scholarly journals Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer

2012 ◽  
Vol 30 (5) ◽  
pp. 507-512 ◽  
Author(s):  
Toni K. Choueiri ◽  
Robert W. Ross ◽  
Susanna Jacobus ◽  
Ulka Vaishampayan ◽  
Evan Y. Yu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Urothelial Cancer ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Double Blind ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy

Purpose Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy. Patients and Methods The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m2 intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives. Results In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months. Conclusion In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.

Randomized double-blind phase II study of maintenance pembrolizumab versus placebo after first-line chemotherapy in patients (pts) with metastatic urothelial cancer (mUC): HCRN GU14-182.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4504-4504 ◽  
Author(s):  
Matt D. Galsky ◽  
Sumanta K. Pal ◽  
Amir Mortazavi ◽  
Matthew I. Milowsky ◽  
Saby George ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Maximum Efficiency ◽  
Double Blind ◽  
Free Survival ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Line Chemotherapy

4504 Background: Platinum-based chemotherapy for 1st-line treatment of pts with metastatic urothelial cancer (mUC) is typically administered for a fixed duration followed by observation until recurrence. PD-1 blockade with pembro improves survival of pts with mUC progressing despite platinum-based chemotherapy. We explored the potential benefit of earlier use of PD-1 blockade using a "switch maintenance" approach. Methods: Pts with mUC achieving at least stable disease after up to 8 cycles of 1st-line platinum-based chemotherapy were enrolled. Pts were randomized 1:1 to pembro 200 mg IV q3 weeks versus placebo for up to 24 months; pts progressing on placebo could cross over to pembro. Randomization was stratified based on pre-chemotherapy visceral metastases (Y/N) and response to 1st-line chemotherapy (CR/PR vs. SD). The primary objective was to determine the progression-free survival (PFS) as per irRECIST among pts treated with pembro versus placebo. Results: Between 12/2015 and 11/2018, 107 pts were randomized to placebo (n=52) versus pembro (n=55). The baseline pt characteristics are shown in the Table. Pts randomized to placebo and pembro received a median of 6 and 8 cycles, respectively. Excluding patients with baseline CRs, the objective response rate was 12% (5/42) on placebo and 22% (10/46) on pembro. Grade 3-4 treatment emergent adverse events occurred in 48% of pts on placebo and 56% on pembro. At a median follow-up of 14.7 months, 41 pts have died and 26/52 pts randomized to placebo have crossed over to pembro. PFS was significantly longer in patients randomized to pembro vs. placebo (Maximum Efficiency Robust Test p=0.036; log-rank p = 0.038). The 18-month restricted mean progression-free survival time was 5.6 months with placebo and 8.2 months with pembro (p=0.023). Conclusions: Switch maintenance pembro may “deepen” responses achieved with 1st-line chemotherapy. Switch maintenance pembro prolongs PFS in pts with mUC completing 1st-line platinum-based chemotherapy. Clinical trial information: NCT02500121. [Table: see text]

A double-blind randomized trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated advanced urothelial cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. LBA239-LBA239 ◽  
Author(s):  
T. K. Choueiri ◽  
U. N. Vaishampayan ◽  
E. Y. Yu ◽  
D. I. Quinn ◽  
N. M. Hahn ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Double Blind ◽  
Molecule Inhibitor ◽  
Platinum Based Chemotherapy ◽  
Visceral Metastases ◽  
Advanced Urothelial Cancer ◽  
Ecog Ps

LBA239 Background: Vandetanib (V) is a novel small-molecule inhibitor that targets key signaling pathways in cancer including VEGF and EGF. V in combination with docetaxel (D) was assessed in patients (pts) who received prior platinum-based chemotherapy for advanced urothelial cancer (UC). Methods: Patients eligible for this randomized, multicenter, double-blind, investigator-initiated trial had metastatic UC after failure of prior platinum-based chemotherapy. Up to 3 prior therapies were allowed including paclitaxel. The primary objective was to determine whether once-daily oral V (100 mg) + D (75 mg/m2 IV q21 days) prolonged progression-free survival (PFS) vs. placebo (P) + D (80% power to detect 60% improvement in median PFS with 1-sided α=0.05). Patients on D+P, had the option to cross over to single agent V. Overall survival (OS), overall response rate (ORR), stable disease (SD), and safety were secondary objectives. Results: One-hundred and forty-two pts were enrolled at 16 institutions, 68% men; median age 65y; ECOG PS 0/1: 52%/48%; visceral involvement: 66%. 80% of patients had ECOG PS 1 and/or visceral metastases. 44% of patients had 2 or more prior systemic therapies and 15% had prior paclitaxel. Baseline characteristics were balanced in both arms. Median PFS was 11.1 weeks (wks) for D+V arm vs. 6.9 wks for D+P arm (HR=1.04, p=0.92). Median OS was 25.4 wks for the D+V arm vs. 30.6 wks for the D+P arm (HR 1.21, p=0.35). ORR was 7.1% for the D+V arm vs. 11.1% for the D+P arm (OR=0.6, 90% CI [0.2–1.6]). SD or better rates were 50.0% vs. 37.5% on D+V and D+P, respectively. As of December 2010, 5 pts were on therapy and 70% of pts died. Median follow-up for pts still alive is 7.2 months. Treatment-related grade >3 toxicities for D+V arm was 60% vs. 36% for the D+P arm (p=0.055) and were generally manageable (grade 4, 14% vs. 11%). Grade >3 toxicities that were more commonly seen in the D+V arm were rash/photosensitivity (11% vs. 0%) and diarrhea (7% vs. 0%). Conclusions: In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR or OS. Toxicities were greater but manageable. [Table: see text]

Fibroblast growth factor receptor status and response to immune checkpoint inhibition in metastatic urothelial cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 458-458 ◽  
Author(s):  
Tracy L Rose ◽  
Michele C Hayward ◽  
Ashley H Salazar ◽  
Patrick Eulitt ◽  
Katrina McGinty ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Immune Checkpoint ◽  
Urothelial Cancer ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Response Rates ◽  
Fibroblast Growth ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy

458 Background: Fibroblast growth factor receptor (FGFR) inhibitors are a promising new targeted therapy for patients with metastatic urothelial cancer (UC) and FGFR alterations. FGFR-altered tumors are more likely to be of the luminal molecular subtype, which is less immune infiltrated and may be less likely to respond to immune checkpoint inhibitors (ICP). Methods: Metastatic UC patients at the University of North Carolina who underwent targeted exon sequencing (any CLIA-certified platform) and were treated with ICP since 2014 were identified. Patients with any FGFR alteration were compared to patients without alterations (including mutations, fusions, and amplifications in FGFR1-4). Overall response rates (ORR) to ICP were assessed by a radiologist (K.M.) per RECIST 1.1 and compared between FGFR-altered and unaltered tumors using Fisher’s exact tests. Patients who died prior to radiologic assessment were considered non-responders. Results: 66 patients (median age 70, 65% male, 76% white, 21% black) were identified. Most patients (74%) had received prior platinum-based chemotherapy, and 13% had received 2 or more prior lines of therapy. At the time of initiation of ICP, 32% of patients had a hemoglobin < 10, 33% had liver metastases, and 72% had a performance status > 0. Fifteen (22%) patients had FGFR alterations. The ORR for all patients was 15%, with ORR of 13% in FGFR-altered patients compared with 16% in unaltered patients (p = 1.0). No patients (0/9, 0%) with known pathogenic mutations in FGFR3 responded to ICP compared to 10/57 (18%) of patients without these alterations (p = 0.33). 46% of FGFR-altered patients who stopped ICP due to progression received subsequent therapy. Conclusions: Response rates to ICP are low and there was no difference in ORR between FGFR-altered and unaltered patients. While no patient with pathogenic FGFR3 mutations responded to ICP in our cohort, this difference did not reach statistical significance. Given low response rates overall, some FGFR-altered patients may benefit from treatment with FGFR inhibitors prior to ICP. Analysis of larger cohorts of patients as well as patients from clinical trials and more in-depth molecular profiling may add further clarity.

scholarly journals Randomized Double-Blind Phase II Study of Maintenance Pembrolizumab Versus Placebo After First-Line Chemotherapy in Patients With Metastatic Urothelial Cancer

2020 ◽  
Vol 38 (16) ◽  
pp. 1797-1806 ◽  
Author(s):  
Matthew D. Galsky ◽  
Amir Mortazavi ◽  
Matthew I. Milowsky ◽  
Saby George ◽  
Sumati Gupta ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stable Disease ◽  
Urothelial Cancer ◽  
Progression Free Survival ◽  
Maximum Efficiency ◽  
First Line ◽  
Double Blind ◽  
Free Survival ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy

PURPOSE Platinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. “Switch maintenance” therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons. PATIENTS AND METHODS Patients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS). RESULTS Between December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival. CONCLUSION Switch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Final results of a randomized, double-blind, phase II study of gemcitabine plus vandetanib or plus placebo in the treatment of advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC) elderly patients (ZELIG study NCT00753714).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7550-7550 ◽  
Author(s):  
Cesare Gridelli ◽  
Silvia Novello ◽  
Nicoletta Zilembo ◽  
Paolo Foa ◽  
Adolfo G. Favaretto ◽  
...  
Keyword(s):  
Single Agent ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Skin Toxicity ◽  
Standard Of Care ◽  
Primary Objective ◽  
Stage Iiib ◽  
Double Blind ◽  
Platinum Based Chemotherapy

7550 Background: Vandetanib (V) is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. Single-agent gemcitabine (G) is a standard of care option for unselected patients (pts) unfit for doublet platinum based chemotherapy. This study assessed the progression-free survival (PFS) benefit of G+V compared to G plus placebo (P) in pts with advanced NSCLC aged ≥ 70 years. Methods: Eligible pts (stage IIIB/IV NSCLC; WHO PS 0-2; all histologies; chemonaïve, aged ≥70) were randomized 1:1 to receive G 1200 mg/m2 i.v. day 1 and 8 of each 21-day cycle, up to 6 cycles plus V 100 mg/day or plus P until progression/toxicity. The primary objective was PFS (80% power to detect a hazard ratio [HR] ≤ 0.667). Secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results: Between Oct 2008-May 2010, 124 pts (median age 75 yrs (70-84); 72.6% male; 57.2% WHO PS 0-1; 74.2% past/never-smoker; 58.1% adenocarcinoma; 89.5% stage IV) were randomized to G+V (n = 61) or G+P (n = 63). Baseline characteristics were similar in both arms. At data cut-off (Apr11), 87.9% pts progressed and 73.4% pts had died. PFS was significantly prolonged for G+V (HR=0.729; 95% CI 0.484-1.096; p=0.0417), median PFS G+V=6.0 months, G+P=5.5 months. No differences were seen in ORR (14.8% and 12.7%; p = 0.74), DCR (72.1% and 66.7%; p =0.51), OS (HR=1.024 [95% CI 0.667-1.571] p=0.8960), proportion of pts alive at 1-year G+V=31.1% and G+P=30.2% (p=0.90). Adverse events (AEs) observed for V 100 mg were generally consistent with previous NSCLC studies of V 100 mg. Common AEs (any grade) occurring with a greater frequency in the G+V arm included skin toxicity (34.4% vs 15.9%) and hypertension (9.8% vs 3.2%). Diarrhea and neutropenia were similar in both arms (14.8% and 14.3%; 19.7% and 19.0%). Conclusions: Despite a marginally statistically significant improvement in PFS the study did not met the primary and secondary end points. The combination G+V was well tolerated in this clinical setting.

scholarly journals Phase II Trial of Cetuximab With or Without Paclitaxel in Patients With Advanced Urothelial Tract Carcinoma

2012 ◽  
Vol 30 (28) ◽  
pp. 3545-3551 ◽  
Author(s):  
Yu-Ning Wong ◽  
Samuel Litwin ◽  
David Vaughn ◽  
Seth Cohen ◽  
Elizabeth R. Plimack ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Single Agent ◽  
Progression Free Survival ◽  
Salvage Chemotherapy ◽  
Free Survival ◽  
Metastatic Urothelial Cancer ◽  
Metastatic Setting ◽  
Previously Treated ◽  
Grade 3

Purpose The benefit of salvage chemotherapy is modest in metastatic urothelial cancer. We conducted a randomized, noncomparative phase II study to measure the efficacy of cetuximab with or without paclitaxel in patients with previously treated urothelial cancer. Patients and Methods Patients with metastatic urothelial cancer who received one line of chemotherapy in the perioperative or metastatic setting were randomly assigned to 4-week cycles of cetuximab 250 mg/m2 with or without paclitaxel 80 mg/m2 per week. We used early progression as an indicator of futility. Either arm would close if seven of the initial 15 patients in that arm progressed at the first disease evaluation at 8 weeks. Results We enrolled 39 evaluable patients. The single-agent cetuximab arm closed after nine of the first 11 patients progressed by 8 weeks. The combination arm completed the full accrual of 28 patients, of whom 22 patients (78.5%) had visceral disease. Twelve of 28 patients had progression-free survival greater than 16 weeks. The overall response rate was 25% (95% CI, 11% to 45%; three complete responses and four partial responses). The median progression-free survival was 16.4 weeks (95% CI, 12 to 25.1 weeks), and the median overall survival was 42 weeks (95% CI, 30.4 to 78 weeks). Treatment-related grade 3 and 4 adverse events that occurred in at least two patients were rash (six cases), fatigue (five cases), and low magnesium (three cases). Conclusion Although it had limited activity as a single agent, cetuximab appears to augment the antitumor activity of paclitaxel in previously treated urothelial cancers. The cetuximab and paclitaxel combination merits additional study to establish its role in the treatment of urothelial cancers.

Phase III Study of Erlotinib in Combination With Cisplatin and Gemcitabine in Advanced Non–Small-Cell Lung Cancer: The Tarceva Lung Cancer Investigation Trial

2007 ◽  
Vol 25 (12) ◽  
pp. 1545-1552 ◽  
Author(s):  
Ulrich Gatzemeier ◽  
Anna Pluzanska ◽  
Aleksandra Szczesna ◽  
Eckhard Kaukel ◽  
Jaromir Roubec ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Small Cell ◽  
Phase Iii ◽  
Small Cell Lung ◽  
Double Blind

Purpose Erlotinib is a potent inhibitor of the epidermal growth factor receptor tyrosine kinase, with single-agent antitumor activity. Preclinically, erlotinib enhanced the cytotoxicity of chemotherapy. This phase III, randomized, double-blind, placebo-controlled, multicenter trial evaluated the efficacy and safety of erlotinib in combination with cisplatin and gemcitabine as first-line treatment for advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients received erlotinib (150 mg/d) or placebo, combined with up to six 21-day cycles of chemotherapy (gemcitabine 1,250 mg/m2 on days 1 and 8 and cisplatin 80 mg/m2 on day 1). The primary end point was overall survival (OS). Secondary end points included time to disease progression (TTP), response rate (RR), duration of response, and quality of life (QoL). Results A total of 1,172 patients were enrolled. Baseline demographic and disease characteristics were well balanced. There were no differences in OS (hazard ratio, 1.06; median, 43 v 44.1 weeks for erlotinib and placebo groups, respectively), TTP, RR, or QoL between treatment arms. In a small group of patients who had never smoked, OS and progression-free survival were increased in the erlotinib group; no other subgroups were found more likely to benefit. Erlotinib with chemotherapy was generally well tolerated; incidence of adverse events was similar between arms, except for an increase in rash and diarrhea with erlotinib (generally mild). Conclusion Erlotinib with concurrent cisplatin and gemcitabine showed no survival benefit compared with chemotherapy alone in patients with chemotherapy-naïve advanced NSCLC.

Response to selpercatinib versus prior systemic therapy in patients (pts) with RET fusion+ non-small-cell lung cancer (NSCLC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9032-9032
Author(s):  
Alexander E. Drilon ◽  
Oliver Gautschi ◽  
Benjamin Besse ◽  
Vivek Subbiah ◽  
Daniel Shao-Weng Tan ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Survival Duration ◽  
Prior Therapy ◽  
Platinum Based Chemotherapy ◽  
Systemic Therapies

9032 Background: Selpercatinib, a first-in-class highly selective, potent, CNS-active RET kinase inhibitor, is approved in multiple countries for treatment of RET fusion+ lung or thyroid cancers. Selpercatinib demonstrated durable antitumor activity in previously treated pts with RET fusion+ NSCLC in an ongoing Phase 1/2 trial, LIBRETTO-001 (Besse et al., ASCO 2021). Methods: Pts with RET fusion+ NSCLC enrolled in the global, multicenter, LIBRETTO-001 trial (NCT03157128; 16 countries, 89 sites). Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival, duration of response, and safety. This post-hoc intrapatient analysis was based on a 30 March 2020 data cutoff date. Historical physician-reported best overall response (BOR) from last systemic therapy received prior to enrollment was compared with selpercatinib BOR by independent review committee per RECIST v1.1, with each patient serving as his/her own control. Results: In efficacy-evaluable pts (N = 218) who previously received platinum-based chemotherapy (chemo), median pt age was 61 years, the majority with ECOG of 0/1 (37%/61%), with a median of 2 (range: 1-15) prior systemic therapies. Overall, 57% of patients responded to selpercatinib while 16% responded to the immediate prior therapy. ORR improvements with selpercatinib were observed regardless of prior therapy: chemotherapy + immune checkpoint inhibitor (ICI) (57% vs 14%), single-agent ICI (48% vs 3%), or chemotherapy (58% vs 15%). A total of 108 patients (49%) did not respond to immediate prior therapy but responded to selpercatinib. Fewer patients had progressive disease as their BOR with selpercatinib (2%) compared to the immediate prior therapy (28%). The median duration of therapy for selpercatinib was notably extended compared with that of the immediate prior therapy (11.8 vs. 3.4 months, respectively). Conclusions: In pts with RET fusion+ NSCLC treated on LIBRETTO-001, systemic therapies administered prior to enrollment achieved less meaningful clinical benefit than selpercatinib. Selpercatinib demonstrated consistent efficacy regardless of the type of prior therapy. Clinical trial information: NCT03157128.

A randomized, double-blind phase II study of the oral tyrosine kinase inhibitor (TKI) axitinib (AG-013736) in combination with docetaxel (DOC) compared to DOC plus placebo (PL) in metastatic breast cancer (MBC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 1003-1003 ◽  
Author(s):  
H. S. Rugo ◽  
A. Stopeck ◽  
A. A. Joy ◽  
S. Chan ◽  
S. Verma ◽  
...  
Keyword(s):  
Adverse Events ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Single Agent ◽  
Metastatic Breast ◽  
Primary Objective ◽  
Hazard Ratio ◽  
Ecog Performance Status ◽  
Double Blind ◽  
Grade 3

1003 Background: Single-agent DOC is commonly used to treat MBC. Axitinib (AG) is a potent TKI of VEGFRs. A phase I lead-in study identified 80 mg/m2 q3wks of DOC in combination with 5 mg BID of AG as the recommended phase 2 dose. The primary objective was to determine whether the time to progression (TTP) of AG+DOC arm is superior to DOC+PL. Methods: Pts with no prior chemotherapy for MBC and =12 mos from adjuvant chemotherapy (aCT), measurable disease, ECOG performance status (PS) of 0–2, and no uncontrolled brain metastases were randomly assigned (2:1) to receive treatment with either DOC+AG or DOC+PL without prophylactic growth factor in cycle 1. Tumor measurements were performed q9wks. Pts were stratified according to estrogen receptor (ER) status, prior aCT and PS (0–1 or 2). Results: A total of 168 pts were randomized. 92 pts had received prior aCT, 27 of whom received a prior taxane. Treatment arms were well balanced for prior adjuvant and taxane therapy. A median of 7 cycles of AG+DOC (range: 1–18) and 7 cycles of DOC+PL (range: 1–23) were administered. The most common non-hematologic adverse events observed in the AG+DOC arm included diarrhea (60%), nausea (53%), alopecia (51%), fatigue (49%), stomatitis (44%) and vomiting (40%). Grade 3/4 adverse events that were increased with AG+DOC vs DOC included febrile neutropenia (16 vs 7%), fatigue (13 vs 5%), stomatitis (13 vs 2%), diarrhea (11 vs 0%) and hypertension (5 vs 2%). Other grade 3/4 hematologic toxicities were similar in both arms. The median TTP (by RECIST) was 8.2 mo with AG+DOC arm and 7 mo with DOC+PL arm with a hazard ratio of 0.73 (prespecified, one-sided p=0.052). The overall response rate (ORR) was 40% for AG+DOC arm and 23% for DOC+PL arm (p=0.038). In a hypothesis-generating subgroup analysis, the median TTP in patients receiving prior aCT was 9.0 mo with AG+DOC arm and 6.3 mo with DOC+PL arm with a hazard ratio of 0.54 (p=0.012). Within this stratum, ORR was 45% for AG+DOC arm and 13% for DOC+PL arm (p=0.003). Conclusions: The anti-angiogenic TKI AG combined with DOC (80 mg/m2 q3wks) as first line therapy for MBC has an acceptable safety profile and promising anti-tumor activity. No significant financial relationships to disclose.

A phase II study of enzastaurin as second- or third-line treatment of non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7543-7543 ◽  
Author(s):  
G. Bepler ◽  
Y. Oh ◽  
H. Burris ◽  
A. Cleverly ◽  
M. Lahn ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Line Treatment ◽  
Platinum Based Chemotherapy ◽  
Third Line ◽  
Third Line Treatment

7543 Background: Enzastaurin, an oral serine/threonine kinase inhibitor, suppresses signaling through PKC and the PI3K/AKT pathway, induces tumor cell apoptosis, reduces proliferation, and suppresses tumor-induced angiogenesis. Over-expression and activity of PKC and PI3K/AKT are associated with poor prognosis and treatment resistance in NSCLC. This multicenter phase II trial of enzastaurin as second- and third-line treatment of NSCLC determined the rate of progression-free survival (PFS) at 6 months (mos). Secondary objectives included safety and the rate of overall survival (OS) at 12 mos. Methods: Eligibility included metastatic (stage IV and wet IIIB) NSCLC and prior platinum-based chemotherapy. Patients (pts) received 500 mg of oral enzastaurin, once daily, until disease progression or unacceptable toxicity occurred. All pts were eligible for 2nd or 3rd line treatment. Results: In the 54 pts enrolled [54% M, 46% F; median age: 63 (range: 43–82); 22.2% stage III, 77.8% stage IV, ECOG PS=2], adenocarcinoma was the most frequent diagnosis (67%). Prior therapies included radiotherapy (74%) and EGFR inhibitors (28%). At the final analysis, the median PFS was 1.9 mos (95% CI: 1.7–1.9), and the PFS rate at 6 mos was 14% (95% CI: 4.4%–23.6%). The median OS was 9.9 mos (95% CI: 6.5–14.6). The OS rate at 12 mos was 46.3% (95% CI: 32.1%–60.5%). Nineteen pts (35%) had stable disease (SD); none had a complete or partial response. Ten (19%) pts were on-study for =6 cycles, 3 of whom continued for >10 months. The most common toxicity, fatigue (grade =2, n=15), occurred within 1 week of enrollment and was not reported in pts with SD. Grade =3 toxicities observed were ataxia (n=1), fatigue (n=2), thrombo-embolism (n=1), and anemia (n=1). Two pts discontinued due to fatigue and dizziness. Five pts died on-study and 4 within 30 days of discontinuation due to PD. Post-study chemotherapy (n=28) included bevacizumab, erlotinib, pemetrexed, gemcitabine, cisplatinum and paclitaxel. Conclusion: Although no objective tumor responses occurred, 14% of the pts were progression-free at 6 months. Based on encouraging survival and tolerability data, further evaluation of enzastaurin as a single agent or in combination, is warranted in NSCLC. No significant financial relationships to disclose.

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