LENVAGIST - A multicenter, comparative, placebo-controlled, double-blinded, phase II study of the efficacy of lenvatinib in patients with locally advanced or metastatic GIST after failure of imatinib and sunitinib.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS11568-TPS11568
Author(s):  
Axel Le Cesne ◽  
Claire Cropet ◽  
Julien Gautier ◽  
Stéphanie Gagne ◽  
Katia Francourt ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Differentiated Thyroid Carcinoma ◽  
Primary Objective ◽  
Rank Test ◽  
Recist 1.1 ◽  
Double Blinded

TPS11568 Background: GastroIntestinal Stromal Tumors (GIST) are paradigmatic models of cancers with a driver mutation of an oncogene, in which imatinib is recommended as adjuvant therapy or treatment of locally advanced and metastatic forms. After failure of imatinib (either progression or toxicity), sunitinib and regorafenib are indicated as 2nd and 3rd lines, respectively. Beyond approved drugs, tyrosine kinase inhibitors (TKI) can bring clinical benefit because some clones remain sensitive to TKI. Lenvatinib is a broad spectrum TKI targeting KIT, RET, PDGFRA, VEGFR 1-3 and FGFR 1-4, that is approved in the treatment of differentiated thyroid carcinoma and metastatic renal cell carcinoma and hepatocellular carcinoma. Methods: This prospective, randomized, placebo-controlled, double-blinded, multicenter trial evaluates the efficacy and safety of Lenvatinib in adult GIST patients (pts) who failed at least to previous imatinib and sunitinib. Seventy-four pts will be randomly allocated in a 1:1 ratio to receive either oral lenvatinib, at a daily dose of 24mg, or its matching placebo, continuously, until progression of disease (PD) or unacceptable toxicity. Randomization will be stratified according to the number of different previous anticancer drugs (2 or > 2). The primary objective is to compare the Progression-free survival (PFS) between arms. The expected median PFS are 1.5 month in the control arm and 3.0 months in the experimental arm (HR = 0.5). Seventy one events will provide 90% power to show significant improvement in PFS, using a 2-sided log-rank test at a 10% level. Secondary endpoints include the overall survival, the objective response rate, the best overall response, the quality of life and the safety profile. Patients allocated in the placebo arm who experience PD (RECIST 1.1) may switch to active lenvatinib. Radiological endpoints will be evaluated using the RECIST 1.1. Translational objectives will be to identify blood and tumor parameters as predictive markers of lenvatinib efficacy. Recruitment has been activated in January 2020. Ten participating sites of the French Sarcoma Group will participate in the trial. Clinical trial information: NCT04193553 .

Hand–foot syndrome (HFS) as a potential biomarker of efficacy in patients (pts) with metastatic renal cell carcinoma (mRCC) treated with sunitinib (SU).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 320-320 ◽  
Author(s):  
M. D. Michaelson ◽  
D. P. Cohen ◽  
S. Li ◽  
R. J. Motzer ◽  
B. Escudier ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Time Dependent ◽  
Phase Iii ◽  
Rank Test ◽  
Significant Independent Predictor ◽  
Potential Biomarker

320 Background: HFS and related skin toxicities are common side effects of tyrosine kinase inhibitors such as SU, a multitargeted inhibitor of VEGF and PDGF receptors plus other receptor tyrosine kinases. In a randomized phase III trial of treatment-naïve mRCC pts, SU showed superior progression-free survival (PFS) and objective response rate (ORR) over interferon-alfa, with a median PFS of 11 mo and median overall survival (OS) of 26.4 mo, establishing SU as a reference standard of care (Motzer et al, 2009). In this retrospective analysis, correlations between SU-associated HFS and efficacy endpoints were investigated in mRCC pts from 5 clinical trials in the first- and second-line treatment settings. Methods: Analyses included pooled data from 770 pts who received single-agent SU as 50 mg/d on a 4-week-on/2-week-off schedule (n=544; 71%) or 37.5 mg continuous once-daily dosing (n=226; 29%). Median PFS and OS were estimated by Kaplan–Meier methods and compared between pts with vs without HFS using a log-rank test. ORR was compared by Pearson's chi-square test. Tumor response was assessed by investigators and adverse events were recorded regularly. Multivariate and time-dependent covariate analyses were performed. Results: Of 770 pts, 179 (23%) developed any-grade HFS, compared with 591 (77%) who did not. Most instances of HFS (63%) initially occurred during the first 3 treatment cycles. Pts who developed HFS had significantly better ORR (55.6% vs. 32.7%), PFS (14.3 vs. 8.3 mo), and OS (38.3 vs. 18.9 mo) than pts who did not develop HFS (p<0.0001). In a multivariate analysis, SU-associated HFS remained a significant independent predictor of both PFS and OS (and of OS by time-dependent covariate analysis). Conclusions: In mRCC pts, SU-associated HFS was significantly and independently associated with improved clinical outcomes. Overall, pts who did not develop HFS still had substantial benefit from SU. However, the presence of HFS identified a subset of pts that manifested highly favorable efficacy results with SU. These findings suggest that development of HFS may serve as a predictive biomarker of SU efficacy, although prospective validation is warranted. [Table: see text]

A phase 2 study of cabozantinib as first-line treatment in collecting ducts renal cell carcinoma: The BONSAI trial.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS709-TPS709
Author(s):  
Giuseppe Procopio ◽  
Raffaele Ratta ◽  
Giovanni Fucà ◽  
Paolo Grassi ◽  
Luca Porcu ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Response To Treatment ◽  
Second Stage ◽  
Collecting Ducts

TPS709 Background: Collecting ducts carcinoma (CDC) is a rare and aggressive form of renal cell carcinoma, characterized by extremely poor prognosis and resistance to agents effective in other forms of RCC. We hypothesized that cabozantinib, an inhibitor of multiple kinases including VEGFR 2, MET and AXL, may be superior in terms of efficacy to other angiogenesis inhibitors in the treatment of CDC due to its high-spectrum of activity against multiple and non-redundant oncogenic pathways. Methods: The BONSAI study is a prospective, single-centre, single-arm phase II trial evaluating cabozantinib in patients with untreated locally advanced or metastatic CDC. Cabozantinib will be administered at the dose of 60 mg orally once daily until the evidence of disease progression (PD) evaluated by RECIST 1.1 or unacceptable toxicity. Primary objective is the evaluation of objective response rate (ORR). Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety profile of cabozantinib. Exploratory objectives include the evaluation of genetic and immunological landscape of CDC and its correlation with response to treatment. Overall, 23 patients will be enrolled into the study based on a Simon’s two-stage optimal design. In order to reject an ORR equal to 15% with a one-sided alpha error of 10% and to detect an ORR equal to 35% with a power of 80%, 9 patients will be enrolled in the first stage. If at least 2 responses will be observed in the first stage, 14 additional patients will be included in the second stage. If at least 6 responses will be observed at the second stage the activity of cabozantinib will be proved. First patient enrollment is scheduled in November 2017.

Results of the JAVELIN Gastric 100 phase 3 trial: avelumab maintenance following first-line (1L) chemotherapy (CTx) vs continuation of CTx for HER2− advanced gastric or gastroesophageal junction cancer (GC/GEJC).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 278-278 ◽  
Author(s):  
Markus H. Moehler ◽  
Mikhail Dvorkin ◽  
Mustafa Ozguroglu ◽  
Min-hee Ryu ◽  
Alina Simona Muntean ◽  
...  
Keyword(s):  
Gastroesophageal Junction ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Clinical Activity ◽  
Primary Analysis ◽  
Open Label ◽  
Phase 3 ◽  
Post Induction

278 Background: We report the primary analysis of JAVELIN Gastric 100, which compared avelumab (anti–PD-L1) maintenance after 1L CTx vs continued CTx in patients (pts) with GC/GEJC. Methods: In this global, open-label, phase 3 trial (NCT02625610), eligible pts had previously untreated, unresectable, locally advanced/metastatic (LA/M) HER2− GC/GEJC. Pts without progressive disease (PD) after 12 weeks of 1L oxaliplatin/fluoropyrimidine induction were randomized 1:1 to avelumab 10 mg/kg Q2W switch maintenance or continued CTx, stratified by region (Asia vs non-Asia). Primary endpoint was overall survival (OS) post induction in all randomized or PD-L1+ (≥1% of tumor cells, 73-10 assay) pts. Results: 805 pts received induction CTx and 499 pts were randomized (avelumab, n = 249; CTx, n = 250). At data cutoff (Sep 13, 2019), minimum follow-up was 18 months. In the avelumab and CTx arms, median OS post induction/randomization was 10.4 months (95% CI 9.1-12.0) vs 10.9 months (95% CI 9.6-12.4), hazard ratio (HR) 0.91 (95% CI 0.74-1.11; p = 0.1779); 24-month OS rates were 22.1% (95% CI 16.8-28.0) vs 15.5% (95% CI 10.8-20.9), respectively. The HR for OS in PD-L1+ pts (n = 54) was 1.13 (95% CI 0.57-2.23). No OS trend was seen in Asian pts (n = 114; HR 0.90 [95% CI 0.59-1.36]) or other subgroups, except for a potential benefit with avelumab in pts with no metastatic sites at randomization (n = 60; HR 0.52 [95% CI 0.28-0.98]). Progression-free survival was similar between arms (HR 1.04 [95% CI 0.85-1.28]). In the avelumab vs CTx arms, objective response rates (post randomization only) were 13.3% (95% CI 9.3-18.1) vs 14.4% (95% CI 10.3-19.4), and 12-month rates for duration of response were 62.3% (95% CI 40.9-77.9) vs 28.4% (95% CI 13.2-45.7), respectively. Treatment-related adverse event rates (all grades/grade ≥3) were 61.3%/12.8% with avelumab and 77.3%/32.8% with CTx. Conclusions: Avelumab maintenance showed clinical activity and favorable safety vs continued CTx in pts with LA/M GE/GEJC; however, JAVELIN Gastric 100 did not meet its primary objective of demonstrating superior OS in the randomized or PD-L1+ population. Clinical trial information: NCT02625610.

scholarly journals Confirmed Activity and Tolerability of Weekly Paclitaxel in the Treatment of Advanced Angiosarcoma

Sarcoma ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-7 ◽  
Author(s):  
Gaetano Apice ◽  
Antonio Pizzolorusso ◽  
Massimo Di Maio ◽  
Giovanni Grignani ◽  
Vittorio Gebbia ◽  
...  
Keyword(s):  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Weekly Paclitaxel ◽  
Ecog Performance Status ◽  
Small Series ◽  
Prospective Phase ◽  
Pretreated Patients

Background.In several prospective and retrospective studies, weekly paclitaxel showed promising activity in patients with angiosarcoma.Patients and Methods. Our study was originally designed as a prospective, phase II multicenter trial for patients younger than 75, with ECOG performance status 0–2, affected by locally advanced or metastatic angiosarcoma. Patients received paclitaxel 80 mg/m2intravenously, at days 1, 8, and 15 every 4 weeks, until disease progression or unacceptable toxicity. Primary endpoint was objective response.Results. Eight patients were enrolled but, due to very slow accrual, the trial was prematurely stopped and further 10 patients were retrospectively included in the analysis. Out of 17 evaluable patients, 6 patients obtained an objective response (5 partial, 1 complete), with an objective response rate of 35% (95% confidence interval 17%–59%). Of note, five responses were obtained in pretreated patients. In the paper, details of overall survival, progression-free survival, and tolerability are reported.Conclusions. In this small series of patients with locally advanced or metastatic angiosarcoma, weekly paclitaxel was confirmed to be well tolerated and active even in pretreated patients.

Fluorouracil, Doxorubicin, and Streptozocin in the Treatment of Patients With Locally Advanced and Metastatic Pancreatic Endocrine Carcinomas

2004 ◽  
Vol 22 (23) ◽  
pp. 4762-4771 ◽  
Author(s):  
Maria A. Kouvaraki ◽  
Jaffer A. Ajani ◽  
Paulo Hoff ◽  
Robert Wolff ◽  
Douglas B. Evans ◽  
...  
Keyword(s):  
Response Rate ◽  
Objective Response ◽  
Locally Advanced ◽  
Evaluation Criteria ◽  
Progression Free Survival ◽  
Response Duration ◽  
Response To Treatment ◽  
Rank Test ◽  
Median Response ◽  
Log Rank Test

Purpose The role of systemic chemotherapy in the management of pancreatic endocrine carcinoma (islet cell carcinoma; PEC) is an area of considerable controversy. Response rates ranging from 6% to 69% have been reported for streptozocin-based chemotherapy. We retrospectively studied 84 patients with locally advanced or metastatic PEC who had been treated with fluorouracil, doxorubicin, and streptozocin (FAS) to determine the objective response rate, duration of progression-free survival (PFS), and duration of overall survival (OS). Patients and Methods Eligible patients had histologic or cytologic confirmation of their tumor and measurable disease on computed tomography or magnetic resonance imaging scans. Response to treatment was evaluated in this study using the new international criteria proposed by the Response Evaluation Criteria in Solid Tumors Committee. Results Sixty-one of the patients were male and 23 were female, with a median age of 54 years (range, 24 to 78 years). The response rate (RR) to FAS was 39%, with a median response duration of 9.3 months. The 2-year PFS rate was 41%, and the 2-year OS rate was 74%. The extent of liver metastatic disease correlated with a worse PFS (P = .01 by log-rank test) and a worse OS (P < .0001 by log-rank test). Analyses showed that metastatic replacement of more than 75% of the liver and prior chemotherapy were independently associated with inferior PFS. Conclusion Patients with locally advanced or metastatic PEC who are treated with FAS may have a reasonable RR, and responders may experience longer PFS and OS. The volume of metastases in the liver is the most important predictor of outcome.

Phase Ib study of tepotinib in EGFR-mutant/c-Met-positive NSCLC: Final data and long-term responders.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 8547-8547 ◽  
Author(s):  
Yi-Long Wu ◽  
Ross A. Soo ◽  
Dong-Wan Kim ◽  
James Chih-Hsin Yang ◽  
Jürgen Scheele ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitors ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Good Tolerability ◽  
Phase Ib ◽  
Final Data ◽  
Egfr Mutant ◽  
Egfr Tki

8547 Background: Patients (pts) with NSCLC that is initially responsive to EGFR tyrosine kinase inhibitors (EGFR TKI) typically develop resistance, often associated with aberrant c-Met activity. Dual inhibition of EGFR and c-Met is therefore a rational option to treat c-Met+ EGFR TKI-resistant NSCLC. Tepotinib is a highly selective c-Met inhibitor with good tolerability and promising activity against solid tumors. We report final data from a phase Ib trial of tepotinib + gefitinib in pts with c-Met+/EGFR-mutant NSCLC conducted in Asia. Methods: Eligible pts were adults with locally advanced/metastatic NSCLC and ECOG PS 0–1. Tumors had to express EGFR with an activating mutation be resistant to EGFR TKI therapy and be c-Met+ by IHC. Pts received tepotinib 300 or 500 mg QD combined with gefitinib 250 mg QD (T300G250 or T500G250). The primary objective was to determine the recommended phase II dose (RP2D) of tepotinib in combination with gefitinib; secondary objectives included pharmacokinetics (PK), safety, and antitumor activity. Results: 18 pts were enrolled (median age 65 [41–78]; 8 male); 6 received T300G250, 12 T500G250. No dose-limiting toxicities were observed, and tepotinib 500 mg QD was confirmed as the RP2D. 17 pts experienced treatment-related treatment-emergent adverse events (TRTEAEs), mostly grade ≤2 and most commonly diarrhea (12), rash (8), and amylase increase (6). Grade ≥3 TRTEAEs were increased amylase (n = 4), increased lipase (3), neutropenia (1), and hyperglycemia (1). The best overall response was partial response in 6 pts; 4/7 pts with IHC 3+ tumors responded (all treated with T500G250) vs 2/11 with IHC 2+ tumors. Response durations of pts with PR were 4.2–12.5 months. 4/18 pts (IHC 2+, n = 3) had stable disease. 8 pts experienced progression free survival > 5 months, 3 pts > 10 months. PK were as expected from previous studies. Conclusions: Tepotinib in combination with gefitinib was well tolerated. The RP2D of tepotinib for use in combination with gefitinib in NSCLC is 500 mg QD. T500G250 showed signs of activity against c-Met+ tumors. A phase II trial is randomizing ≈156 pts with c-Met+/T790M– tumors who have failed first-line EFGR TKI 2:1 to tepotinib + gefitinib or pemetrexed + cisplatin/carboplatin. Clinical trial information: NCT02864992.

Phase II study for the evaluation of efficacy of pembrolizumab (MK-3475) in patients with cancer of unknown primary.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3103-TPS3103 ◽  
Author(s):  
Gauri R. Varadhachary ◽  
Kanwal Pratap Singh Raghav ◽  
Shubham Pant ◽  
Filip Janku ◽  
Siqing Fu ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Cancer Of Unknown Primary ◽  
Unknown Primary ◽  
Progression Rate ◽  
Pathologic Evaluation ◽  
Recist 1.1 ◽  
Imaging Characteristics

TPS3103 Background: Cancer of unknown primary is a biopsy proven malignancy for which an anatomic primary remains unidentified after a focused search. It accounts for 3-4 % of all solid cancers and most investigators limit it to epithelial and undifferentiated cancers. Patients with metastatic melanoma and sarcoma are excluded. Sophisticated imaging, robust pathologic evaluation including immunostains, and genomic and proteomic characterization of these cancers have challenged the management of CUP. The paradigm has shifted from empiric platinum based combination doublets to a personalized approach. Nevertheless, without an anatomic primary, clinical trial opportunities are limited. There remains an unmet research need to evaluate the role of immunotherapy, specifically checkpoint blockade drugs in specific subsets of CUP patients. Methods: Adult Patients ≥ 18 years of age with ECOG PS 0-1, must meet the definition of a CUP cancer. Patients must be intolerant and/or refractory to at least one line of established therapy known to provide clinical benefit for their condition within the last 6 months (often, a platinum based therapy for carcinomas). Patients must have either measurable (RECIST 1.1) or evaluable disease. Although not limited to subtypes, there is a signficant interest in enrolling patients with isolated disseminated lymphadenopathy, HPV (+) CUP and those who have an IHC profile of those known cancers for which anti-PD therapy has been approved (lung, renal, others) The primary objective of this trial is to evaluate efficacy by evaluation of non-progression rate (NPR) at 27 weeks (9 cycles) as defined as the percentage of CUP patients who are alive and progression-free at 27 weeks (9 cycles) as assessed by RECIST 1.1. Secondary objectives include evaluating safety and tolerability of pembrolizumab (MK-3475); correlating efficacy, non-progression rate (NPR) at 27 weeks (9 cycles), objective response (CR or PR), progression-free survival (PFS), overall survival (OS) and duration of response (DOR) to PD-L1 status; and identifying imaging characteristics associated with immunological changes in tumor following treatment with pembrolizumab. Enrollment is ongoing. Clinical trial information: NCT02721732.

CARSKIN: Pembrolizumab as first line therapy in patients with unresectable cutaneous squamous cell carcinoma (cSCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS9596-TPS9596 ◽  
Author(s):  
Eve Maubec ◽  
Sabine Helfen ◽  
Isabelle Scheer-Senyarich ◽  
Marouane Boubaya ◽  
Olivier Schischmanoff ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Options ◽  
Locally Advanced ◽  
Immune Surveillance ◽  
Death Receptor ◽  
Progression Free Survival ◽  
The Elderly ◽  
Primary Objective ◽  
Open Label ◽  
Recist 1.1

TPS9596 Background: Treatment options are limited for patients (pts) with locally advanced or metastatic cSCCs. Cisplatin-based combinations have some efficacy but their toxicity often prohibits their use, particularly for the elderly. New therapeutic options are needed. Tumors divert the programmed death receptor 1 (PD-1) pathway suppressing immune control. Pembrolizumab (MK-3475) is a high-affinity humanized monoclonal anti-PD-1 antibody. It leads to dual PD-1 ligand (PD-L1 and PD-L2) blockade that may reactivate the immune surveillance and elicit anti-tumor response. It has antitumor activity in several tumors including head and neck SCCs. Moreover, an efficacy of pembrolizumab in cSCCs has been reported recently in a series of 6 cases. Methods: CARSKIN (ClinicalTrials.gov, NCT02883556) is a French multicenter, open-label, nonrandomized phase 2 trial, designed to evaluate the efficacy and safety of pembrolizumab in 39 pts with unresectable and/or metastatic cSCCs, naive of chemotherapy and of EGFR inhibitors. Pembrolizumab is administered (200 mg IV Q3W) for up to 24 months or until disease progression or unacceptable toxicity. Eligible pts must undergo a baseline biopsy of the tumor prior to treatment for PD-L1 evaluation. Response is to be assessed at baseline, wk 9, 15 and 24, and thereafter Q12W by central radiology review per RECIST 1.1 and per modified RECIST v1.1. The primary objective is response rate (RR) at wk 15 per RECIST 1.1. Secondary efficacy objectives are to assess whether patients with PD-L1+ tumors have a better RR than the whole sample at wk 15 and to assess in the whole sample and in PD-L1+ pts, disease control rate (DCR) at wk15, RR at wk 24, best RR, overall survival (OS), progression free survival (PFS), duration of response / control and time to disease progression. A Simon optimal two-stage design will be used. Four responders among 19 pts will be needed in the 1st step to continue the trial. Overall 9 responses will be needed to conclude the effectiveness. Kaplan-Meier statistics will assess PFS and OS. Adverse events (AEs) will be assessed throughout the study and for 30 d thereafter (6 m for serious AEs) and graded per NCI CTCAE v4.0. Clinical trial information: NCT02883556.

Quality-of-life (QoL) in RANGE: A phase 3 study of ramucirumab (RAM) plus docetaxel (DOC) versus placebo (P) plus DOC in platinum-refractory locally advanced or metastatic urothelial carcinoma (UC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 419-419 ◽  
Author(s):  
Andrea Necchi ◽  
Hiroyuki Nishiyama ◽  
Nobuaki Matsubara ◽  
Jae-Lyun Lee ◽  
Daniel Peter Petrylak ◽  
...  
Keyword(s):  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Median Number ◽  
Rank Test ◽  
Point Change ◽  
Exact Test ◽  
Eortc Qlq C30 ◽  
Platinum Refractory ◽  
Eortc Qlq

419 Background: RAM + DOC in RANGE (NCT02426125) improved progression free survival (hazard ratio [HR] = 0.757) with a higher objective response rate (24.5% vs 14%) and an acceptable safety profile (Petrylak, et al Lancet 2017). QoL was a secondary objective. Methods: Patients (pts) whose UC progressed following platinum-based therapy were randomized to receive RAM (10 mg/kg) + DOC (75 mg/m2) or P + DOC on Day 1 of a 21-day cycle. Treatment continued until disease progression or unacceptable toxicity with a maximum of 10 cycles for DOC. Pts completed the EORTC QLQ-C30 (v3) prior to each cycle & at the 30-day follow up visit. QoL scales were analyzed for: 1) rates of improved/stable scores (compared with Fisher’s exact test) & 2) time to sustained deterioration (TtD), defined as randomization to first worsening with no subsequent non-worsened assessment (compared with unstratified log-rank test). A ≥10 point change (on 100-point scale) was deemed clinically meaningful. Results: 530 pts were randomized. 254/263 (97%) RAM-DOC & 260/267 (97%) P-DOC pts provided baseline (BL) QoL data & ≥85% for post-BL, on-therapy assessments. Median number of cycles was 4 for RAM-DOC & 3 for P-DOC. Mean BL scores were similar between arms & indicated greatest impairment for global QoL, fatigue, pain, & insomnia. For all scales, rates of improved/stable scores were not different, except for pain at Cycles 4 & 7 where rates were higher for RAM-DOC (p < 0.05). Relative to other QoL scales, pain generally had highest rates of improved scores in both arms (14-25% for RAM-DOC & 8-24% for P-DOC for Cycles 1-4). In a post hoc analysis, Cycles 1-4 rates of improved pain scores were 31-32% for RAM-DOC & 14-26% for P-DOC in tumor responders, but 17-29% for RAM-DOC & 16-28% for P-DOC in pts with stable disease. For TtD, 14/15 QoL scales had HRs < 1, indicating similar or numerically longer TtD in QoL for RAM-DOC (HRs 0.67- 1.06; all 95% confidence intervals included 1). Conclusions: The addition of RAM to DOC for platinum-refractory UC pts did not adversely impact QoL relative to P-DOC. Trends in improved TtD and improved rates of pain associated with tumor response favored RAM-DOC. Clinical trial information: NCT02426125.

Randomized phase II study of vandetanib (VAN) alone or in combination with carboplatin and paclitaxel (CP) as first-line treatment for advanced non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7544-7544 ◽  
Author(s):  
J. Heymach ◽  
L. Paz-Ares ◽  
F. De Braud ◽  
M. Sebastian ◽  
D. J. Stewart ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Circulating Endothelial Cells ◽  
Once Daily ◽  
Randomized Phase Ii ◽  
Biomarker Analysis

7544 Background: VAN (ZD6474) is a once-daily oral agent that selectively inhibits VEGFR, EGFR and RET signaling. This randomized phase II trial investigated VAN alone or in combination with CP vs CP. Methods: Eligible patients (pts) had previously untreated locally advanced or metastatic (IIIB-IV) NSCLC. The primary objective was to determine whether VAN (300 mg/day) ± CP (C, target AUCss = 6 mg/ml·min; P; 200 mg/m2 iv) prolonged progression-free survival (PFS) vs CP (75% power to detect 30% prolongation; 1-sided P=0.2). An initial run-in phase had established VAN 300 mg/day as an appropriate dose to be given with CP. Results: A total of 181 pts (median age 61 yrs, range 27–83) received VAN (n=73), VAN + CP (n=56) or CP (n=52). The primary objective was met, with VAN + CP prolonging PFS vs CP (HR = 0.76, 95% CI 0.50–1.15; P=0.098): median PFS = 24 wks (VAN + CP) and 23 wks (CP). The VAN monotherapy arm was stopped early after a planned interim PFS analysis met the criterion for discontinuation (HR > 1.33 vs CP). The objective response rates were 32%, 25% and 7% for VAN + CP, CP and VAN, respectively. Overall survival (OS), a secondary endpoint, was not significantly different between pts receiving VAN + CP or CP (HR = 1.07, 95% CI 0.63–1.81; P=0.595). Exploratory subgroup analyses suggest advantages in PFS and OS for VAN + CP vs CP for the 56 female pts. There was a higher incidence of some adverse events with VAN + CP vs CP, including rash (64% vs 33%), diarrhea (53% vs 32%), asymptomatic QTc-related events (22% vs 4%) and hypertension (32% vs 4%). Pts receiving VAN + CP, including 7 who entered with CNS metastases and 11 with squamous histology, did not experience any intracranial bleeding, or hemoptysis of CTC grade 2 or higher. A biomarker analysis, including circulating endothelial cells and 35 plasma angiogenic factors and cytokines, suggests several potential markers predictive of clinical outcome and will be reported separately. Conclusions: In this randomized phase II trial of 1st-line advanced NSCLC, VAN + CP met the primary endpoint of prolonging PFS vs CP alone but did not provide a detectable survival advantage. No significant financial relationships to disclose.

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