Phase II study of sitravatinib in combination with nivolumab in patients undergoing nephrectomy for locally-advanced clear cell renal cell carcinoma (ccRCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS686-TPS686
Author(s):  
Jose A. Karam
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Suppressor Cells ◽  
Primary Objective ◽  
Clinical Activity ◽  
Open Label ◽  
Cell Renal Cell Carcinoma

TPS686 Background: Sitravatinib is a receptor tyrosine kinase inhibitor (RTKI) that targets multiple closely related RTK pathways including VEGFR, PDGFR, KIT, MET and the TAM receptors (TYRO3, AXL and MERTK) Nivolumab is a monoclonal antibody against PD-1 and releases PD-1-mediated inhibition of T-cell proliferation and cytokine production. Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity than either agent alone, as sitravatinib is predicted to enhance several steps in the cancer immunity cycle that may augment nivolumab’s efficacy. Mechanisms by which sitravatinib may augment an antitumor immune response include enhanced antigen presentation; depletion of immunosuppressive regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) via inhibition of split kinases VEGFR and KIT; and shifting tumor-associated macrophages from an immunosuppressive M2 to a pro-immunogenic M1 phenotype via inhibition of TAM RTKs. Each of these factors converge on promoting T effector cell expansion, tumor infiltration and an antigen-specific anti-tumor immune response. Methods: This open-label, non-randomized, preoperative window of opportunity Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with locally-advanced ccRCC undergoing nephrectomy. Study treatment consists of 2 weeks of sitravatinib monotherapy followed by 4 weeks of the combination. Sitravatinib is administered orally daily at 120 mg; nivolumab intravenously every 2 weeks at 240 mg. The primary objective is to evaluate clinical activity using percentage of pts achieving a presurgical point-in-time objective response. Secondary objectives include evaluation of safety and tolerability, and determination of the immune effects of sitravatinib monotherapy and the combination through serial tissue and blood collections (temporal changes in PD-L1 expression, selected cytokines and immune cell populations including MDSCs, Tregs and ratio of M1:M2 macrophages). The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03680521.

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.

Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS541-TPS541
Author(s):  
Neeraj Agarwal ◽  
Ulka N. Vaishampayan ◽  
Bradley Alexander McGregor ◽  
Marjorie C. Green ◽  
Nehal Mohamed ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Phase 1B

TPS541 Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.

Phase II study of sitravatinib in combination with nivolumab in patients with advanced or metastatic urothelial carcinoma (UC) after checkpoint inhibitor therapy (CIT).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS498-TPS498
Author(s):  
Gurjyot K. Doshi ◽  
Nicholas J. Vogelzang ◽  
Donald A. Richards ◽  
Daniel Chong ◽  
David R. Shaffer ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Primary Objective ◽  
Rational Approach ◽  
Clinical Activity ◽  
Phase 2 ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Phase 2 Study

TPS498 Background: Combination therapy with agents targeting molecular and cellular mechanisms of CIT resistance is a rational approach to restoring CIT efficacy in patients (pts) with immunotherapy-resistant UC. Sitravatinib is a tyrosine kinase inhibitor (TKI) that targets multiple closely-related receptor tyrosine kinase (RTK) pathways, including the split RTKs VEGFR-2 and KIT, as well as the TAM (TYRO3, AXL, and MER) RTKs. Inhibition of the split RTKs enhances antitumor activity by reduction of immunosuppressive regulatory T cells and myeloid-derived suppressor cells (MDSCs) within the tumor microenvironment (TME). Inhibition of TAM RTKs further restores a more immune-supportive TME by depletion of MDSCs and repolarization of tumor-associated macrophages to the M1 phenotype associated with secretion of pro-inflammatory cytokines. Given these pleiotropic immune-activating effects, the combination of sitravatinib with nivolumab is a rational approach to restoring or enhancing CIT clinical activity in pts with immunotherapy-resistant UC. This combination has been shown to be safe and tolerable in an ongoing Phase 2 study in pts with metastatic non-small cell lung cancer. Methods: This open-label Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with advanced or metastatic UC who experienced disease progression on or after CIT as the most recent systemic therapy. Enrollment is stratified by prior receipt of platinum-based chemotherapy. If the initial 2 cohorts are of high interest for efficacy, the protocol allows for addition of new cohorts to include pts previously treated with selected immunotherapies (anti-CTLA-4, anti-OX40 or anti–CD137 therapy) or who are CIT-naïve. The primary objective is Objective Response Rate. A Predictive Probability Design will be applied allowing for expansion to 40 pts per cohort. Sitravatinib is administered orally daily in continuous 28-day cycles at 120 mg; nivolumab intravenously at 240 mg every 2 weeks or 480 mg every 4 weeks. Status: The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03606174.

Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. TPS42-TPS42 ◽  
Author(s):  
Manuel C. Maia ◽  
Neeraj Agarwal ◽  
Bradley Alexander McGregor ◽  
Ulka N. Vaishampayan ◽  
Toni K. Choueiri ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Phase 1B

TPS42 Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.

A phase II study of sitravatinib (Sitra) in combination with nivolumab (Nivo) in patients (Pts) undergoing nephrectomy for locally-advanced clear cell renal cell carcinoma (accRCC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 312-312
Author(s):  
Jose A. Karam ◽  
Pavlos Msaouel ◽  
Surena F. Matin ◽  
Matthew T Campbell ◽  
Amado J. Zurita ◽  
...  
Keyword(s):  
Phase Ii ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Unmet Need ◽  
Cell Renal Cell Carcinoma

312 Background: Sitra is a spectrum-selective receptor tyrosine kinase inhibitor (TKI) that targets TAM receptors (TYRO3, AXL, MERTK), VEGFR2, c-Kit, and MET. These receptors regulate several immune suppressive cell types in the tumor microenvironment, including M2-polarized macrophages, MDSCs, and T regulatory cells, which are implicated in resistance to checkpoint inhibitors. ccRCC is characterized by upregulation of VEGF and overexpression of MET and AXL. Sitra may combine effectively with immune checkpoint inhibition to augment antitumor activity in ccRCC. About 39% of patients with accRCC who receive surgery with curative intent relapse representing an unmet need in this setting. Together these data support the evaluation of neoadjuvant sitra with nivo in accRCC. Methods: This phase II study (NCT03680521) evaluated sitra and nivo in pts with locally- advanced ccRCC who were candidates for curative nephrectomy. Single-agent sitra (120 mg) was administered daily (QD) for 2 weeks, with nivo (240 mg intravenously Q2W) added to sitra for 4-6 weeks. A plan for potential dose de-escalation was implemented using a modified toxicity probability interval method with a maximum toxicity of 20% at the tolerated dose. Pts underwent pathology/tissue evaluation at 3 timepoints: biopsy prior to treatment, biopsy prior to the addition of nivo, and nephrectomy specimen evaluation at time of nephrectomy. The primary endpoint was objective response (RECIST 1.1); secondary endpoints included safety, PK, and correlative immune effects (selected protein and gene expression and immune cell populations). Results: A total of 20 pts were evaluated for safety (95% had T3 or higher stage tumors, 65% with baseline hypertension). Dose-limiting toxicities (DLTs) led to a dose de-escalation, resulting in 7 pts treated at 120 mg QD sitra and 13 pts treated at 80 mg QD. DLTs included grade 3 (Gr3) hypertension (n=6); deep vein thrombosis and pulmonary embolism (Gr3) were observed in 1 additional pt. Median duration of sitra treatment was 6.3 weeks at the 80 mg dose and 7.1 weeks at the 120 mg dose. With a median follow-up of 9.4 months after initiation of systemic therapy, no pts have relapsed. In 17 pts evaluable for efficacy, the investigator-assessed confirmed ORR was 11.8%, including 2 PRs (33.3% ORR in pts who received 120 mg sitra). No pts experienced progressive disease while on therapy. Median DFS was not reached. There was 1 delayed surgery due to nivo-related thyroiditis that resolved. Reported TRAEs: Gr1/Gr2 in 55% of pts (dysphonia 50%, fatigue 45%, diarrhea 40%, hypertension 30%, increased ALT 30%), Gr3 in 45% of pts (hypertension 30%). There were no Gr4/Gr5 TRAEs. Correlative blood and tissue analyses will be presented. Conclusions: The combination of sitra and nivo is clinically active with a manageable safety profile as a neoadjuvant therapy for accRCC. Clinical trial information: NCT03680521 .

Phase (Ph) 1b/2 evaluation of olaratumab in combination with gemcitabine and docetaxel in advanced soft tissue sarcoma (STS).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11517-11517
Author(s):  
Steven Attia ◽  
Victor Manuel Villalobos ◽  
Nadia Hindi ◽  
Brian Andrew Van Tine ◽  
Andrew J. Wagner ◽  
...  
Keyword(s):  
Systemic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Clinical Activity ◽  
Parameter Estimates ◽  
Second Line ◽  
Line Therapy ◽  
Significant Difference ◽  
Ecog Ps

11517 Background: Doxorubicin (doxo) remains standard first-line therapy for advanced STS. Doxo in combination with olaratumab (O) demonstrated superior clinical activity compared to doxo alone in a Ph 2 trial (NCT01185964), although this was not confirmed in the subsequent Ph 3 trial (NCT02451943). Gemcitabine (G) plus docetaxel (D) is a second line therapy for advanced STS. Here, we report a concurrent Ph 2 study that explored a second-line addition of O to G and D for advanced STS (ANNOUNCE 2 NCT02659020). Methods: Adult patients (pts) with unresectable locally advanced or metastatic STS, ≤ 2 prior lines of systemic therapy, and ECOG PS 0-1 were eligible. Pts were enrolled from 2 cohorts: O-naïve and O-pretreated. In both cohorts, pts were randomized 1:1 to either O, G plus D or placebo (PBO), G plus D. Pts received 21-day cycles of O (20 mg/ kg cycle 1 and 15 mg/kg other cycles, day (d) 1 and d8), G (900 mg/m2, d1 and d8) and D (75 mg/m2, d8). Pts continued treatment until progression, toxicity, or withdrawal. Randomization was stratified by histology (leiomyosarcoma [LMS] vs non-LMS), prior systemic therapy, ECOG PS, and prior pelvic radiation. The primary objective was overall survival (OS) in the O-naïve population using an alpha level of 0.20. Secondary endpoints included OS (O-pretreated) and other efficacy parameters, as well as safety and pharmacokinetics (PK). Results: 167 pts were enrolled in the O-naïve cohort and 89 pts in the O-pretreated cohort. Baseline patient characteristics were well balanced. OS for O-naïve pts was 16.8 vs 18.0 months (m) (hazard ratio [HR] = 0.95, 95% CI: 0.64-1.40; p = 0.78) for the investigational vs control arm, respectively. Other efficacy outcomes are presented in the table. Safety was manageable across treatment arms. PK parameter estimates for O were consistent with previous studies. Conclusions: There was no statistically significant difference in OS between the two arms in the O-naïve population. However, while not statistically significant, the combination of O, G and D demonstrated favorable OS in the O-pretreated cohort, and PFS and objective response rate (ORR) in both cohorts. For O-naïve pts, a clinically meaningful progression-free survival (PFS) improvement was observed. Further investigations in specific histological subtypes are ongoing. Clinical trial information: NCT02659020. [Table: see text]

Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4096-4096
Author(s):  
Sophie Cousin ◽  
Carine A. Bellera ◽  
Jean Philippe Guégan ◽  
Thibault Mazard ◽  
Carlos A. Gomez-Roca ◽  
...  
Keyword(s):  
Phase Ii ◽  
Adaptive Design ◽  
Objective Response ◽  
Locally Advanced ◽  
Survival Rates ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Open Label

4096 Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

ICORG 06-41: A phase II trial of single-agent sorafenib in the treatment of platinum-pretreated relapsed gastroesophageal adenocarcinoma (GECa).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 88-88 ◽  
Author(s):  
Louise Catherine Connell ◽  
Seamus O'Reilly ◽  
Glenn Webb ◽  
Brian Moulton ◽  
Imelda Parker ◽  
...  
Keyword(s):  
Phase Ii ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Locally Advanced ◽  
Safety Data ◽  
Primary Objective ◽  
Open Label ◽  
Oncology Research ◽  
Translational Studies ◽  
Gastroesophageal Adenocarcinoma

88 Background: Over 1 million individuals worldwide annually are diagnosed with GECa. The majority of patients(pts) present with inoperable locally advanced or metastatic disease(dx). Even with resectable dx 5 year survival is low at ~40% with current best treatment (tx). Following initial platinum based therapy there is no established standard 2nd line tx. Besides HER2-directed therapy there has been little progress with targeted biologic agents. ICORG, the all-Ireland Cooperative Oncology Research Group investigated the utility of the tyrosine kinase inhibitor sorafenib in a multicentre trial. Methods: A prospective Phase II, nonrandomised, open label, one arm study of single agent sorafenib in the tx of platinum pre-treated relapsed GECa was conducted. Primary objective was dx control rate (DCR) post 4 months of tx. Secondary endpoints were OS, PFS, TTP, ORR, tolerability/toxicity and biomarkers of tx response/resistance. The protocol allowed for an interim analysis to be performed if clinically indicated. A sample size of 54 pts was identified using the single stage Fleming design approach to test whether the proportion responding, P, is ≤ 0.35 or ≥ 0.50. Pts received Sorafenib 400mg bid p.o. continuously q28days until dx progression or intolerable toxicity. Response by RECIST was evaluated by CT q8weeks. For pts with sufficient tumour samples translational studies were done. Results: An interim review performed in Nov 2012 (35 months post study opening) indicated that 33/41 evaluable pts recruited to date had progressed before completing 4 months of tx. Therefore, the number of evaluable pts with dx control could not reach the pre-specified figure of 22, & the hypothesis P >= 0.50 was rejected. Fifteen pts had just 1 cycle of tx, 5 of whom completed ≤ 2 weeks. A further 14 pts had 2 cycles. Median survival time to progression was 56 days (95% CI 53 – 59 days).Median OS was 120 days (95% CI 91 – 149 days). Safety data analyses and translational studies are ongoing and will be available for presentation at the meeting. Conclusions: Sorafenib as monotherapy is inactive in platinum pretreated pts with relapsed GECa. A significant unmet clinical need for novel effective therapies remains. Clinical trial information: 2008-005062-31.

Updated efficacy and tolerability of durvalumab in locally advanced or metastatic urothelial carcinoma (UC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4525-4525 ◽  
Author(s):  
Noah M. Hahn ◽  
Thomas Powles ◽  
Christophe Massard ◽  
Hendrik-Tobias Arkenau ◽  
Terence W. Friedlander ◽  
...  
Keyword(s):  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Kidney Injury ◽  
Progression Free Survival ◽  
Anticancer Therapy ◽  
Clinical Activity ◽  
Open Label ◽  
Duration Of Response ◽  
Grade 3

4525 Background: Anti-PD-L1 immunotherapy shows promising clinical activity in UC. We report a planned update of the safety and efficacy of durvalumab in patients (pts) with locally advanced/metastatic UC from a multicenter, phase 1/2 open-label study. Methods: Pts received durvalumab 10 mg/kg every 2 weeks (Q2W) up to 12 months (mo) or until unacceptable toxicity, progression, or starting another anticancer therapy. Primary endpoints were safety and confirmed objective response rate (ORR) by blinded independent central review (RECIST v1.1). Duration of response (DoR), progression-free survival (PFS) and overall survival (OS) were key secondary endpoints. Tumor PD-L1 expression was assessed by Ventana SP263 assay (PD-L1 high = ≥25% PD-L1 expression on tumor or immune cells). Results: As of Oct 24, 2016 (data cutoff [DCO]), 191 pts had received treatment. Median follow-up was 5.78 mo (range, 0.4–25.9). All pts had Stage 4 disease and 99.5% had prior anticancer therapy (95.3% post-platinum). As of DCO, ORR was 17.8% (34/191), including 7 CRs, with responses observed regardless of PD-L1 status (Table). Responses occurred early (median time to response, 1.41 mo) and were durable (median DoR not reached [NR]). Median PFS and OS were 1.5 mo (95% CI, 1.4, 1.9) and 18.2 mo (95% CI, 8.1, not estimable [NE]), respectively; the 1-year OS rate was 55.0% (95% CI, 43.9%, 64.7%). Grade 3/4 treatment-related AEs occurred in 6.8% of pts; grade 3/4 immune-mediated (im)AEs occurred in 4 pts; 2 pts discontinued due to imAEs (acute kidney injury and autoimmune hepatitis). Conclusions: Durvalumab 10 mg/kg Q2W shows favorable clinical activity and an excellent safety profile in locally advanced/metastatic UC pts. Table. Antitumor activity in UC pts, including second-line or greater (≥2L) post-platinum pts Clinical trial information: NCT01693562. [Table: see text]

Phase I study of irinotecan/5-fluorouracil/leucovorin (FOLFIRI) with sunitinib for advanced gastroesophageal cancers (EGC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15569-e15569
Author(s):  
Sarbajit Mukherjee ◽  
Christos Fountzilas ◽  
Patrick McKay Boland ◽  
Kristopher Attwood ◽  
Wei Tan ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Clinical Activity ◽  
Free Survival

e15569 Background: Sunitinib (S) is a multi-targeted tyrosine kinase inhibitor with activity against VEGFR, PDGRF, KIT, FLT-3, and RET. S is synergistic with chemotherapy in preclinical models. We hypothesized that S+FOLFIRI combination will have increased efficacy in advanced EGC. Methods: This was a phase I study for patients with advanced chemo naïve EGC. Dose escalation used a standard 3+3 design. The primary objective was to determine the tolerability and safety of S+FOLFIRI. Secondary objectives were overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: Twenty-three patients participated in the study (Male 78%, Female 22%). Median age was 60 (Range: 37-77) years. Median follow up time was 67.5 (95% CI: 58.9, 76) months. The most frequently reported adverse events were neutropenia (78%; G3/4: 43%), nausea (74%; G3/4:13%), diarrhea (65%; G3/4: 4%), vomiting (61%, G3/4: 9%) lymphopenia (52%; G3/4: 13%) and fatigue (52%; G3/4:17%).Two dose limiting toxicities (DLTs) were noted each at dose level (DL) 1 and 1A, one at DL 1B and 3 at DL 2 (Table 1). Maximum tolerated dose was determined at DL 1B. At the time of data reporting 21 patients had died. Two patients came off the study per investigator request. All patients were evaluated for efficacy. The median OS and PFS were 12.4 (95% CI: 8.9, 16.5) months and 6.2 (95% CI: 3.4, 13.5) months, respectively. Conclusions: S+FOLFIRI was reasonably tolerated, with a manageable safety profile and signs of clinical activity in patients with advanced EGC. This study was supported by a research grant from Pfizer, Inc. Clinical trial information: NCT00524186. [Table: see text]

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