Randomized phase II trial of the carboxylesterase (CES)-converted novel drug EDO-S7.1 in patients (pts) with advanced biliary tract cancers (BTC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 264-264
Author(s):  
Ulrich-Frank Pape ◽  
Stefan Kasper ◽  
Johannes Meiler ◽  
Marianne Sinn ◽  
Arndt Vogel ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Primary Objective ◽  
The Novel ◽  
Treatment Difference ◽  
Randomized Phase Ii ◽  
Significant Efficacy ◽  
Prior Surgery ◽  
Novel Drug

264 Background: The novel drug EDO-S7.1 (CAP7.1) is converted to active etoposide by CES allowing administration of higher doses, reducing resistance, and permitting treatment of advanced tumors. Methods: The primary objective was to compare disease control rate (DCR) in 22 pts with unresectable BTC randomized 1:1 to 3-week cycles of EDO-S7.1 (200 or 150mg/m2; iv) given on days (d) 1–5, or best supportive care (BSC) until progression (assessed every 4 weeks). Secondary objectives were progression-free survival (PFS), time to treatment failure (TTF), overall survival (OS) and safety. BSC pts could crossover to EDO-S7.1 upon progression. Results: DCR favored EDO-S7.1 (55.6% [CI 21.2, 86.3] vs BSC (20.0% [2.5, 55.6]; treatment difference –12.80, 72.39). More EDO-S7.1 treated pts achieved sustainable stable disease (SD) or partial response (PR) vs BSC. Progressive disease occurred in 40% EDO-S7.1 vs 70% BSC pts. Three pts (30%) who progressed on BSC achieved SD following crossover to EDO-S7.1, and one pt (10%) PR (total: 40.0% [12.2, 73.8]) vs two pts with SD following BSC (20.0% [2.5, 55.6]; treatment difference –0.17, 0.57; p=0.0786). Median PFS was 103d with EDO-S7.1 vs 39d with BSC (p=0.006), and median TTF 92d vs 39d, respectively (p=0.006). Median OS was 227d with EDO-S7.1 vs 162d with BSC (p=0.088), and estimated 1-year OS 44% vs 11.3%, respectively. EDO-S7.1 had significant efficacy in pts with metastatic disease (p=0.029) or without prior surgery (p=0.032). Seven pts were eligible for exploratory analysis of tumor CES via immunohistochemistry. 4/7 pts had CES+ tumors and longer median PFS (195d [163, 233]) and OS (302d [214, 838]) vs pts with CES– tumors (46d [46, 83] and 83d [43, 319], respectively). The most common drug-related adverse events (G3–4) (%) were leukopenia 65 (26.1), neutropenia 78.3 (56.5), thrombocytopenia 56.5 (17.4), anemia 52.2 (17.4), alopecia 34.4 (0), fatigue 26.1 (0), and abdominal pain 30.4 (0). Conclusions: EDO-S7.1 demonstrated efficacy in pts with advanced BTC and may provide a new biomarker-guided therapeutic option with stratification by intra-tumor CES assessment. These findings will be explored in a larger patient cohort. Clinical trial information: NCT02094560.

Vinflunine maintenance therapy versus best supportive care (BSC) after platinum combination in advanced bladder cancer: A phase II, randomized, open-label study (MAJA study)—SOGUG 2011-02.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4674-TPS4674
Author(s):  
Sonia Maciá ◽  
Jesus Garcia-Donas ◽  
Albert Font Pous ◽  
Montserrat Domenech ◽  
Xavier Garcia del Muro ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transitional Cell ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Primary Objective ◽  
Open Label ◽  
Microtubule Inhibitor ◽  
Translational Study ◽  
First Line Therapy ◽  
Radiological Response

TPS4674 Background: Vinflunine is a novel microtubule inhibitor currently approved by EMA as treatment after platinum progression, in metastasic bladder cancer. It is distinguished from the other vinca-alkaloids because it binds relatively weakly to tubulin, suggesting an improved tolerance profile as a result of less neuropathy. Based on the fact that no cumulative toxicity is expected and the results reported in second-line, we aim to test the role of vinflunine in first line therapy, as maintenance treatment for patients who obtain clinical benefit after platinum. Methods: This is a multicenter, randomized, open label, proof-of-concept study that will be performed in 20 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Subjects will be randomized in a 1:1 ratio to receive vinflunine 320 mg/m2 every 21 days plus BSC vs BSC alone until disease progression. Vinflunine dose will be 280mg/m2 for patients with PS=1, age ≥ 75 years, prior pelvic radiotherapy or creatinine clearance Cr <60ml/min. Stratification factors are: 1) Scheduled dose at randomization (320 vs 280mg/m2) 2) Liver metastasis (Y/N). Main inclusion criteria are: Subjects ≥18 and< 80 years of age with histological diagnosis of transitional cell carcinoma of the urothelial tract and measurable disease with radiological response or stabilization after 6 cycles of a platinum containing doublet for metastasic/advanced disease. Primary objective will be progression free survival (PFS), considering as clinically relevant 6 months in experimental arm. To guarantee an overall type-1 α error (one side) no greater than 0.05 and a type II (β) error 0.1 for the primary endpoint of PFS, a sample size of 86 patients allocated in a 1:1 ratio is planned. Recruitment is scheduled to start by February 2012. A pharmacogenomic translational study will also be conducted.

A randomized single blind controlled trial of beads versus doxorubicin-eluting beads for arterial embolization of hepatocellular carcinoma (HCC).

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 143-143 ◽  
Author(s):  
Karen T. Brown ◽  
Mithat Gonen ◽  
Kinh Gian Do ◽  
Anne M. Covey ◽  
George I. Getrajdman ◽  
...  
Keyword(s):  
Therapeutic Option ◽  
Controlled Trial ◽  
Arterial Embolization ◽  
Progression Free Survival ◽  
Cost Effective ◽  
Median Number ◽  
Primary Objective ◽  
Post Treatment ◽  
Intention To Treat ◽  
Effective Therapeutic Option

143 Background: HAE using particles is a method of treatment for HCC. The added role of doxorubicin has never been fully understood biologically. To date, no study has demonstrated any difference in outcome using HAE versus trans-arterial chemoembolization (TACE). Methods: Patients (pts) with unresectable Okuda stage I or II HCC with adequate liver function were randomized to BB or LC loaded with 150 mg of doxorubicin. Pts were evaluated by multiphasic CT 2-3 weeks post-treatment. Progression by RECIST and/or evidence of ≤5% necrosis was considered treatment failure. Otherwise pts were followed with CT every 3 months until progression or death. Pts with either recurrent tumor or new tumor outside the treated area could be re-treated. The primary objective was response rate (RR) by RECIST. With 50 pts in each arm response rates can be estimated to within +/- 14%. Secondary objectives included assessing safety and tolerability, time to progression (TTP), progression free survival (PFS), and overall survival (OS). Quantification of tumor necrosis (TN) using CT volumetric data was correlated with outcome. Analyses were intention-to-treat. Results: Between December of 2007 and March of 2012, 101 pts were randomized, 51 to BB and 50 to LC. Demographics in the two groups were comparable: median age was 67, 77% were male and 81% were Okuda I. Median number of embolizations was 2 in both arms. There was no difference in adverse events, the most common being post-embolization syndrome of pain, fever, nausea, or vomiting (84% in both groups). There was no difference in RR: BB 11% vs LC 9% (p=0.58). Median TTP was not reached. 12 month TTP was 49 versus 56% (p=0.84), median PFS was 7 versus 9 (p=0.6), and OS 14 versus 16 months (p=0.7) for BB and LC respectively. Change in TN/tumor volume post treatment did not predict OS in either group (p=0.28). Conclusions: No difference in response was noted between pts treated with BB versus LC. Given the comparable safety profile, TTP, PFS and OS, HAE should be considered a reasonable and cost-effective therapeutic option and may be preferable to LC. Clinical trial information: NCT00539643.

Final efficacy results of NCIC CTG IND.202: A randomized phase II study of recombinant interleukin-21 (rIL21) in patients with recurrent or metastatic melanoma (MM).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9032-9032 ◽  
Author(s):  
Teresa M. Petrella ◽  
Catalin Liviu Dragos Mihalcioiu ◽  
Elaine McWhirter ◽  
Karl Belanger ◽  
Kerry J. Savage ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Progression Free Survival ◽  
Lesion Size ◽  
Primary Objective ◽  
Effector Memory ◽  
Prior Therapy ◽  
Randomized Phase Ii ◽  
Elevated Liver Enzymes ◽  
Biomarker Analysis

9032 Background: rIL21 is a T-cell derived cytokine with antitumor activity dependent on NK cells or CD8+ T cells through induction of central and effector memory cells. A previous phase II study demonstrated an ORR of 22.5% in previously untreated patients with MM. We conducted a multicentre randomized phase II study of MM evaluating the efficacy, toxicity, pharmacokinetics, immunogenicity, and biomarkers of rIL21 versus dacarbazine (DTIC). Methods: Eligible patients: Recurrent or MM, with either maximum tumour lesion size of < 50 mm or LDH < 2.5 x ULN and prior therapy with BRAF/MEK inhibitors allowed. Patients were treated with either rIL-21, 30 µg /kg/day dose IV daily x 5 days weeks 1, 3, 5 q 8 weeks or dacarbazine (DTIC) 1000 mg/m2 IV q 3 weeks. The primary objective was to compare progression free survival (PFS). The trial was designed to detect a hazard ratio of 1.75 with one-sided alpha of 0.1; 58 progression events were required to provide 80% power. Results: 64 patients were randomized, 32 in the rIL-21 arm and 32 in the DTIC arm. The Table summarizes key demographic and efficacy endpoints. Common rIl21 related adverse events were fatigue, rash, diarrhea, nausea, myalgia and elevated liver enzymes. At least one dose reduction/ interruption or discontinuation occurred in 32 (100%) and 27 (96.4%) of rIL21 and DTIC patients. Conclusions: Despite encouraging efficacy in prior phase I/II studies, the results suggest that rIL-21 is comparable to DTIC in this patient population. Additional biomarker analysis from this study is pending and combination studies are currently ongoing. Clinical trial information: NCT00514085. [Table: see text]

Vinflunine maintenance therapy versus best supportive care after platinum combination in advanced bladder cancer: A phase II, randomized, open label, study (MAJA study, SOGUG 2011-02)—Interim analysis on safety.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 359-359 ◽  
Author(s):  
Susana Hernando Polo ◽  
Aranzazu Gonzalez del Alba ◽  
Begoña Perez-Valderrama ◽  
José Carlos Villa Guzman ◽  
Miguel Angel Climent ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Supportive Care ◽  
Interim Analysis ◽  
Primary Tumour ◽  
Transitional Cell ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Primary Objective ◽  
Open Label ◽  
Microtubule Inhibitor

359 Background: Vinflunine (VFL) is a novel microtubule inhibitor currently approved by EMA as treatment after platinum progression, in metastasic bladder cancer. We evaluated whether maintenance vinflunine delays progression after response to CT. Methods: Multicenter, randomized, open label, proof-of-concept study that is being performed in 21 institutions members of the Spanish Oncology Genitourinary Group (SOGUG). Subjects are randomized to receive (arm A) VFL 320 mg/m2 (280mg/m2 for patients with PS=1, age ≥ 75 years, prior pelvic radiotherapy or creatinine clearance Cr <60ml/min) every 21 days plus best supportive care (BSC) vs. (arm B) BSC alone until disease progression. Main inclusion criteria: Subjects ≥18 and< 80 years of age with histological diagnosis of transitional cell carcinoma of the urothelial tract and measurable disease whith radiological response or stabilization after 4 to 6 cy of a cisplatin-containing doublet for metastasic/advanced disease (carboplatin allowed on cy 5-6). Primary objective: progression free survival (PFS). A sample size of 86 patients allocated in a 1:1 ratio is planned. Recruitment started on April 2012. A pharmacogenomic translational study will be conducted. Results: To September 2013, 46 pts have been enrolled, 20 in the VFL+BSC group, 26 in the BSC group. We present the results of the interim analysis including data from first 25 patients who have completed at least 2 cycles. Median age 65.6 years (range 54-77); PS 0/1, 44%/56%; CrCl <60 ml/min 16%; liver metastasis 16%; prior pelvic RT 8%. Primary tumour location: bladder 76%, upper urinary tract 20%, urethra 4%. Pure transitional cells 84%. Metastatic/locoregional disease, 72% / 28%. We analyzed 63 cy in the chemotherapy arm. Most common G3/4 (% cycles) AEs on vinflunine were constipation (12.7%), neutropenia (7.9%), fatigue (4.8%), myalgia (3.2%). One death was reported due to dyspnea, not related to the treatment. No febrile neutropenia was reported at the time of the analysis. Conclusions: Maintenance with vinflunine presented an acceptable security profile leading to trial continuation. Clinical trial information: 2011-001271-39.

Randomized, multicenter phase II trial of CAP7.1 in patients with advanced biliary tract cancers.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 441-441
Author(s):  
Ulrich-Frank Pape ◽  
Stefan Kasper ◽  
Marianne Sinn ◽  
Karel Caca ◽  
Jan Kuhlmann ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Biliary Tract ◽  
Progression Free Survival ◽  
Complete Response ◽  
Best Supportive Care ◽  
Primary Objective ◽  
Free Survival ◽  
Biliary Tract Cancers ◽  
Multicenter Phase ◽  
Recist 1.1

441 Background: Non-resectable biliary tract cancers (BTC) have poor prognosis, but are chemosensitive. CAP7.1 is a new chemical entity that releases etoposide in the presence of carboxylesterases, leading to higher intra-tumor etoposide (E) with improved safety and efficacy. Methods: The primary objective of this trial is to determine the rate of disease control (DCR) (stable disease, SD; partial response, PR and complete response, CR) according to Recist 1.1. of CAP7.1 in patients (pts) with BTC. Secondary objectives are progression free survival (PFS), overall survival (OS) and safety. Pts with adenocarcinoma arising from bile ducts or gallbladder were randomized (1:1) to either CAP7.1 or best supportive care (BSC) group (institutional palliative treatment). Pts in CAP7.1 arm subjected to a 3-week cyle (cy) with CAP7.1 on days 1-5 in 3-week cy was given with either 200 or 150mg/m2. until progression. At progression BSC pts were allowed to cross over to CAP7.1. Safety was assessed with CTCAE v 3.0 and efficacy after 2 cy of treatment. 18 /50 pts (9 in each study arm) finalized 1st stage and analyzed for efficacy and safety. Results: DCR in the CAP7.1 arm was 56%, with 5/9 of pts with SD (including tumor shrinkages), while all pts in the BSC arm progressed. The median PFS time was 3.5 months (95% CI, 1.9 to 8.4 months) in the CAP7.1 arm. 5 pts crossed over to the CAP7.1 arm. 2/3 pts continued CAP7.1 treatment up to 5 and 8 cycles as SD, respectively, while one pts achieved PR. The median OS time from first treatment with CAP7.1 was 5.9 months (95% CI, 2.6 to 15.3 months) over all evaluable pts, including BSC after crossing to CAP7.1. Commonly observed drug related adverse events (AE) are hematoxicity/myeolosuppression, various events of infection, alopecia, fatigue, nausea and abdominal pain, which were in general well managed. G3-4 neutropenia occurred in 4/10 pt at a dose of 150 mg/m²/d and in 6/11 pts at 200 mg/ m2/d; uncomplicated g 3-4 thrombocytopenia occurred in 2/11 pt at 200 and in 1/10 at 150 mg/ m2/d. Non-hematological AE were mainly mild or moderate e.g. abdominal pain and alopecia as most frequent AEs. Conclusions: CAP7.1 showed promising activity in therapy refractory advanced BTC patients.

Randomized, phase II study of ficlatuzumab with or without cetuximab in patients with pan-refractory, recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS6594-TPS6594
Author(s):  
Julie E. Bauman ◽  
Denise Roe ◽  
Nabil F. Saba ◽  
Jessica Ruth Bauman ◽  
John M. Kaczmar ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Trial ◽  
Resistance Mechanism ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Platinum Resistance ◽  
Intrinsic Resistance ◽  
Eligibility Criteria ◽  
Randomized Phase Ii ◽  
Clinical Resistance

TPS6594 Background: Patients with pan-refractory R/M HNSCC, with clinical resistance to cytotoxic therapy, anti-EGFR molecular targeting, and immunotherapy, have poor survival. An established tumor-intrinsic resistance mechanism to cetuximab, an anti-EGFR IgG1 monoclonal antibody (mAb), is activation of the hepatocyte growth factor (HGF)/cMet pathway, which converges with the EGFR network at both the PI3K/Akt and MAPK nodes allowing for reciprocal compensation. Moreover, over-expression of HGF in the tumor microenvironment is immunosuppressive. Convergent data suggest that HGF/cMet pathway inhibition concurrent with EGFR blockade may overcome cetuximab resistance. We previously reported a Phase I study of ficlatuzumab, a humanized anti-HGF IgG1 mAb, with cetuximab in cetuximab-resistant R/M HNSCC. The combination showed promising safety, overall response rate (ORR) and progression-free survival (PFS). Preliminary biomarker analyses showed that high circulating cMet was associated with poor PFS whereas serum Veristrat, a proteomic classifier associated with worse prognosis in the setting of anti-EGFR monotherapy, was not. An increase in total peripheral T cells, particularly the CD8+ subset, was associated with treatment response while progression was associated with expansion of a unique myeloid population. We designed a follow-on randomized phase II trial evaluating ficlatuzumab with or without cetuximab in pan-refractory, R/M HNSCC with signaling and immune correlatives. Methods: This is a multicenter phase II trial with a randomized, non-comparative, two-arm design (ficlatuzumab 20 mg/kg with or without cetuximab 500 mg/m2 every 2 weeks) in patients with pan-refractory R/M HNSCC. Key eligibility criteria include: R/M HNSCC; cetuximab resistance (progression during or within 6 months of cetuximab-radiation or palliative cetuximab); platinum resistance; prior exposure to anti-PD1 mAb; ECOG 0-1; consent to baseline research biopsy. The primary objective is to evaluate the efficacy of each arm as measured by PFS. To test the hypothesis that either regimen improves historical PFS from 2 to 3.33 months requires 66 eligible patients. Key secondary endpoints are ORR and survival. Mechanistic biomarkers include tumor HGF/cMet pathway activation, tumor and peripheral immune profiles, soluble cMet, and serum Veristrat. Thirty-five of 66 subjects have enrolled at 6 centers. A Bayesian continuous monitoring rule for futility has not been triggered for either arm. Clinical trial information: NCT03422536 .

scholarly journals Randomized Phase II/III Trial Assessing Gemcitabine/Carboplatin and Methotrexate/Carboplatin/Vinblastine in Patients With Advanced Urothelial Cancer Who Are Unfit for Cisplatin-Based Chemotherapy: EORTC Study 30986

2012 ◽  
Vol 30 (2) ◽  
pp. 191-199 ◽  
Author(s):  
Maria De Santis ◽  
Joaquim Bellmunt ◽  
Graham Mead ◽  
J. Martijn Kerst ◽  
Michael Leahy ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Error Rates ◽  
Phase Iii ◽  
Rank Test ◽  
Treatment Groups ◽  
Randomized Phase Ii ◽  
Grade 3

Purpose This is the first randomized phase II/III trial comparing two carboplatin-based chemotherapy regimens in patients with urothelial cancer who are ineligible (“unfit”) for cisplatin chemotherapy. Patients and Methods The primary objective of the phase III part of this study was to compare the overall survival (OS) of chemotherapy-naive patients with measurable disease and an impaired renal function (glomerular filtration rate < 60 but > 30 mL/min) and/or performance score of 2 who were randomly assigned to receive either gemcitabine/carboplatin (GC) or methotrexate/carboplatin/vinblastine (M-CAVI). To detect an increase of 50% in median survival with GC compared with M-CAVI (13.5 v 9 months) based on a two-sided log-rank test at error rates α = .05 and β = .20, 225 patients were required. Secondary end points were overall response rate (ORR), progression-free survival (PFS), toxicity, and quality of life. Results In all, 238 patients were randomly assigned by 29 institutions over a period of 7 years. The median follow-up was 4.5 years. Best ORRs were 41.2% (36.1% confirmed response) for patients receiving GC versus 30.3% (21.0% confirmed response) for patients receiving M-CAVI (P = .08). Median OS was 9.3 months in the GC arm and 8.1 months in the M-CAVI arm (P = .64). There was no difference in PFS (P = .78) between the two arms. Severe acute toxicity (death, grade 4 thrombocytopenia with bleeding, grade 3 or 4 renal toxicity, neutropenic fever, or mucositis) was observed in 9.3% of patients receiving GC and 21.2% of patients receiving M-CAVI. Conclusion There were no significant differences in efficacy between the two treatment groups. The incidence of severe acute toxicities was higher for those receiving M-CAVI.

Maintenance treatment with cetuximab versus observation in RAS wild-type metastatic colorectal cancer: Results of the randomized phase II PRODIGE 28-time UNICANCER study.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 15-15
Author(s):  
Valerie Boige ◽  
Eric FRANCOIS ◽  
Meher BEN Abdelghani ◽  
Jean Marc Phelip ◽  
Valerie Le Brun-Ly ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Maintenance Therapy ◽  
Metastatic Colorectal Cancer ◽  
Phase Ii ◽  
Tumor Response ◽  
Progression Free Survival ◽  
Circulating Tumor Dna ◽  
Primary Objective ◽  
Wild Type ◽  
Randomized Phase Ii

15 Background: Compared to observation, maintenance therapy with a fluoropyrimidine +/- bevacizumab showed significant improvement in progression-free survival (PFS) but not in overall survival (OS) in patients with unresectable metastatic colorectal cancer (mCRC) and disease control after first-line doublet chemotherapy (CT) +/- bevacizumab. Few studies are available on the role of maintenance therapy after induction anti-EGFR-based CT, and the benefit from anti-EGFR maintenance monotherapy during CT-free intervals (CFI) in patients with RAS wild-type (wt) mCRC. Methods: RAS wt unresectable mCRC patients with controlled disease after FOLFIRI + cetuximab (8 cycles) were randomized (1:1) to receive maintenance with bi-weekly cetuximab alone (arm A) or observation (arm B) until disease progression (PD)/unacceptable toxicity/death. Randomization was stratified according to tumor response, center, baseline Köhne Score, CEA and platelet count. In case of tumor progression during the CFI, FOLFIRI + cetuximab was to be reintroduced for 8 cycles, followed by a new CFI. Tumor response was assessed per RECIST1.1 every 8 weeks. The primary objective of this multicenter non-comparative randomized phase II trial was 6-month PFS rate after initiation of maintenance therapy. A total of 134 randomized and evaluable patients (67 per arm) were required (Fleming’s one-step design, one-sided α=5%, β=20%, H0: 40%; H1: 55%). Secondary endpoints were overall response rate (ORR), time to strategy failure, PFS, OS, safety, quality of life, circulating tumor cells and circulating tumor DNA detection and dynamic changes during treatment. Results: From January 2014 to April 2019, 214 patients were included and 139 randomized (67 arm A/72 arm B) in 35 centers. Baseline characteristics were: males, 67%/69%; median age, 64/68 years; ECOG PS 0, 54%/46%; previous adjuvant therapy, 25%/14%; single metastatic site, 58%/47%; right-sided primary, 24%/18%. The ORR in the overall and the randomized population was 55% and 72%, respectively. The median follow-up was 30 months. The 6-month PFS rate after initiation of maintenance therapy was 30% 95%CI[19; 42] in the maintenance arm, and 6% 95%CI[2;14] in the observation arm, with a median PFS of 5.3 95%CI[3.7;6.5] and 2.0 95%CI[1.8;2.8] months, respectively. Any grade treatment-related toxicity, including skin rash (40%/4%), diarrhea (33%/8%), and hypomagnesemia (46%/10%) was more frequent in arm A. Conclusions: Based on the study hypothesis, the cetuximab maintenance arm did not meet the primary objective. However, the clinically meaningful difference in PFS without any overlap in the confidence intervals between the two arms warrants further investigation. Clinical trial information: NCT02404935.

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.

Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis.

2020 ◽  
Vol 38 (18_suppl) ◽  
pp. LBA1-LBA1 ◽  
Author(s):  
Thomas Powles ◽  
Se Hoon Park ◽  
Eric Voog ◽  
Claudia Caserta ◽  
B.P. Valderrama ◽  
...  
Keyword(s):  
Supportive Care ◽  
Stable Disease ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Best Supportive Care ◽  
Primary Objective ◽  
Phase Iii ◽  
Platinum Based Chemotherapy ◽  
Grade 3

LBA1 Background: Platinum-based chemotherapy is an active 1L regimen for advanced UC; however, progression-free survival (PFS) and overall survival (OS) are generally short because of chemotherapy resistance. This randomized, phase 3 trial (JAVELIN Bladder 100; NCT02603432) evaluated avelumab (anti–PD-L1) as maintenance therapy following response or stable disease with 1L platinum-based chemotherapy in patients with advanced UC. Methods: Eligible patients with unresectable locally advanced or metastatic UC without disease progression after 4-6 cycles of gemcitabine with either cisplatin or carboplatin were randomized 1:1 to receive maintenance avelumab (10 mg/kg IV every 2 weeks) + best supportive care (BSC) or BSC alone, stratified by best response to 1L chemotherapy (complete/partial response vs stable disease) and by visceral vs nonvisceral disease when initiating 1L chemotherapy. The primary endpoint was OS, assessed from randomization in 2 primary populations: all randomized patients and patients with PD-L1+ tumors (Ventana SP263 assay). Secondary endpoints included PFS, objective response, and safety. Results: 700 patients were randomly assigned to maintenance avelumab + BSC (n=350) or BSC alone (n=350) and were followed for a median of 19.6 and 19.2 months, respectively. Overall, 358 (51%) had PD-L1+ tumors. Avelumab + BSC significantly prolonged OS vs BSC alone in all randomized patients (hazard ratio [HR] 0.69; 95% CI 0.56, 0.86; 1-sided p=0.0005); median OS with avelumab + BSC vs BSC alone was 21.4 vs 14.3 months, respectively. Avelumab + BSC also significantly prolonged OS vs BSC alone in patients with PD-L1+ tumors (HR 0.56; 95% CI 0.40, 0.79; 1-sided p=0.0003); median OS was not reached vs 17.1 months, respectively. An OS benefit was also observed across all prespecified subgroups. The HR for PFS based on blinded independent central review with avelumab + BSC vs BSC alone was 0.62 (95% CI 0.52, 0.75) in all randomized patients and 0.56 (95% CI 0.43, 0.73) in patients with PD-L1+ tumors. In treated patients in the avelumab + BSC (n=344) vs BSC alone (n=345) arms, respectively, all-causality adverse events (AEs) were reported at any grade in 98.0% vs 77.7% and at grade ≥3 in 47.4% vs 25.2%, and the most frequent grade ≥3 AEs were urinary tract infection (4.4% vs 2.6%), anemia (3.8% vs 2.9%), hematuria (1.7% vs 1.4%), fatigue (1.7% vs 0.6%), and back pain (1.2% vs 2.3%). Conclusions: JAVELIN Bladder 100 met its primary objective, demonstrating significantly prolonged OS with 1L maintenance avelumab + BSC vs BSC alone in advanced UC in all randomized patients and patients with PD-L1+ tumors. Efficacy benefits were seen across all prespecified subgroups, and the safety profile of avelumab was consistent with previous studies of monotherapy. Clinical trial information: NCT02603432 .

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