A phase II study of afatinib (BIBW 2992) in patients with advanced HER2-positive trastuzumab-refractory esophagogastric cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS4144-TPS4144 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
David Ilson ◽  
David Paul Kelsen ◽  
Mark Schattner ◽  
Adriana Heguy ◽  
...  
Keyword(s):  
Phase Ii ◽  
De Novo ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Single Agent ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Irreversible Inhibitor ◽  
Clinical Issue ◽  
Esophagogastric Cancer

TPS4144 Background: Trastuzumab, approved by the FDA, has been the standard of care for patients (pts) with HER2-positive esophagogastric cancer. Acquired and de novo resistance to trastuzumab is an important clinical issue. Afatinib, an oral irreversible inhibitor of the ErbB-family of tyrosine kinase receptors, EGFR (ErbB1), HER2 (ErbB2), and HER4 (ErbB4), in combination with cetuximab, demonstrated a 40% partial response (PR) rate, with clinical benefit in >90% in lung cancer patients with acquired resistance to erlotinib. (Janjigian Y. ASCO 2011). MSKCC data in a HER2-positive NCI-N87 gastric cancer xenograft showed that while trastuzumab alone was minimally effective, single-agent afatinib resulted in near complete tumor regression by inducing apoptosis and downregulation of HER2, p-HER2, EGFR, p-EGFR with minimal additive benefit of trastuzumab. In light of these data and the efficacy of afatinib in patients with trastuzumab-refractory breast cancer, we designed a phase II study to determine if afatinib will benefit patients with trastuzumab-refractory HER2-positive esophagogastric cancer. We hypothesize that simultaneous inhibition of ErbBB receptor family components with afatinib will overcome trastuzumab resistance. Molecular bases of trastuzumab resistance will be examined. Methods: Pts with metastatic HER2-positive (IHC 3+ or FISH >2.0) esophagogastric cancer with disease progression on a trastuzumab-containing regimen will receive afatinib 40 mg once daily. Primary endpoint RECIST 1.1 response (SD+CR+PR) at 4 months, with imaging every 8 wks. 13 pts will be enrolled in the 1st stage and if ≥1 responses are observed, additional 14 ps (total of 27) will be treated. An initial biopsy prior to the start of therapy, a second biopsy after 1 wk of afatinib, analysis of archival pre-trastuzumab tissue and blood sample for matched normal DNA control are mandated. Changes in signaling following afatinib therapy will provide insight into response heterogeneity. Degree of target inhibition will be correlated with responses. Archival baseline (pre-trastuzumab) and pre-afatinib tissue will be assessed for abnormalities in pathways implicated in trastuzumab resistance.

A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15017-e15017
Author(s):  
Yelena Yuriy Janjigian ◽  
Marinela Capanu ◽  
Christopher M. Gromisch ◽  
David Paul Kelsen ◽  
Geoffrey Y. Ku ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Single Agent ◽  
Cancer Resistance ◽  
Trastuzumab Resistance ◽  
Her2 Positive ◽  
Recist 1.1 ◽  
Disease Stabilization

e15017 Background: Trastuzumab, approved by the FDA, has been the standard of care for pts with HER2-positive EG cancer. Resistance to trastuzumab is now emerging in this population. Afatinib, an oral inhibitor of EGFR, HER2, and HER4 has potent single agent activity in HER2-positive EG cancer NCI-N87 and MSKCC patient derived xenografts (Janjigian JNM 2013). We report the initial results of a phase II study of afatinib in patients with trastuzumab refractory EG cancer. Methods: Pts with HER2 positive (IHC 3+ or FISH>2.0) metastatic EG adenocarcinoma, following failure of at least one trastuzumab/chemotherapy regimen received afatinib 40 mg daily. Archival tissue from pre-trastuzumab biopsy, a new biopsy prior to the start of therapy and after 1 wk of afatinib are mandated. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD), complete response (CR), or partial response (PR) by RECIST 1.1. Results: Nine patients treated with afatinib; median follow up 2.7mos (0.5 to 5.3mos). Median age 62, KPS 80, 6 males, 56% IHC3+; 44% IHC1+/2+/FISH>2.0. Number of prior trastuzumab containing regimens: median 2 (1 to 4). The following treatment emergent adverse events were observed: nausea/vomiting (Grade 1/2: 22%), diarrhea (Grade 1/2:67%), fatigue (Grade1/2: 33%), rash (Grade 1/2:44%), anorexia (Grade 1/2:33%,Grade 3:11%), mucositis (Grade1/2: 11%), paronychia/nail loss (Grade 1/2:11%). To date, 7 pts evaluable for response, 3 of 7 patients (43%) derived clinical benefit; 1 pt (14%) with ongoing RECIST 1.1 confirmed PR - a durable 50% regression of biopsy proven metastases in lung and lymph nodes at 5.3 mo. A second patient had 20% tumor regression in biopsy proven liver metastasis, 3.6 mos disease stabilization. A third patient experienced 4.7 mos disease stabilization and regression of biopsy proven skin metastasis. Conclusions: Single agent afatinib shows clinical efficacy in patients with trastuzumab refractory EG cancer. The study has been expanded to accrue additional patients. Efforts to elucidate the mechanisms of trastuzumab resistance in EG cancer are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.

A phase II study of afatinib in patients (pts) with metastatic human epidermal growth factor receptor (HER2)-positive trastuzumab-refractory esophagogastric (EG) cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 52-52 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Marinela Capanu ◽  
Tooba Imtiaz ◽  
David Paul Kelsen ◽  
Geoffrey Yuyat Ku ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Cancer Resistance ◽  
Her2 Positive ◽  
Tumor Biopsy ◽  
Disease Stabilization ◽  
Erbb Family Blocker

52 Background: Trastuzumab (T) combined with chemotherapy has been the standard of care for pts with HER2+ EG cancer. Resistance to T is now emerging in this population. Afatinib (A), a potent ErbB Family Blocker, induced nearly complete tumor regression in MSKCC HER2+ patient derived xenografts (PDX). We report the initial results of a phase II study of afatinib in patients with T refractory EG cancer. Methods: Pts with HER2+ (IHC 3+ or FISH>2.0) EG adenocarcinoma –progressive on trastuzumab -received A 40 mg. Archival pre-T tissue, tumor biopsy after progression on T and after 1 week on A mandated on protocol. The primary endpoint-overall clinical benefit at 4 months: stable disease (SD) or partial response (PR). Results: 14 pts treated with A; median duration 5.1 mos (1.7 to 12.1 mos). Median age 62, KPS 80, median 2 (1 to 4) prior T containing regimens, 64% of tumors IHC3+; 36% IHC2+/FISH>2.2. Adverse events included: diarrhea (Grade 1/2:69%), fatigue (Grade 1/2:54%), rash (Grade 1/2:54%), mucositis (Grade 1:23%), paronychia (Grade 1/2:15%). To date, 13 pts evaluable for response, 3 of 13 pts (23%) had disease stabilization (PR or SD); 1 pt with confirmed PR - a durable 75% regression of biopsy proven metastases. Median OS 6.6 mos (1.9 to NR). PDXs established from biopsies of T refractory tumors of 5 pts. Next generation sequencing of matched pre-T and post-T progression tumors from 6 pts was performed and results will be reported. Conclusions: Afatinib shows clinical efficacy in patients with T refractory EG cancer. The study has been expanded to accrue additional patients. Efforts to elucidate the mechanisms of T resistance including validation of potential drivers of T resistance using HER2+ PDXs are ongoing. Updated molecular and clinical data will be presented. Clinical trial information: NCT01522768.

A phase II study of voreloxin as single agent therapy for elderly patients (pts) with newly diagnosed acute myeloid leukemia (AML)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7048-7048
Author(s):  
M. B. Maris ◽  
F. Ravandi ◽  
R. Stuart ◽  
R. Stone ◽  
L. Cripe ◽  
...  
Keyword(s):  
Phase Ii ◽  
De Novo ◽  
Phase Ii Study ◽  
Ex Vivo ◽  
Single Agent ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Elderly Age ◽  
Secondary Aml ◽  
Early Results

7048 Background: Voreloxin is a naphthyridine analog that intercalates DNA and inhibits topoisomerase II, inducing apoptosis. Interim results of REVEAL-1, a phase II study of single agent voreloxin in newly diagnosed elderly AML pts, are reported. Methods: Phase II study of 3 voreloxin schedules (approximately 30 pts/schedule): A) 72 mg/m2qw x 3; B) 72 mg/m2qw X 2; or C) 72 mg/m2/dose on D1 and D4. Eligibility: newly diagnosed AML (de novo or secondary AML), pts age ≥ 60 and ≥ 1 additional adverse risk factor (age ≥ 70, secondary AML, intermediate or unfavorable cytogenetics, or PS 2). PK were evaluated in a pt subset in cycle 1. ex vivo sensitivity of pt BMA to voreloxin was evaluated by CellTiter-Glo proliferation assay. Results: Enrollment targets for schedules: A) (29) and B) (31) are met. Demographics (N = 54): 66% male, 35% female; median age 75 years; ECOG PS 0–1 90%, PS 2 10%. 20% AHD and cytogenetics were intermediate in 29%, unfavorable in 34%, and unknown in 36%. Final CR + CRp rate: A) 38%; B) too early to evaluate. Median duration of remission has not been reached. Thirty day all-cause mortality: A) 17%; B) 1 of 22, 4.5%. Infection was the most common cause of early mortality. Tolerability improved markedly in B): G3 or higher pneumonia (A 24%, B 11%) and mucositis (A 21%, B 11%) incidence were reduced. Voreloxin PK were similar to those in an earlier single agent phase I study in relapsed/refractory AML. C) enrollment is pending. Ex-vivo sensitivity did not predict clinical response. Conclusions: In REVEAL-1, voreloxin demonstrates clinical activity with 2 dosing schedules in previously untreated elderly (age ≥ 60) patients with AML who are unlikely to benefit from standard chemotherapy. CR + CRp rate was 38% (11 of 29 pts) for 3 weekly voreloxin doses (A). Early results from 2 weekly voreloxin doses (B) show 6 CR + CRp of 21 evaluable pts, with 2 pts in heme recovery, and improved tolerability. Enrollment to (C), voreloxin dosed D1 and D4, is pending. [Table: see text]

Randomized phase II study of neratinib with or without temsirolimus in patients (pts) with non-small cell lung cancer (NSCLC) carrying HER2-activating mutations.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS8124-TPS8124 ◽  
Author(s):  
Leena Gandhi ◽  
Jean-Charles Soria ◽  
Richard Bryce ◽  
Benjamin Besse
Keyword(s):  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Single Agent ◽  
In Vivo Studies ◽  
Type I ◽  
Braf Mutations ◽  
Activating Mutations ◽  
Promising Therapeutic Approach

TPS8124 Background: Recent advances in NSCLC have highlighted the importance of identifying mutations in driver oncogenes (eg EGFR, ALK) and the use of targeted agents to treat genetically-defined pt populations. HER2 (ERBB2) is a member of the ERBB receptor tyrosine kinase (TK) family which, once activated, stimulates several downstream effector pathways including PI3K, MAPK and JAK/STAT. Activating HER2 mutations are documented in approx 2–4% of pts with NSCLC and occur independently of EGFR, KRAS, NRAS and BRAF mutations. The efficacy of single-agent neratinib in HER2-mutated NSCLC is currently unknown; however, in vivo studies suggest that dual inhibition with an irreversible TK inhibitor (TKI) and an mTOR inhibitor is a promising therapeutic approach for HER2-mutated NSCLC [Perera et al. PNAS 2009]. This concept has been supported recently by a phase I study of neratinib, an irreversible pan-ERBB TKI, plus temsirolimus, which showed tumor regression in 5/6 evaluable pts with HER2-mutated NSCLC [Gandhi et al. WCLC, Amsterdam, Netherlands, 2011]. Methods: This international, randomized, open-label phase II study includes pts with previously treated stage IIIB/IV NSCLC and HER2-activating mutations. Pts are randomized 1:1 to oral neratinib 240mg od continuously ± IV temsirolimus 8mg/w (dose escalation to 15mg/w after one 4w cycle if tolerated). The addition of temsirolimus is permitted in pts assigned to neratinib monotherapy after progression. Tumor evaluations will be conducted every 8w. The primary endpoint is overall response rate (RECIST 1.1). Secondary endpoints are: clinical benefit rate; response duration; progression-free and overall survival; safety; health outcomes. Exploratory analyses include: correlative studies between tumor and plasma biomarkers and outcomes; pharmacokinetics. The trial has an optimal 2-stage design. Sample size (13–52 pts/arm) is based on a null response rate of 0.09, an alternative response rate of 0.25, power of 80% and 0.05 type I error rate. Both arms will be compared independently against historical controls. Enrollment is scheduled to open in March 2013. EudraCT identifier: 2012-004743-68. Clinical trial information: 2012-004743-68.

SOlar: A translational phase II study of single-agent olaparib in the treatment of advanced esophagogastric cancer.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS471-TPS471
Author(s):  
Elizabeth Cartwright ◽  
Caroline Yean Kit Fong ◽  
Michael Hubank ◽  
Claire Saffery ◽  
Eleftheria Kalaitzaki ◽  
...  
Keyword(s):  
Disease Control ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Tumour Response ◽  
Predictive Biomarkers ◽  
Molecular Features ◽  
Anti Tumour Activity ◽  
Esophagogastric Cancer ◽  
Tumour Activity

TPS471 Background: Oesophagogastric (OG) cancers represent a significant health burden and leading cause of cancer related death. Prognosis in advanced disease is poor and novel therapies are needed to improve outcomes. Molecular features of advanced OG cancer suggest that assessment of DDR (DNA damage repair) targeted agents is warranted. Specifically, ATM and ARID1A defects and mutational scars indicative of homologous recombination defects are present in a subset of OG cancers and are associated with polyadenosine 5’diphosphoribose polymerase inhibitor (PARPi) sensitivity. Methods: SOlar is a multi-centre, open-label, single arm, phase II study of olaparib, a PARPi, in patients with advanced oesophageal, gastro-oesophageal junction and gastric adenocarcinoma. The trial will use a single-arm Simon two-stage design to evaluate the anti-tumour activity of olaparib in advanced OG cancers. The primary endpoint is disease control rate (DCR) at 8 weeks by RECIST v1.1. To rule out a DCR of ≤15% while aiming for DCR ≥30% (alpha = 0.09, power = 89%), 54 patients must be recruited it total. An interim analysis will take place when 27 patients have been accrued, dosed and followed until the 8-week disease evaluation. If 4 or fewer patients have disease control (DC) the study will be terminated. If 5 or more patients have DC, an additional 27 patients will be enrolled to a total of 54 patients. If ≥12/54 have DC in the final analysis then it will be concluded that the treatment has shown anti-tumour activity compatible with 30% and an investigation of potential biomarkers of response will be carried out. Secondary endpoints are ORR, DoR, OS, PFS, time to radiological progression and safety. This highly translational study incorporating serial tumour biopsies will investigate candidate predictive biomarkers of PARPi sensitivity with the aim of identifying responder/non-responder subpopulations. Further exploratory objectives will investigate the predictive role of early FDG-PET/CT in assessing tumour response and the creation of an organoid biobank. The trial opened to recruitment in July 2019 and will recruit up to 54 patients over 3 years. Clinical trial information: NCT03829345.

scholarly journals Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma

2021 ◽  
Author(s):  
Cara Kenney ◽  
Tricia Kunst ◽  
Santhana Webb ◽  
Devisser Christina ◽  
Christy Arrowood ◽  
...  
Keyword(s):  
Cancer Patients ◽  
Phase Ii ◽  
Pancreas Cancer ◽  
Phase Ii Study ◽  
Mapk Pathway ◽  
Single Agent ◽  
Objective Response ◽  
Ductal Adenocarcinoma ◽  
Active Inhibitor ◽  
Orally Active

SummaryBackground Preclinical evidence has suggested that a subset of pancreatic cancers with the G12R mutational isoform of the KRAS oncogene is more sensitive to MAPK pathway blockade than pancreatic tumors with other KRAS isoforms. We conducted a biomarker-driven trial of selumetinib (KOSELUGO™; ARRY-142886), an orally active, allosteric mitogen-activated protein kinase 1 and 2 (MEK1/2) inhibitor, in pancreas cancer patients with somatic KRASG12R mutations. Methods In this two-stage, phase II study (NCT03040986) patients with advanced pancreas cancer harboring somatic KRASG12R variants who had received at least one standard-of-care systemic therapy regimen received 75 mg selumetinib orally twice a day until disease progression or unacceptable toxicity occurred. The primary outcome of the study was best objective response (BOR). Results From August 2017 to February 2018 a total of 8 patients with confirmed somatic KRASG12R mutations and a median age of 61.5 years were treated with selumetinib. Seven out of eight (87.5%) had received two or more lines of prior systemic chemotherapy. After a median follow-up period of 8.5 months (range 2 to 20), three patients had stable disease for more than 6 months while receiving selumetinib. No patients achieved an objective partial response. Median progression-free survival (PFS) was 3.0 months (95% CI, 0.8–8.2) and median overall survival (OS) 9 months (95% CI, 2.5–20.9). Conclusion This study in heavily pre-treated pancreatic adenocarcinoma patients suggests alternative strategies beyond single agent MEK inhibition are required for this unique, molecular subset of pancreatic cancer patients. The trial was registered on February 2nd, 2017 under identifier NCT03040986 with ClinicalTrials.gov.

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