An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10006-10006 ◽  
Author(s):  
Isabelle Ray-Coquard ◽  
Hans Gelderblom ◽  
Christine Chevreau ◽  
Judith R. Kroep ◽  
Antoine Italiano ◽  
...  
Keyword(s):  
Phase Ii ◽  
Interim Analysis ◽  
Phase Ii Study ◽  
Primary Tumour ◽  
Disease Stabilisation ◽  
Primary Objective ◽  
Neoplastic Disease ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Grade 3

10006 Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare pathological entity affecting the synovium in young adults. This neoplastic disease is driven by a t(1;2) translocation which results in the fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on M-CSF receptor pathway which could be of therapeutic interest in pts with non resectable PVNS. Methods: In this open-label International, multicenter, non-randomized, phase II study the primary objective is to evaluate the efficacy of nilotinib treatment in patients (pts) with progressive or relapsing PVNS not amenable to surgery or in whom surgery would be mutilating, as measured by the 12-week progression-free rate (12-w PFR) validated by an independent committee. Using a Bayesian design with a stopping rule for futility, interim analyses were planned after the inclusion of 10 pts and then every 5 pts. Results: From December 2010 to November 2011, 33 pts with progressive disease from 17 institutions from Europe and Australia were enrolled. 14 pts (median age 37 y (range: 19-68), 7 males) were analyzed in the 2nd interim analysis. Median time since diagnosis was 4.4 years (range: 0.2-26). Primary tumour was located on a knee for 10 pts (71%) and on hip (1 pt, 7%), finger (7%), foot (7%), hand (7%), respectively. 69% of pts had a inoperable PVNS and 31% had a resectable tumour but requiring mutilating surgery. All pts started nilotinib at the planned dose of 800 mg/day. At a median follow-up of 8.9 months (range: 0.6-11), 2 pts had a dose reduction and 1 pt had discontinued nilotinib after 14 days due to toxicity. Nilotinib was well tolerated, with only 2 pts experiencing grade 3 adverse events (anorexia: 1 pt; hepatic failure: 1 pt).The 12-w PFR was 85.7% (95%CI, 57.2%-98.2%), in favour of the study continuation. No OR was observed at w-12; 1 pt (7%) was in PR at w-30. Updated results will be presented after the 3rd interim analysis. Conclusions: Nilotinib treatment induces disease stabilisation in a large proportion of PVNS patients with non resectable disease or in whom resection would be mutilating.

An open-label international multicentric phase II study of nilotinib in progressive pigmented villo-nodular synovitis (PVNS) not amenable to a conservative surgical treatment.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10516-10516 ◽  
Author(s):  
Hans Gelderblom ◽  
David Pérol ◽  
Christine Chevreau ◽  
Martin HN Tattersall ◽  
Silvia Stacchiotti ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Primary Tumour ◽  
Disease Stabilisation ◽  
Primary Objective ◽  
Neoplastic Disease ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Maximum Sample Size ◽  
Grade 3

10516 Background: PVNS, also known as tenosynovial giant cell tumor (TGCT), is a rare pathological entity affecting the synovium in young adults. This neoplastic disease is driven by a t(1;2) translocation resulting in the fusion of COL6A3 and M-CSF genes. Nilotinib has inhibitory properties on M-CSF receptor pathway which could be of therapeutic interest in patient (pts) with non resectable PVNS. Methods: In this open-label international, multicentric, non-randomized, phase II study the primary objective is to evaluate the efficacy of nilotinib treatment (800 mg/day) in pts with progressive or relapsing PVNS not amenable to surgery or in whom surgery would be mutilating, as measured by the 12-week progression-free rate (12-w PFR) validated by an independent committee. Using a Bayesian design with a futility stopping rule and a maximum sample size set to 50 evaluable pts, interim analyses (IA) were planned after the inclusion of 10 and then every 5 pts. Results: From December 2010 to September 2012, 56 pts with progressive disease were enrolled by 17 institutions from Europe and Australia. Successive previous IA led to positive results in favour of the study continuation. 47 pts (median age 37 y (range: 18-74), 51% of males) were evaluable at the time of the last IA, with a median follow-up of 11.2 months (range: 0.6-12.7). Median time since diagnosis was 2.5 years (range: 0.02-26). Primary tumour was mainly located on knee (25 pts, 53%), hip (6 pts, 13%), ankle (6 pts, 13%). 4 pts had already received imatinib, 76% of pts had undergone a previous surgery. The 12-w PFR was 93.6% (95%CI, 82.5%-98.7%), without any OR. PR were observed later (2 at w-24 and 1 at w-48). Nilotinib was well tolerated, with only 4 pts experiencing grade 3 adverse events (anorexia: 1 pt; prurit: 1 pt; diarrhea: 1 pt; hepatic failure: 1 pt). 8 pts (17%) had a dose reduction and/or temporary discontinuation of nilotinib due to toxicity. Final results will be further presented. Conclusions: Nilotinib treatment induces disease stabilisation in a large proportion of PVNS patients with non resectable disease or in whom resection would be mutilating. Clinical trial information: NCT01261429.

Bortezomib With or Without Irinotecan in Relapsed or Refractory Colorectal Cancer: Results From a Randomized Phase II Study

2008 ◽  
Vol 26 (14) ◽  
pp. 2320-2326 ◽  
Author(s):  
Peter S. Kozuch ◽  
Caio Max Rocha-Lima ◽  
Tomislav Dragovich ◽  
Howard Hochster ◽  
Bert H. O'Neil ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Sensory Neuropathy ◽  
Primary Objective ◽  
Response To Treatment ◽  
Open Label ◽  
Open Label Phase ◽  
Grade 3

PurposeTo evaluate the efficacy and toxicity of bortezomib with or without irinotecan, in patients with relapsed or refractory colorectal cancer (CRC).Patients and MethodsPatients were randomly assigned in a 3:4 ratio to bortezomib 1.5 mg/m2(arm A) or bortezomib 1.3 mg/m2plus irinotecan 125 mg/m2(arm B). A treatment cycle of 21 days consisted of four bortezomib doses on days 1, 4, 8, and 11, plus, in arm B, irinotecan on days 1 and 8. The primary objective of this randomized, multicenter, open-label, phase II study was to determine tumor response to treatment. Secondary objectives were safety and tolerability.ResultsA preplanned interim analysis to assess efficacy revealed inadequate activity, resulting in early termination of this study. A total of 102 patients were treated, 45 in arm A and 57 in arm B. Baseline characteristics were comparable. The investigator-assessed response rate was 0 in arm A and 3.5% in arm B (all partial responses). Adverse events in both treatment arms were as expected, with no significant additive toxicity. The most common grade ≥ 3 adverse events reported, per patient, during the study were fatigue (27%), vomiting (13%), nausea (11%), and peripheral sensory neuropathy (11%) in arm A, and diarrhea (33%), fatigue (25%), neutropenia (23%), thrombocytopenia (18%), dyspnea (12%), abdominal pain (12%), dehydration (12%), and anemia (11%) in arm B.ConclusionBortezomib alone or in combination with irinotecan was not effective in patients with relapsed or refractory CRC.

Randomized phase II study of three doses of the integrin inhibitor cilengitide versus docetaxel as second-line treatment for patients (pts) with stage IV non-small cell lung cancer (NSCLC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8014-8014
Author(s):  
C. Manegold ◽  
J. Vansteenkiste ◽  
F. Cardenal ◽  
W. Schütte ◽  
P. Woll ◽  
...  
Keyword(s):  
Survival Rate ◽  
Tumor Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Open Label ◽  
Randomized Phase Ii ◽  
Grade 3 ◽  
One Year

8014 Background: Cilengitide (EMD 121974) is the most advanced compound in clinical development of a new class of oncology drugs, the integrin inhibitors. Integrins (heterodimeric transmembrane receptors) play key roles in cell interactions. Cilengitide selectively inhibits the cell-surface integrins αVβ3 and αVβ5 on activated endothelial cells during angiogenesis and on tumor cells. Methods: Multicenter, open-label, randomized, phase II study in 140 pts with relapsed stage IV NSCLC. Pts received 1 of 3 cilengitide doses (240 [n=35], 400 [n=35], or 600 [n=36] mg/m2) twice weekly or docetaxel 75 mg/m2 (n=34) once every 3-week cycle for 6 months. Responding pts could continue cilengitide for up to 1 year. Primary endpoint: progression-free survival (PFS). Results: Median age (range) was 60 (33–80) years; 94 pts were male (67%); 83% of pts had KPS ≥80%. Median PFS (95% CI) was 54 (43–64), 63 (53–66), 63 (42–67), and 67 (61–123) days for cilengitide 240, 400, 600, and docetaxel 75 mg/m2, respectively. Median OS (95% CI) was 173 (81–197), 117 (92–209), 181 (90–326), and 194 (135–298) days, respectively. One-year survival rate (95% CI) was 13% (1–24%), 13% (0–26%), 29% (12–37%), and 27% (10–43%), respectively. Survival was similar with cilengitide 600 mg/m2 and docetaxel 75 mg/m2: median OS 181 versus 194 days and 1-year survival rate (95% CI) 29% (12–37%) versus 27% (10–43%). Five docetaxel pts (15%) had a partial response. Most pts (98%) had ≥1 adverse event (AE). Most common AEs were dyspnea (33%), nausea (30%), tumor progression (29%), and cough (23%). Dyspnea and tumor progression were more common with cilengitide than with docetaxel. Grade 3/4 treatment-related AEs were more common with docetaxel (n=13, 41%) than cilengitide 240 (n=2, 6%), 400 (n=4, 11%), or 600 (n=4, 11%) mg/m2. For cilengitide, these were nausea, chest pain, dyspnea, and fatigue. Conclusions: PFS in the docetaxel group was greater than that of cilengitide at all doses. However, cilengitide monotherapy at a dose of 600 mg/m2 showed similar OS to docetaxel and better tolerability. Combination studies with standard chemotherapy and cilengitide are warranted. [Table: see text]

A phase II trial of the effect of perindopril on hand foot syndrome (HFSR) incidence and severity in patients receiving regorafenib with refractory metastatic colorectal carcinoma (mCRC).

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 824-824
Author(s):  
Barbara L. Melosky ◽  
Howard John Lim ◽  
Janine Davies ◽  
Sharlene Gill ◽  
Christian K. Kollmannsberger ◽  
...  
Keyword(s):  
Phase Ii ◽  
Interim Analysis ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Capillary Endothelium ◽  
Open Label ◽  
Grade 3 ◽  
Overall Survival Benefit ◽  
Ecog Ps

824 Background: Regorafenib is an oral multi-kinase inhibitor (MKI), with a demonstrated overall survival benefit in mCRC refractory to standard therapy ( PMID 23177514). The most common grade 3 adverse event (AE) reported in this trial was HFSR, with 47% of patients (pts) experiencing HFSR of all grades, and 17% with grade 3 severity. The pathogenesis of regorafenib-induced HFSR is not well established, but may be related to alterations in the capillary endothelium. Perindopril is an Angiotensin Converting Enzyme (ACE) Inhibitor indicated for the treatment of hypertension, and may also play a role in preventing endothelial dysfunction ( PMID 17140552). We hypothesized that perindopril may prevent or reduce the severity of regorafenib-induced HFSR. Methods: In this single center Phase II, open label trial, 34 pts with refractory mCRC were planned to be treated with regorafenib (160 mg/day) and perindopril (4 mg/day) with both agents given 3 weeks on and 1 week off. An interim analysis was planned after 10 evaluable pts. The primary objective was to assess the proportion of pts with any grade HSFR toxicity. Secondary endpoint included time to development of worst (grade 3) HSFR toxicity, proportion of all grades of hypertension and all grade toxicities, and progression free survival. All toxicities were evaluated using CTCAE v4.03. Results: 12 pts were accrued over a 9 month time period, and 10 pts were considered evaluable as they completed one cycle of treatment. Pt characteristics included (6 M/ 6F, mean age 62, ECOG PS 0 (25%)/ 1 (75%). A planned interim analysis was performed after 10 evaluable pts had completed their first cycle of study treatment. 5/10 (50%) experienced Grade 3 HFSR, and based on the statistical plan it was deemed highly unlikely that perindopril would lead to reduced levels of regorafenib induced HSFR compared with regorafenib alone thus enrolment was stopped. The most frequent other grade 3 toxicities included hypertension (16.7%), and increased AST (16.7%). Conclusions: The addition of perindopril to regorafenib did not appear to reduce HSFR incidence and severity in pts with refractory mCRC. Clinical trial information: NCT02651415.

scholarly journals Oral vinorelbine and cisplatin as first-line therapy for advanced squamous NSCLC patients: a prospective randomized international phase II study (NAVoTrial 03)

2021 ◽  
Vol 13 ◽  
pp. 175883592110229
Author(s):  
Francesco Grossi ◽  
Piotr Jaśkiewicz ◽  
Marion Ferreira ◽  
Grzegorz Czyżewicz ◽  
Dariusz Kowalski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Current Knowledge ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Comparable Efficacy ◽  
Open Label ◽  
Oral Vinorelbine ◽  
First Line Therapy ◽  
Nsclc Patients

Objective: The study investigated the efficacy and safety of oral vinorelbine-cisplatin (OV-CDDP) and gemcitabine-cisplatin (GEM-CDDP) in patients with squamous non-small cell lung cancer (sq-NSCLC). Patients and methods: This was an open-label, prospective, multicenter, international phase II study that enrolled untreated patients with advanced sq-NSCLC. Patients were randomized to receive 3-week cycles of either 60–80 mg/m2 OV days 1 and 8 in combination with 80 mg/m2 CDDP day 1 (arm A) or 1250 mg/m2 GEM days 1 and 8 in combination with 75 mg/m2 CDDP day 1 (arm B). After four cycles, patients without disease progression continued maintenance dose of OV or GEM until progression or unacceptable toxicity. The primary objective was disease control rate (DCR). Secondary objectives included progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS), safety, and quality of life (QoL). Results: A total of 114 patients with sq-NSCLC were randomized, and 113 were treated (57 in arm A and 56 in arm B). DCR was high in both arms: 73.7% (95%CI: 62.4–100.0) in arm A and 75.0% (95%CI: 63.7–100.0) in arm B. Median PFS and TTF were similar in arm A and B 4.2 and 2.8 months, and 4.3 and 3.1 months, respectively. Even though the difference was not significant, the OS was 10.2 for arm A and 8.4 months for arm B. The safety profiles were consistent with the current knowledge of adverse events. QoL results revealed an improvement in patients under OV treatment. Conclusion: The OV-CDDP combination showed comparable efficacy to GEM-CDDP with acceptable safety profile and enhanced patients’ QoL. Trial registration: The study was registered under EudraCT number 2012-003531-40.

scholarly journals LGG-52. BINIMETINIB IN CHILDREN WITH PROGRESSIVE OR RECURRENT LOW-GRADE GLIOMA NOT ASSOCIATED WITH NEUROFIBROMATOSIS TYPE 1: INITIAL RESULTS FROM A MULTI-INSTITUTIONAL PHASE II STUDY

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii376-iii376
Author(s):  
Nathan Robison ◽  
Jasmine Pauly ◽  
Jemily Malvar ◽  
Sharon Gardner ◽  
Jeffrey Allen ◽  
...  
Keyword(s):  
Creatine Kinase ◽  
Dose Reduction ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Neurofibromatosis Type ◽  
Primary Objective ◽  
Preclinical Model ◽  
Low Grade ◽  
Type I ◽  
Open Label

Abstract BACKGROUND RAS/RAF/MEK/ERK pathway activation is the primary driver for most pediatric low-grade gliomas (LGG). Binimetinib is an orally bioavailable MEK1/2 inhibitor found to have significant central nervous system penetration in a preclinical model. OBJECTIVE The primary objective of this multi-institutional open-label phase II study was to assess preliminary efficacy of binimetinib in progressive pediatric LGG. The study included strata for both neurofibromatosis type I (NF1) and non-NF1 associated tumors, as well as a target validation (surgical) stratum. NF1 and surgical strata remain open to enrollment and will be reported separately. METHODS Children aged 1–18 years with previously treated recurrent or progressive LGG were eligible. The dose of binimetinib was 32 mg/m2/dose twice daily. Partial and minor responses were defined, respectively, as 50% and 25% decrease in maximal two-dimensional measurements. RESULTS Fifty-seven eligible patients without NF1, median age 8 years, were enrolled and began treatment; 26 were female; 28 had documented KIAA1549-BRAF fusion. Eleven patients discontinued drug in the first year due to toxicity, and an additional 27 required dose reduction. The most common drug-attributable grade 3 toxicities included creatine kinase elevation (n=9 patients), rash (n=8), and truncal weakness (n=8). Truncal weakness improved or resolved with dose reduction or cessation. Grade 4 toxicities included creatine kinase elevation (n=2) and transient colitis (n=1). Of 44 patients with preliminary response data available, 22 (50%) showed a minor (n=7) or partial (n=15) response. CONCLUSION Binimetinib is active, with manageable toxicities, in children without NF1 with progressive LGG.

Randomized Multicenter Phase II Study Comparing a Combination of Fluorouracil and Folinic Acid and Alternating Irinotecan and Oxaliplatin With Oxaliplatin and Irinotecan in Fluorouracil-Pretreated Metastatic Colorectal Cancer Patients

2001 ◽  
Vol 19 (22) ◽  
pp. 4195-4201 ◽  
Author(s):  
Yves Bécouarn ◽  
Erick Gamelin ◽  
Bruno Coudert ◽  
Sylvie Négrier ◽  
Jean-Yves Pierga ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Folinic Acid ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Survival Times ◽  
Activity Data ◽  
Randomized Phase Ii ◽  
Grade 3 ◽  
Intent To Treat ◽  
Colorectal Cancer Patients

PURPOSE: To assess antitumor activity and safety of two regimens in advanced colorectal cancer (CRC) patients with proven fluorouracil (5-FU) resistance in a randomized phase II study: 5-FU/folinic acid (FA) combined with alternating irinotecan (also called CPT-11) and oxaliplatin (FC/FO tritherapy), and an oxaliplatin/irinotecan (OC) combination. PATIENTS AND METHODS: Sixty-two patients were treated: arm FC/FO (32 patients) received, every 4 weeks, FA 200 mg/m2 followed by a 400-mg/m2 5-FU bolus injection, then a 600-mg/m2 continuous infusion of 5-FU on days 1 and 2 every 2 weeks administered alternately with irinotecan (180 mg/m2 on day 1) and oxaliplatin (85 mg/m2 on day 15). Arm OC (30 patients) received oxaliplatin 85 mg/m2 and irinotecan 200 mg/m2 every 3 weeks. RESULTS: In an intent-to-treat analysis, two partial responses lasting 10.7 and 16 months were observed with the tritherapy regimen, and seven (median duration, 11 months; range, 10.6 to 11.4 months) were observed with the bitherapy regimen. Median progression-free and overall survival times were 8.2 and 9.8 months, respectively, in the FC/FO arm and 8.5 and 12.3 months, respectively, in the OC arm. Main grade 3/4 toxicities were, respectively, neutropenia, 53% and 47%; febrile neutropenia, 13% and 3%; diarrhea, 19% and 10%; vomiting, 6% and 13%; and neurosensory toxicity, 3% and 3%. No treatment-related deaths occurred. CONCLUSION: The every-3-weeks OC combination is safe and active in advanced 5-FU–resistant CRC patients. The lower activity data seen with the tritherapy regimen may be related to the lower dose intensities of irinotecan and oxaliplatin in this schedule.

scholarly journals Pyrotinib in HER2-Mutant Advanced Lung Adenocarcinoma After Platinum-Based Chemotherapy: A Multicenter, Open-Label, Single-Arm, Phase II Study

2020 ◽  
Vol 38 (24) ◽  
pp. 2753-2761 ◽  
Author(s):  
Caicun Zhou ◽  
Xingya Li ◽  
Qiming Wang ◽  
Guanghui Gao ◽  
Yiping Zhang ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Phase Ii ◽  
Objective Response Rate ◽  
Response Rate ◽  
Phase Ii Study ◽  
Objective Response ◽  
Unmet Need ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Grade 3

PURPOSE Targeted therapies against non–small-cell lung cancer (NSCLC) harboring HER2 mutations remain an unmet need. In this study, we assessed the efficacy and safety of pyrotinib in patients with HER2-mutant advanced NSCLC in a prospective, multicenter, open-label, single-arm, phase II study. PATIENTS AND METHODS Patients with stage IIIB or IV HER2-mutant lung adenocarcinoma who were previously treated with platinum-based chemotherapy were enrolled to receive pyrotinib at a dose of 400 mg/d for 21-day cycles. The primary end point was objective response rate per independent review committee (IRC). RESULTS Between October 20, 2016, and December 10, 2018, 60 patients received pyrotinib monotherapy. At baseline, 58 (96.7%) were stage IV, and 25 (41.7%) received at least 2 lines of prior chemotherapy. As of data cutoff on June 20, 2019, IRC-assessed objective response rate was 30.0% (95% CI, 18.8% to 43.2%). All subgroups of patients with different HER2 mutation types showed a favorable objective response rate. The objective response rates were similar between patients with and without brain metastases (25.0% v 31.3%). The median duration of response was 6.9 months (95% CI, 4.9 to 11.1 months). The median progression-free survival was 6.9 months (95% CI, 5.5 to 8.3 months) per IRC. The median overall survival was 14.4 months (95% CI, 12.3 to 21.3 months). Treatment-related adverse events of grade 3 or 4 occurred in 28.3% of patients, with the most common being diarrhea (20.0%; all grade 3). No treatment-related deaths were reported. CONCLUSION Pyrotinib showed promising antitumor activity and an acceptable safety profile in chemotherapy-treated patients with HER2-mutant NSCLC.

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