Imatinib failure-free survival (IFS) in patients with localized gastrointestinal stromal tumors (GIST) treated with adjuvant imatinib (IM): The EORTC/AGITG/FSG/GEIS/ISG randomized controlled phase III trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10500-10500 ◽  
Author(s):  
Paolo Giovanni Casali ◽  
Axel Le Cesne ◽  
Andres Poveda Velasco ◽  
Dusan Kotasek ◽  
Piotr Rutkowski ◽  
...  
Keyword(s):  
High Risk ◽  
Kinase Inhibitor ◽  
Phase Iii ◽  
Open Label ◽  
Eligibility Criteria ◽  
Secondary Resistance ◽  
Significance Level ◽  
End Point ◽  
Consensus Classification ◽  
Advanced Gist

10500 Background: In 2004 we launched an open-label randomized trial with adjuvant IM for 2 yrs in localized, surgically resected, high/intermediate-risk GIST. Methods: Pts were randomized between 2 yrs of IM, 400 mg daily, and no further therapy after surgery. The primary end-point was OS, while RFS, RFI and toxicity were secondary end-points. Main eligibility criteria were: age >18 yrs, PS 0-2, localized CD117-positive GIST, intermediate or high risk according to the 2002 Consensus classification, R0 or R1 surgical margins, no previous medical therapy. Pts were stratified by risk, tumor site and margins. An accrual of 400 pts was planned, then escalated to 900. Given the prognostic improvement of advanced GIST pts, in 2009 the study IDMC authorized to change the primary end-point into IFS, whose failure was defined as the time when a different tyrosine kinase inhibitor (TKI) is started. We report on a planned interim analysis carried out after 115 events according to the new primary end-point, with a significance level of 1.5%. Hazard ratios (HR) and p-values were adjusted for stratification factors. Results: 908 pts were randomized between 2005 and 2008, 454 to IM and 454 to observation arm; 835 pts were eligible. 17% of pts treated with IM stopped early due to toxicity or refusal. With a median follow-up of 4.7 yrs, 5-yr IFS was 87% in the IM-arm vs 84% in the control arm (HR=0.80, 98.5% CI [0.51; 1.26], p=0.23); RFS was 84% vs 66% at 3 yrs, and 69% vs 63% at 5 yrs (p<0.001); 5-yr OS was 100% vs 99%. Among 528 pts with high-risk GIST by local pathology, 5-yr IFS was 79% vs 73% (p=0.11), and 77% vs 73% (p=0.44) amongst 336 high-risk GIST pts by centrally reviewed pathology. Conclusions: This study confirms that adjuvant IM has an overt impact on short-term freedom from relapse. In the high-risk subgroup, a non-statistically significant trend in favor of the adjuvant arm was observed in terms of IFS. This new end-point for the adjuvant setting, i.e. survival free from any failure of the first employed TKI, was designed to incorporate secondary resistance, i.e. the currently main factor adversely affecting prognosis of advanced GIST pts. Clinical trial information: NCT00103168.

CONTACT-01: A phase III, randomized study of atezolizumab plus cabozantinib versus docetaxel in patients with metastatic non-small cell lung cancer (mNSCLC) previously treated with PD-L1/PD-1 inhibitors and platinum-containing chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9134-TPS9134
Author(s):  
Joel W. Neal ◽  
Palak Kundu ◽  
Tomohiro Tanaka ◽  
Ida Enquist ◽  
Sid Patel ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Randomized Study ◽  
Phase Iii ◽  
Clinical Activity ◽  
Open Label ◽  
Eligibility Criteria ◽  
Recist 1.1 ◽  
Platinum Based Chemotherapy ◽  
Patient Reported ◽  
Previously Treated

TPS9134 Background: Patients with mNSCLC who progress on anti–PD-L1/PD-1 therapy administered in combination with or after platinum-based chemotherapy (PBC) are mainly treated with docetaxel or pemetrexed monotherapy. These therapies only have modest clinical activity, leaving a high unmet medical need. Cabozantinib, a tyrosine kinase inhibitor (TKI), promotes an immune-permissive environment and may enhance the efficacy of PD-L1/PD-1 inhibitors, offering a promising second/third-line therapeutic opportunity for patients with mNSCLC. In a Phase Ib multi-cohort study (COSMIC-021; NCT03170960), cabozantinib plus atezolizumab (anti–PD-L1) showed an acceptable safety profile and promising efficacy (ORR: 27%; mDOR: 5.7 mo [range: 2.6-6.9]; disease control rate [CR + PR + SD]: 83%) in 30 patients with mNSCLC who had progressed after prior anti–PD-L1/PD-1 therapy plus chemotherapy (Neal et al. J Clin Oncol 2020). The Phase III CONTACT-01 study will further evaluate the efficacy and safety of atezolizumab plus cabozantinib versus docetaxel monotherapy in patients with mNSCLC who have progressed during or after prior treatment with anti–PD-L1/PD-1 therapy and PBC. Methods: CONTACT-01 (NCT04471428) is a Phase III, multi-center, randomized, open-label study that will enroll ≈350 patients from 150 to 200 sites internationally. Key eligibility criteria include histologically or cytologically confirmed mNSCLC, disease progression with concurrent or sequential anti–PD-L1/PD-1 treatment and PBC, measurable disease (RECIST 1.1), ECOG PS of 0-1 and the availability of tissue specimens for centralized PD-L1 testing or known PD-L1 status using a health authority–approved PD-L1 assay. Patients with NSCLC previously treated with cabozantinib, docetaxel or anti–PD-L1/PD-1 + VEGFR TKIs are excluded. Patients with known sensitizing EGFR/ALK mutations and active or untreated CNS metastases are also excluded. Patients will be randomized 1:1 to receive either atezolizumab (1200 mg IV every 3 weeks) + cabozantinib (40 mg orally once daily) or docetaxel (75 mg/m2 IV every 3 weeks). The primary endpoint is OS. Secondary endpoints include investigator-assessed PFS, ORR and DOR per RECIST 1.1; TTD in patient-reported physical function and global health status (EORTC QLQ-C30); investigator-assessed PFS rates at 6 months and 1 year; OS rates at 1 and 2 years; safety and PK. Clinical trial information: NCT04471428.

scholarly journals Time to Definitive Failure to the First Tyrosine Kinase Inhibitor in Localized GI Stromal Tumors Treated With Imatinib As an Adjuvant: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Intergroup Randomized Trial in Collaboration With the Australasian Gastro-Intestinal Trials Group, UNICANCER, French Sarcoma Group, Italian Sarcoma Group, and Spanish Group for Research on Sarcomas

2015 ◽  
Vol 33 (36) ◽  
pp. 4276-4283 ◽  
Author(s):  
Paolo G. Casali ◽  
Axel Le Cesne ◽  
Andres Poveda Velasco ◽  
Dusan Kotasek ◽  
Piotr Rutkowski ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Randomized Trial ◽  
Data Monitoring Committee ◽  
Adjuvant Imatinib ◽  
Secondary Resistance ◽  
Free Survival ◽  
End Point ◽  
Significant Difference ◽  
Advanced Gist

Purpose In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery patients with localized, high- or intermediate-risk GI stromal tumor (GIST). Patients and Methods Patients were randomly assigned to 2 years of imatinib 400 mg daily or no further therapy after surgery. The primary end point was overall survival; relapse-free survival (RFS), relapse-free interval, and toxicity were secondary end points. In 2009, given the concurrent improvement in prognosis of patients with advanced GIST, we changed the primary end point to imatinib failure–free survival (IFFS), with agreement of the independent data monitoring committee. We report on a planned interim analysis. Results A total of 908 patients were randomly assigned between December 2004 and October 2008: 454 to imatinib and 454 to observation. Of these, 835 patients were eligible. With a median follow-up of 4.7 years, 5-year IFFS was 87% in the imatinib arm versus 84% in the control arm (hazard ratio, 0.79; 98.5% CI, 0.50 to 1.25; P = .21); RFS was 84% versus 66% at 3 years and 69% versus 63% at 5 years (log-rank P < .001); and 5-year overall survival was 100% versus 99%, respectively. Among 528 patients with high-risk GIST by local pathologist, 5-year IFFS was 79% versus 73%; among 336 centrally reviewed high-risk patients, it was 77% versus 73%, respectively. Conclusion This study confirms that adjuvant imatinib has an overt impact on RFS. No significant difference in IFFS was observed, although in the high-risk subgroup there was a trend in favor of the adjuvant arm. IFFS was conceived as a potential end point in the adjuvant setting because it is sensitive to secondary resistance, which is the main adverse prognostic factor in patients with advanced GIST.

Masitinib in comparison to imatinib as first-line therapy of patients with advanced gastrointestinal stromal tumor (GIST): A randomized phase III trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS10102-TPS10102
Author(s):  
Antoine Adenis ◽  
Loic Chaigneau ◽  
Pierre Michel ◽  
Nicolas Isambert ◽  
François Bertucci ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Phase Iii ◽  
First Line ◽  
Current Standard ◽  
Open Label ◽  
Naive Patient ◽  
Post Surgery ◽  
Advanced Gist

TPS10102^ Background: Masitinib is an oral tyrosine kinase inhibitor (TKI) that has greater in vitro kinase activity and/or selectivity than imatinib against KIT and PDGFRA/B. A phase 2 study has previously reported that masitinib treatment produced clinically relevant activity in imatinib-naïve patients with advanced GIST. Considering the promising long term response observed in overall survival (OS) (see Table) there is compelling evidence to compare masitinib against imatinib (the current standard of care) in the first-line setting. Methods: A multicenter, randomized, open label, phase 3, 1:1 study to compare efficacy and safety of masitinib (7.5 mg/kg/day) to the active control of imatinib (400 or 600 mg/day) in first-line treatment of patients with advanced GIST. Primary endpoint is progression-free survival (PFS), with secondary endpoints including OS, time to progression (TTP), and clinical response rates (RECIST). Based on a planned sample size of 222 patients (111/arm) this 15% non-inferiority study was designed to have an 85% power using a 95% two-sided CI of the hazard ratio. Patient eligibility criteria include: histologically proven, metastatic or locally advanced nonresectable, or recurrent post-surgery GIST; TKI naïve patient or patient previously receiving imatinib only as a neoadjuvant or adjuvant therapy; and confirmed KIT-positive or PDGFRA-positive tumors. Recruitment is ongoing. On 09/2011, the DMC recommended continuation of this study. Clinicaltrial.gov: NCT00812240. [Table: see text]

Continuous daily dosing (CDD) of sunitinib malate (SU) compares favorably with intermittent dosing in pts with advanced GIST

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 10015-10015 ◽  
Author(s):  
S. George ◽  
J. Y. Blay ◽  
P. G. Casali ◽  
A. Le Cesne ◽  
J. A. Morgan ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Safety Data ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Sunitinib Malate ◽  
Phase Iii Study ◽  
Multitargeted Tyrosine Kinase Inhibitor ◽  
Dosing Strategy ◽  
To Receive ◽  
Advanced Gist

10015 Background: SU, an oral multitargeted tyrosine kinase inhibitor of KIT, PDGFRs, VEGFRs, RET and FLT3, is approved multinationally for the treatment of imatinib (IM)-resistant or -intolerant GIST. SU 50 mg/d on a 4/2 schedule (6-wk cycles: 4 wks on treatment, 2 wks off) has demonstrated efficacy and acceptable tolerability in pts with advanced IM-resistant GIST. The current study assesses the efficacy and safety of CDD of SU in this pt population. Methods: In this multicenter phase (ph) II trial, pts with IM-resistant/intolerant GIST were randomized to receive morning or evening dosing of SU 37.5 mg daily. The primary endpoint was clinical benefit rate (CBR; percentage of pts with confirmed CR, PR or SD for =24 wks per RECIST). Investigator-assessed efficacy and safety data compiled in this ph II study and an earlier ph III study were compared informally, and the PK of SU and its metabolite were also analyzed. Results: Of 61 pts randomized, 60 received treatment with SU (30 pts/arm; ITT population). At a median duration on study of 30 wks (range: 4–52+), 33 pts remain on study and 27 have discontinued. The SU dose was reduced to 25 mg/d in 9 pts due to AEs. The most common non-hematologic AEs of any cause (primarily grade [gr] 1/2) were diarrhea (40%), asthenia (38%) and fatigue (35%). Gr 3 AEs were asthenia (13%), fatigue (7%) and diarrhea (7%); gr 4 abdominal pain was reported in 3% pts. Hematologic toxicities included gr 3 anemia (10%), neutropenia (17%, all non-febrile) and thrombocytopenia (7%) and gr 4 anemia (3%). Toxicities were similar in the morning and evening dosing groups. Preliminary PK data indicated no unexpected accumulation with CDD. To date, median PFS is 27 wks (CI: 24–41) and overall CBR is 24%, including 11% pts with PRs, which compares favorably with results obtained with the approved regimen of SU 50 mg/d on the 4/2 schedule (N=207; PR: 7%; CBR: 25%; PFS 28 wks [CI: 14–34]; phase III study). Conclusions: SU is well tolerated and clinically active when given as 37.5 mg CDD in pts with IM- resistant/-intolerant GIST. The AE profile for SU CDD appears similar to that of the 4/2 schedule. Morning and evening dosing seem to have similar tolerability. SU CDD appears to be a safe and effective alternative dosing strategy for pts with IM-resistant/intolerant GIST. No significant financial relationships to disclose.

A randomized, open-label, phase III trial of NOV-002 in combination with paclitaxel (P) and carboplatin (C) versus paclitaxel and carboplatin alone for the treatment of advanced non-small cell lung cancer (NSCLC).

2010 ◽  
Vol 28 (18_suppl) ◽  
pp. LBA7007-LBA7007 ◽  
Author(s):  
P. Fidias ◽  
T. A. Ciuleanu ◽  
O. Gladkov ◽  
G. M. Manikhas ◽  
I. N. Bondarenko ◽  
...  
Keyword(s):  
Overall Survival ◽  
Advanced Nsclc ◽  
Objective Response ◽  
Stage Iv ◽  
Phase Iii ◽  
Open Label ◽  
Significance Level ◽  
Phase Ii Studies ◽  
Grade 3 ◽  
Positive Results

LBA7007 Background: NOV-002 is a formulation of disodium glutathione disulfide (GSSG). GSSG is a naturally occurring substance that functions as a component of the glutathione (GSH) pathway, vital to the regulation of the intracellular redox state. A key function of the GSH/GSSG redox couple is to dynamically regulate protein functions, including cell signaling pathways, through the reversible formation of mixed disulfides between protein cysteines and GSH (S-glutathionylation). Based on positive results from a randomized, phase I/II study of carboplatin and paclitaxel (CP) with or without NOV-002, as well as positive results from 2 ex-U.S. phase II studies with cisplatin-based chemotherapy, an international phase III randomized trial was launched. Methods: Patients with advanced NSCLC (stages wet IIIB and IV, inclusive of all histological subtypes) were eligible if they had a PS of 0-1 and adequate end-organ function. Patients with CNS metastases were excluded. Eligible patients were randomized to C (AUC 6), P (200 mg/m2), and NOV-002 (Group A) or C and P alone (Group B). NOV-002 was administered as two-60 mg IV boluses on day -1 of cycle 1 and as one IV bolus on day 1 of each cycle, followed by daily 60-mg subcutaneous injections. A total of 725 events were required to detect a difference in overall survival (OS) from 10.0 to 12.5 months with 85% power and a two-sided significance level of 0.05. No interim analysis was performed. Results: From 11/06 until 9/09, 903 patients were randomized, with target enrollment reached in March 2008. Patient characteristics for Groups A and B were as follows: stage IV (91.5/90.8%), PS 1 (76.6/72.6%), male (69.9/72.4%), never smoker (22.3/19.1%) median age (59.6/59.5), and histology (adenocarcinoma [40.0/36.8%] squamous [41.2/40.8%]). The median overall survival for Groups A and B was 10.2/10.8 months (p = 0.375), median progression-free survival was 5.3/5.6 months, objective response rate was 26.6/26.0% and 54/53% of patients completed at least six cycles of chemotherapy. Major toxicities for Groups A and B included grade 3/4 neutropenia (29.7/26.3%), febrile neutropenia (2.2/1.8%), grade 3/4 thrombocytopenia (3.8/2.9%), and grade 3/4 neuropathy (2.9/2.4%). Adverse events resulting in death in Groups A and B were reported in 5.6 and 3.1%, respectively. Conclusions: The addition of NOV-002 to CP does not improve overall survival in patients with advanced NSCLC. NOV002 does not appear to add to the overall toxicity of chemotherapy. [Table: see text]

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