Crizotinib in patients with advanced or metastatic ROS1-rearranged lung cancer (EUCROSS): A European phase II clinical trial–Updated report on progression-free and overall survival.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9066-9066
Author(s):  
Sebastian Yves Friedrich Michels ◽  
Jeremy Franklin ◽  
Bartomeu Massuti ◽  
Martin Sebastian ◽  
Hans-Ulrich Schildhaus ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trial ◽  
Overall Survival ◽  
Primary Endpoint ◽  
Objective Response ◽  
In Situ Hybridisation ◽  
Progression Free Survival ◽  
Fluorescence In Situ Hybridisation ◽  
Eligibility Criteria ◽  
Tp53 Mutations

9066 Background: ROS1 rearrangements are found in 1% of non-small cell lung cancer (NSCLC) patients. Early clinical trials in the US and East Asia have proven the therapeutic efficacy of crizotinib in this subset of patients. EUCROSS is the first prospective European trial to evaluate the acitivity of crizotinib in ROS1-positive lung cancer. Here we present an updated analysis of the investigator-assessed progression-free survival (PFS) and overall survival (OS). Methods: EUCROSS is a multi-centre, single arm phase 2 trial (NCT02183870). Key eligibility criteria: ≥18 years of age, advanced/metastatic lung cancer, centrally confirmed ROS1-rearranged (fluorescence-in situ hybridisation). Treatment with crizotinib was initiated at a dose of 250 mg twice daily. Primary endpoint of the trial: investigator-assessed objective response rate (ORR) in the response-evaluable population (Response Evaluation Criteria in Solid Tumors, version 1.1). Key endpoints of this report: updated PFS and OS and updated molecular characterization of tumour tissue. Results: Thirty-four patients received treatment with crizotinib and were included in the intention-to-treat analysis. Four patients were excluded from the primary endpoint analysis due to violation of eligibility criteria (response-evaluable set, N = 30). Median follow-up period was 44.9 months. At the time of data cut-off for this report 19 patients (63%) discontinued treatment due to progression or death. Investigator ORR was 70% (95% CI, 51–85; 21/30), disease control rate was 90% (95% CI, 73.5-97.9; 27/30) and median PFS was 19.4 months (95% CI, 10.1-31.2). Median OS was not reached, but 24-months-OS probability was 66% (95% CI, 48.3-82.9). Tissue of 18 patients was available for hybrid-capture-based sequencing. Co-occurring genetic aberrations were found in 61% (11/18). TP53 mutations were most frequent (28%; 5/18). PFS (24-months probability, TP53-mut. 0% vs. TP53 wild-type (wt) 61%; p = 0.0219) and OS (24-months, TP53-mut. 40% vs. TP53 wt 83%; p = 0.015) were significantly shorter in TP53-mutant patients. Differences in OS and PFS stratified by number of prior treatment lines (0-1 vs. > = 2), brain metastases (yes vs. no) or CD74-rearrangement ( CD74- ROS1 vs. other fusion type) status were not significant. Conclusions: Updated PFS and OS results show that crizotinib is highly effective in ROS1-rearranged lung cancer. Co-occurring TP53 mutations were associated with a significantly worse outcome. Clinical trial information: NCT02183870.

Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): A randomized, double-blind phase III trial (ZODIAC)

2009 ◽  
Vol 27 (18_suppl) ◽  
pp. CRA8003-CRA8003 ◽  
Author(s):  
R. S. Herbst ◽  
Y. Sun ◽  
S. Korfee ◽  
P. Germonpré ◽  
N. Saijo ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Phase Iii ◽  
Positive Trend ◽  
Primary Analysis ◽  
Eligibility Criteria ◽  
Double Blind

CRA8003 Background: Vandetanib is a once-daily oral inhibitor of VEGFR, EGFR and RET signaling. Addition of vandetanib to docetaxel (doc) prolonged progression-free survival (PFS) in a randomized phase II study in patients (pts) with previously treated NSCLC (Heymach et al, JCO, 2007). Methods: The primary objective was to determine whether vandetanib 100 mg/day + doc 75 mg/m2 every 21 days (max 6 cycles) prolonged PFS vs placebo + doc. Secondary endpoints included overall survival, objective response rate (ORR), time to deterioration of symptoms (TDS) and safety. Efficacy and safety in females were assessed as a co-primary analysis population. Eligibility criteria included stage IIIB/IV NSCLC, PS 0–1, and previous first-line chemotherapy. Results: Between May 2006 and April 2008, 1,391 pts (mean age, 58 years; 30% female; 25% squamous; 10% brain mets) were randomized to vandetanib + doc (n=694) or placebo + doc (n=697). Baseline characteristics were similar in both arms. Median duration of follow-up was 12.8 months, with 87% patients progressed and 59% dead. Addition of vandetanib to doc showed a statistically significant improvement in PFS vs doc (hazard ratio [HR] 0.79, 97.58% CI 0.70–0.90; P<0.001), and a similar advantage in females (HR 0.79; P=0.024). Significant advantages for vandetanib + doc were also seen for ORR (17% vs 10%, P<0.001) and TDS (HR 0.78, P=0.002; FACT-L Lung Cancer Subscale). Overall survival showed a positive trend for vandetanib + doc that was not statistically significant (HR 0.91, 97.52% CI 0.78–1.07; P=0.196). The adverse event (AE) profile was consistent with that previously observed for vandetanib in NSCLC. Common AEs occurring more frequently in the vandetanib arm included diarrhea (42% vs 33%), rash (42% vs 24%) and neutropenia (32% vs 27%). Nausea (23% vs 32%), vomiting (16% vs 21%) and anemia (10% vs 15%) were less frequent in the vandetanib arm. The incidence of protocol-defined QTc prolongation was <2% in pts receiving vandetanib. Conclusions: The study met its primary objective of PFS prolongation with vandetanib + doc vs doc. Vandetanib is the first oral targeted therapy in phase III trials to show significant evidence of clinical benefit when added to standard chemotherapy in NSCLC. [Table: see text]

A phase II, multicenter, open-label study of YM155 plus docetaxel in subjects with stage III (unresectable) or stage IV melanoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8587-8587 ◽  
Author(s):  
Joyce Leta Steinberg ◽  
Agop Y. Bedikian ◽  
D. Scott Ernst ◽  
Bartosz Chmielowski ◽  
Bruce Redman ◽  
...  
Keyword(s):  
Overall Survival ◽  
Continuous Infusion ◽  
Primary Endpoint ◽  
Clinical Benefit ◽  
Response Rate ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Open Label ◽  
Clinical Benefit Rate

8587 Background: Survivin is a microtubule-associated protein implicated in both preservation of cell viability and regulation of mitosis in tumor cells. It is over-expressed in melanoma, breast, and non-Hodgkin’s lymphoma. YM155 is a first in class survivin inhibitor. Methods: The study had 2 parts: Part 1 established the dose of docetaxel that was tolerable in combination withYM155 at 5 mg/m2/day continuous infusion over 168 hours q 3 weeks. Part 2 utilized the dose of docetaxel established in Part 1 to further evaluate the tolerability and activity of the combination. The primary endpoint was 6-month progression-free survival (PFS). Secondary endpoints were overall response rate, 1-year overall survival (OS), time from first response to progression, clinical benefit rate, time to response, and safety. Results: 64 patients with metastatic melanoma were treated with docetaxel followed by continuous infusion YM155. 7 patients were treated with 100mg/m2 of docetaxel and 57 patients were treated with 75mg/m2 of docetaxel. Median age was 59, with 44 men and 20 women treated. 6-month PFS per Independent Review Committee (IRC) was 34.8% (95% CI 21.3 – 48.6%). Overall objective response rate per IRC was 12.5%, with no complete responses (CR) and 8 patients with partial responses (PR). The Stable disease (SD) rate was 51.6%, leading to a clinical benefit rate (CR + PR + SD) of 64.1%. Estimated 1-year overall survival is 50.5%. 87.5% of patients experienced a Grade 3 (G3) or Grade 4 (G4) event attributable to either YM155 or docetaxel. The clinically pertinent G3 or 4 toxicities occurring in greater than 5% of patients treated included neutropenia (59.4%), febrile neutropenia (12.5%), mucositis (9.4%), fatigue (7.8%), diarrhea (6.3%), and dehydration (6.3%). There were 3 deaths on study, all attributable to disease progression. Conclusions: YM155 is a novel agent that shows modest activity when combined with docetaxel in patients with melanoma. YM155 was generally well tolerated, but the pre-determined primary endpoint for efficacy was not achieved.

PrE0204: A multi-institutional, single arm, two-stage phase II trial of nab-paclitaxel and gemcitabine for first-line treatment of patients with advanced or metastatic cholangiocarcinoma—A PrECOG LLC study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4072-4072
Author(s):  
Vaibhav Sahai ◽  
Paul J. Catalano ◽  
Sam Joseph Lubner ◽  
Mark R. Menge ◽  
Hidayatullah G. Munshi ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Null Hypothesis ◽  
Cytidine Deaminase ◽  
Objective Response ◽  
Progression Free Survival ◽  
Eligibility Criteria ◽  
Poor Overall Survival ◽  
Intention To Treat ◽  
Metabolizing Enzyme ◽  
Ecog Ps

4072 Background: Pts with advanced or metastatic cholangiocarcinoma (CCA) have limited response to current chemotherapy regimens and poor overall survival (OS). Nab-Paclitaxel (nabPAC) can increase the intra-cellular concentration of gemcitabine (GEM) through depletion of its metabolizing enzyme, cytidine deaminase (CDA). We investigated the nabPAC+GEM combination in a ph II single arm trial in advanced or metastatic CCA pts with exploratory biomarker evaluation, including CDA, hENT1, SPARC and circulating tumor cells (CTCs). Methods: Key eligibility criteria: advanced or metastatic CCA with no prior systemic chemotherapy, age > 18, ECOG PS 0-1 and Child-Pugh < 8. Pts received nabPAC (125 mg/m2 IV) and GEM (1000 mg/m2 IV) days 1, 8 and 15 Q4 weeks until progression. Primary endpoint: progression-free survival (PFS) rate at 6 months. Secondary endpoints: safety, time to progression (TTP), objective response (ORR) and disease control rates (DCR), median PFS and OS, as well as correlation of change in CA 19-9 to clinical efficacy. The study required > 43 of 67 evaluable patients alive and progression-free at 6 months to conclude the 6-month PFS rate is at least 70% against a null hypothesis of 55% based on historical data. Results: 73 eligible patients (41.1% male, 91.8% Caucasian, 45.2% ECOG PS 0) were enrolled across 22 sites with a median age of 62 (range 36-87) years and received a median of 6 (range 1-18) cycles. The primary endpoint of PFS rate at 6 months was 54.7% on intention to treat analysis. Response evaluation is underway and will be reported at the meeting. The median PFS and OS were 6.5 (95% CI, 5.1-7.7) and 10.3 (95% CI, 9.1-14.6) months, respectively. The safety profile of nabPAC+GEM was similar to that reported in ph III MPACT trial. The most common treatment-related G3/4 toxicities were neutropenia (24.3%), fatigue (13.5%) and anemia (12.2%). Five patients remain on the trial. Exploratory analyses are pending. Conclusions: The observed PFS rate at 6 months with nabPAC+GEM in CCA is insufficient to reject the null hypothesis of 55% PFS at 6 months, and appears to be as effective as the historical control. Clinical trial information: NCT02181634.

scholarly journals Phase II trial of S-1 plus cisplatin combined with bevacizumab for advanced non-squamous non-small cell lung cancer (TCOG LC-1202)

2019 ◽  
Vol 49 (8) ◽  
pp. 749-754
Author(s):  
Akihiko Miyanaga ◽  
Kaoru Kubota ◽  
Yukio Hosomi ◽  
Yusuke Okuma ◽  
Koichi Minato ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Primary Endpoint ◽  
Objective Response ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Standard Chemotherapy Regimen ◽  
Grade 3

Abstract Background S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine. Methods Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1–14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4–6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL). Results From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9–8.7), 21.4 months (95% CI: 14.7—not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen. Conclusions S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.

A phase 2 prospective trial of cabozantinib as first-line treatment for metastatic collecting ducts renal cell carcinoma: The BONSAI trial (Meeturo 2) clinical trial information—NCT03354884.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4571-4571
Author(s):  
Giuseppe Procopio ◽  
Pierangela Sepe ◽  
Sebastiano Buti ◽  
Melanie Claps ◽  
Maurizio Colecchia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Primary Endpoint ◽  
Molecular Subtypes ◽  
Objective Response ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Overall Response ◽  
Collecting Ducts ◽  
Immune Related Genes ◽  
Clinical Trial Information

4571 Background: Metastatic collecting ducts carcinoma (mCDC) is a rare disease with bad prognosis and no standard treatments. Due to its rarity, mCDC is biologically poorly characterized and under-represented in prospective randomized trials. We recently identified two different molecular subtypes of mCDC based on relative expression levels of angiogenesis, metabolic and immune-related genes. Methods: : This prospective, monocentric, phase II trial evaluated cabozantinib (cabo) 60 mg orally once daily until progression or unacceptable toxicity in untreated mCDC patients (pts). Primary endpoint was objective response rate (ORR) as the proportion of pts with best overall response of confirmed complete (CR) or partial responses (PR) per RECIST 1.1. Secondary endpoints were progression-free survival (PFS), overall survival and safety profile. Exploratory objectives were: to identify somatic mutations by targeted NGS-based sequencing; to define molecular subtypes, signatures and transcript fusions genes by RNA sequencing; to monitor circulating immune cells and study the immunological context of tumor cells. A central pathological review was mandatory. The study was based on a Simon’s two stage optimal design: at least 2 responses in 9 pts in the first stage were needed to proceed to the second stage where at least 6 responses in 14 additional pts were needed to prove activity of cabo. Results: From January 2018 to November 2020, 25 pts were enrolled, of whom 23 started treatment. Median age was 66 years, 19 pts were male. 19 (83%) pts received a previous nephrectomy. 9 pts presented with only one metastatic site, 8 pts with two, while the remaining part with multiple sites. The most common metastatic sites were lymphnodes and bone (15 and 13 pts respectively), followed by lung and liver (10 and 4 pts respectively). Median follow up was 8 months. As best overall response, 6 pts presented a stable disease (26%),1 pt achieved a confimed CR and 7 a PR for an ORR of 35%. Median PFS was 6 months. Treatment was feasible and well tolerated. All pts reported at least one grade (G) 1-2 adverse event (AE): the most common were fatigue (43%), hypotiroidism (28%), stomatitis (28%), anorexia (26%), Hand-Foot Syndrome (13%), hypertension (17%), and diarrhea (13%). 5 pts reported G3 AEs (2 thromboembolic events, 2 arterial hypertension, 1 fatigue), while no G4-5 AEs were reported. 17% of pts required dose reduction. DNA sequencing on CDC showed to be feasible, finding 256 mutations in 119 genes (missens mutations the majority). Altered genes, molecular subtypes and signatures will be associated to different outcomes and responses to cabo. Conclusions: The study met its primary endpoint showing promising efficacy and acceptable tolerability of cabo in mCDC pts. Mature results according to mutational profiles and gene signatures will be presented. Clinical trial information: NCT03354884.

Relevance of a medicosurgical strategy combining cetuximab and chronomodulated (Chrono) chemotherapy (chemo) with metastases resection as 3rd line treatment for patients (pts) with metastatic colorectal cancer (MCRC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14505-14505
Author(s):  
A. Karaboue ◽  
M. Bouchahda ◽  
R. Adam ◽  
P. Innominato ◽  
M. P. Bralet ◽  
...  
Keyword(s):  
Objective Response ◽  
In Situ Hybridisation ◽  
Progression Free Survival ◽  
Fluorescence In Situ Hybridisation ◽  
Term Survival ◽  
Survival Estimate ◽  
Gene Copies ◽  
Acneiform Rash

14505 Background: Metastases surgery offers long tem survival for pts with chemo-downstaged MCRC (Adam et al. Ann Surg 2004). The relevance of this medicosurgical strategy was investigated in pts given cetuximab (Cetux) and Chrono after chemo failure. Methods: 56 pts with progressive MCRC on prior chemo received Cetux (400 mg/m2 on 1st dose then 250 mg/m2/week) and q2w Chrono based on irinotecan (34 pts), oxaliplatin (14 pts) or both (8 pts). Toxicity grades (G) and response were assessed q2w and q8w, respectively. Tumour EGFR was determined by immunohistochemistry (all pts) and gene copies by fluorescence in situ hybridisation (27 pts). Metastases surgery was attempted whenever complete resection was foreseen. Results: Median of 3 prior chemo (1 to 8); median age: 61 years (35 to 79); M/F: 34/22; WHO PS 0/1/2/3: 37/14/4/1; colon/rectum: 32/24; M sites 1/2/=3: 15/22/19; liver/lung: 45/40. EGFR was detected in the tumor of 39 pts (69.6%). 3 pts had G4 allergy. 53 evaluable pts received a median of 5 courses of Cetux-Chrono (1–22). G2–3 acneiform rash occurred in 36 pts (67.8%; G3: 30.4%). Main G3–4 toxicities were diarrhea (26.5%), neutropenia (23.1%) and neuropathy (22.6%). The objective response rate (ORR) was 32% [95% CI, 19.4 to 44.6] (13 PR and 3 CR). ORR was correlated positively with acneiform rash (p= 0.019) but negatively with the detection of EGFR+ tumor cells (0%, ORR=54.5%; 1–10%, 33%; >10%, 16.7%; p = 0.044). No EGFR amplification was documented including 8 OR. Median progression-free survival (PFS) and overall survival were 5.1 [3.2–6.9] and 13.9 months [6.5–21.3] respectively. Metastases surgery was performed in 10 pts (8 R0, 2 R1) after 3–15 courses of Cetux-Chrono as 2nd-5th line. Median PFS in resected pts was 11.7 months [5.8–17.6], with a survival estimate of 80% at 21 months. Conclusions: Cetux-Chrono safely reverted MCRC resistance and allowed successful metastases resection in 17.8% of these pts, like 1st line chemo. This medicosurgical strategy impacted favourably on long term survival, despite its application as 3rd treatment line. Supported by ARTBC, Hôpital Paul Brousse, Villejuif, France No significant financial relationships to disclose.

Randomized phase II study of IV topotecan versus CRLX101 in the second-line treatment of recurrent extensive-stage small cell lung cancer (ES-SCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS7610-TPS7610
Author(s):  
Thomas A. Hensing ◽  
Theodore Karrison ◽  
Edward Graeme Garmey ◽  
Meliessa G. Hennessy ◽  
Ravi Salgia
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Objective Response ◽  
Systemic Exposure ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Phase 2 ◽  
Polymer Conjugate

TPS7610 Background: SCLC remains an area of high unmet medical need with an aggressive clinical course and < 10% 5-year overall survival. In the U.S., topotecan (Hycamtin, GlaxoSmithKline) is the reference standard for treatment of chemotherapy (C)-sensitive (S) relapsed disease but its use remains compromised by toxicity. There currently exists no standard therapy for patients (pts) with C-resistant (R) disease (relapse occurring < 60 days from last C). CRLX101 is a novel cyclodextrin-containing polymer conjugate of camptothecin (CPT) that self-assembles into nanoparticles and delivers sustained levels of active CPT into cancer cells while substantially reducing systemic exposure. In vitro and in vivo data suggest superior activity of CRLX101 compared to approved agents in multiple animal tumor models including SCLC. A monotherapy recommended phase 2 dose of 15 mg/m2 IV every 2 weeks has now been administered to over 150 cancer pts across five ongoing phase 2 clinical trials. Methods: This ongoing, randomized phase 2 clinical trial compares the effect on progression free survival (PFS) of 2nd-line treatment with IV CRLX101 (15 mg/m2 on days 1 and 15 every 28 days) to IV topotecan (1.5 mg/m2 on days 1-5 every 21 days) in pts with CS relapsed ES-SCLC. In parallel, the effect of 2nd-line CRLX101 on 3-mo. PFS rate of pts with CR relapsed ES-SCLC will be evaluated. Secondary objectives in both cohorts include evaluation of objective response rates (by RECIST v1.1), overall survival, and safety. In the randomized cohort, 112 pts (56/arm) will be enrolled in order to achieve 90% power to detect an improvement in median PFS from 3 to 5 mos. (HR=0.60). An interim analysis will be performed after 1/2 of expected PFS events have occurred. Pts with CR disease will all receive CRLX101 and the trial will employ a 2-stage design: 14 pts will be enrolled in stage 1 and the study will be terminated if ≤ 3 pts remain progression free at 3 mos. Otherwise, an additional 30 pts will be enrolled and if ³ 15/44 (34%) pts remain progression free at 3 mos., the drug will be considered worthy of further investigation. The first patient on this clinical trial was enrolled on January 30, 2013. Clinical trial information: NCT# is pending.

Updated overall survival analysis of NAPOLI-1: Phase III study of nanoliposomal irinotecan (nal-IRI, MM-398), with or without 5-fluorouracil and leucovorin (5-FU/LV), versus 5-FU/LV in metastatic pancreatic cancer (mPAC) previously treated with gemcitabine-based therapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 417-417 ◽  
Author(s):  
Andrea Wang-Gillam ◽  
Chung-Pin Li ◽  
Gyorgy Bodoky ◽  
Andrew Dean ◽  
Yang-Shen Shan ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Analysis ◽  
Primary Endpoint ◽  
Descriptive Analysis ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
P Value ◽  
Nanoliposomal Irinotecan ◽  
Previously Treated

417 Background: NAPOLI-1 is a global, randomized Phase 3 study evaluating nal-IRI—a nanoliposomal irinotecan—with or without 5-FU/LV in 417 patients with mPAC previously treated with gemcitabine-based therapy. Primary survival analysis was based on 313 events. Nal-IRI+5FU/LV significantly improved overall survival (OS, primary endpoint), 6.1 months (mo) vs 4.2 mo; with 5-FU/LV (unstratified hazard ratio [HR] = 0.67; P = 0.012). Primary endpoint was supported by improved progression-free survival, time to treatment failure, objective response and CA19-9 tumor marker response rates, and manageable toxicities. An updated analysis of OS, 6- and 12-month-survival estimates, and safety is presented. Methods: The updated descriptive analysis of OS, based on 378 events (25 May 2015), includes data from all randomized patients across the 3 arms. Results: After 378 OS events, nal-IRI+5-FU/LV (n = 117) retained an OS advantage relative to 5-FU/LV (n = 119): 6.2 mo (95% confidence interval [CI], 4.8–8.4) vs 4.2 mo (95% CI, 3.3–5.3) with an unstratified HR of 0.75 (P = 0.0417). In contrast, there was no OS advantage with nal-IRI monotherapy (n = 151) vs 5-FU/LV (n = 149): 4.9 mo [95% CI, 4.2–5.6] vs 4.2 mo [95% CI, 3.6–4.9], HR = 1.08; P = 0.5. Six-month survival estimates were 53% (95% CI, 44–62%) for nal-IRI+5-FU/LV vs 38% (95% CI, 29–47%) for 5-FU/LV; 12-month survival estimates were 26% (95% CI, 18-35%) for nal-IRI+5-FU/LV vs 16% (95% CI, 10–24%) for 5-FU/LV. With events in nearly all patients, the OS curves converge at ~20 mo with 19 patients (16.2%) surviving beyond 20 mo. This is a reason for attenuation of the HR estimate and unstratified log rank p-value. The most common grade 3+ adverse events occurring at a ≥ 2% incidence in the nal-IRI-containing arms were neutropenia, diarrhea, vomiting, and fatigue. Conclusions: In an updated analysis, the median OS benefit for nal-IRI+5FU/LV over 5-FU/LV was maintained, with a similar safety profile. Nal-IRI+5-FU/LV may be a new standard of care for patients with mPAC previously treated with gemcitabine-based therapy. Clinical trial information: NCT01494506.

A phase 1b/2 study of napabucasin with weekly paclitaxel in advanced, previously treated non-squamous non-small cell lung cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9052-9052 ◽  
Author(s):  
Carlos Becerra ◽  
Wahid Tewfik Hanna ◽  
Stephen Lane Richey ◽  
Gregory Michael Cote ◽  
Scott Andrew Laurie ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Overall Survival ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Small Cell ◽  
Small Cell Lung ◽  
Free Survival ◽  
Anti Cancer ◽  
Cancer Activity

9052 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Napabucasin has shown potent synergistic preclinical anti-tumor activity with paclitaxel (PTX). In a phase Ib dose escalation study in patients (pts) with advanced solid tumors, napabucasin plus weekly PTX was well tolerated. A phase II expansion cohort was opened for pts with advanced non-small cell lung cancer (NSCLC). Methods: Pts with metastatic non-squamous NSCLC were enrolled to confirm safety and preliminary anti-cancer activity. Prior platinum-based systemic therapy was required, and patients with an EGFR or ALK mutation required appropriately targeted therapy. Napabucasin was administered orally at a starting dose of 240 or 480 mg BID with PTX 80 mg/m2 IV weekly 3 of every 4 weeks. AEs were evaluated using CTCAE v4.03 and objective assessments were performed every 8 weeks per RECIST 1.1. Results: A cohort of 23 pts with advanced non-squamous NSCLC was evaluated. The median number of prior systemic treatment lines was 3, including taxane-based therapy in 100% and immune checkpoint inhibitor in 48% (n = 11). Treatment was well tolerated; related grade 3 AE included diarrhea (n = 4) and fatigue (n = 1). The objective response rate was 26% (6 partial responses [PR]) and the disease control rate (DCR; proportion with SD at 8 weeks plus PR per RECIST) was 70% (n = 16). Tumor regression, including PR, occurred in 35% (n = 8). The median progression-free survival (mPFS) was 5.4 months, and 43% (n = 10) of pts were alive and free of progression at the 24 week time-point or longer. The median overall survival (mOS) was 11.0 months, and 30% (n = 7) of pts were alive for 52 weeks or longer. Conclusions: Clinical safety and encouraging signs of anti-cancer activity were observed in pts with heavily pretreated non-squamous NSCLC who received napabucasin plus weekly paclitaxel. The objective response rate, progression free survival, and overall survival in this population warrant further clinical evaluation and a controlled phase 2/3 trial (CanStem43L) has been initiated. Clinical trial information: NCT01325441.

Phase Ib study of talimogene laherparepvec (T-VEC) injection into liver metastases (LMs) in combination with intravenous (IV) atezolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC) or colorectal cancer (CRC).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS725-TPS725
Author(s):  
J. Randolph Hecht ◽  
Arlene Chan ◽  
Miguel Martin ◽  
Nicolas Mach ◽  
Sara A. Hurvitz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Primary Objective ◽  
Intralesional Injection ◽  
Ecog Performance Status ◽  
Eligibility Criteria ◽  
The Usa

TPS725 Background: T-VEC is a genetically modified, oncolytic herpes simplex virus type 1 designed to selectively replicate within tumors and produce GM-CSF to enhance systemic antitumor immune responses. Atezolizumab is a monoclonal antibody checkpoint inhibitor (CPI) that targets PD-L1. The safety of intrahepatic administration of T-VEC has been demonstrated in a prior clinical trial (NCT02509507). A previous trial of T-VEC in combination with a CPI in advanced melanoma demonstrated improved responses compared to those with a CPI alone (Puzanov et al. JCO. 2016; 34:2619-26). We hypothesize that T-VEC combined with a CPI may also be effective in other tumor types. This phase 1b, multicenter study evaluates the safety of intrahepatic injection of T-VEC in combination with IV atezolizumab in pts with TNBC or CRC with LMs. Methods: The study will enroll up to 36 pts in two parallel cohorts (18 TNBC, 18 CRC) at sites in the USA, Europe, and Australia. The primary objective is to evaluate the incidence of dose-limiting toxicities (DLTs). Secondary objectives include objective response rate, lesion-level responses in injected and uninjected tumors, progression-free survival, and overall survival. Key eligibility criteria include age ≥ 18 years, confirmed diagnosis of TNBC or CRC with LMs, ECOG performance status 0/1, adequate organ function, disease progression during or after ≥ 1 prior standard-of-care systemic therapy for metastatic disease, and ≥ 1 measurable, injectable LM. T-VEC will be given by image-guided intralesional injection of up to 4 mL of 106 plaque forming units (PFU)/mL on day 1 and up to 4 mL of 108 PFU/mL every 21 days thereafter; atezolizumab 1,200 mg IV will be given on day 1 and every 21 days thereafter. The DLT-evaluation period is the first two cycles (1 cycle = 21 days). Interim safety analysis will occur after the first 4–6 pts have become DLT evaluable. Up to six cycles of T-VEC will be given with an additional 6 cycles allowed. After cycle three, nonhepatic lesions may be injected, subject to protocol-defined criteria. The study opened for enrollment in January 2018. (NCT03256344) Clinical trial information: NCT03256344.

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