%), cough (11.7%), herpes zoster infection (11.7%), nasopharyngitis (10.8%), constipation (10.0%), gamma-glutamyl transferase level increased (10.0%), and headache (10.0%), and most were grade 1/2. Serious AEs were reported for 24.2% of pts, and 65.8% of all pts had grade 3/4 AEs. The most common new or worsening laboratory abnormalities were low hemoglobin (all grade 3, 55.7%), low lymphocyte (grade 3/4, 19.5%), low platelet (grade 3/4, 15.3%), and low ANC (grade 3/4, 7.6%) levels. AEs observed in this study were consistent with those observed in the 2 large phase 3 COMFORT studies. Six pts (5%) died on treatment or within 30 days of discontinuation. Summary/conclusions Findings from this study demonstrated that ruxolitinib was relatively well tolerated in Asian pts with MF and provided substantial reductions in splenomegaly and modest improvements in MF-associated symptoms. The AEs observed with ruxolitinib treatment in this study are consistent with those observed in the large phase 3 COMFORT studies, and there were no new AEs associated with ruxolitinib in Asian pts with MF. Disclosures: Okamoto: Novartis: Honoraria, Research Funding. Sirulnik:Novartis: Employment. Ruiz:Novartis: Employment. Amagasaki:Novartis: Employment. Ito:Novartis: Employment. Akashi:Novartis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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