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.

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.

Preliminary results of a phase II study of continuous low dose metronomic (LDM) cyclophosphamide (CTX) and celecoxib (CEL) for asymptomatic hormone refractory prostate cancer (HRPC) with assessment of anti-angiogenic biomarkers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14046-14046 ◽  
Author(s):  
S. R. Berry ◽  
Y. Ko ◽  
U. Emmenegger ◽  
Y. Shaked ◽  
R. Choo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Control ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Tumour Response ◽  
Clinical Work ◽  
Circulating Endothelial Cells ◽  
Measurable Disease ◽  
Cox 2 ◽  
Angiogenic Biomarkers

14046 Background: LDM CTX is a minimally toxic anti-angiogenic therapy that has demonstrated activity in multiple tumour types including HRPC. Increased Cyclooxygenase 2 (COX 2, a prostaglandin synthase enzyme) expression appears to be a consistent feature of a variety of human tumours, including prostate cancer. COX 2 inhibitors like CEL exhibit anti-tumour activity in pre-clinical studies, at least in part due to their anti-angiogenic activity. Pre-clinical work supports the concept that the combination of selective angiogenesis inhibitors like CEL with metronomic chemotherapy can enhance the effects of these agents on tumour angiogenesis. Methods: Men with asymptomatic HRPC at a single Canadian centre received celecoxib 400 mg po BID and cyclophosphamide 50 mg po daily. The primary efficacy endpoint of this 2 stage phase II study is disease control rate (DCR): 50% PSA response, tumour response or prolonged (=6 mos) PSA or stable measurable disease. This study is also assessing the safety of LDM CTX and CEL as well as potential anti-angiogenic biomarkers in these patients including circulating endothelial cells and their precursors (CEC/P), plasma levels of thrombospondin-1 (TSP-1) and vascular endothelial growth factor (VEGF). Results: Enrollment for the first stage of this study (10 men) has been completed. There were 2 patients with disease control by the a priori criteria: one patient with a partial tumour response (PR) (PR duration 13 mos with PSA stabilization for 12 mos) and one patient that had both prolonged stable PSA (7 mos) and prolonged stable measurable disease (8 mos). In addition, another patient had an unconfirmed PR. The therapy was well tolerated. One patient had angina that responded well to medical therapy but there were no serious arterial-thromboembolic events. One patient developed grade 3 hypertension. All other toxicities were grade 1/2. Data on CEC/P, TSP-1 and VEGF levels will be presented at the meeting. Conclusions: LDM CTX + CEL is a well tolerated therapy in men with asymptomatic HRPC. 2/10 patients achieved disease control in the first stage of the trial, meeting the criteria to proceed to the second stage. [Table: see text]

A phase II study of ganetespib (G) as second- or third-line therapy for metastatic pancreatic cancer (MPC).

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 297-297 ◽  
Author(s):  
Ramya Thota ◽  
Laura Williams Goff ◽  
Emily Chan ◽  
Jordan Berlin ◽  
C. Michael Jones ◽  
...  
Keyword(s):  
Disease Control ◽  
Cancer Progression ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Heat Shock Protein 90 ◽  
Cytotoxic Agents ◽  
Stopping Rules ◽  
Cancer Center ◽  
Line Setting

297 Background: Heat shock protein 90 (HSP90) regulates folding, stability and function of signaling proteins such as EGFR, IGF-1R, c-Met, ERBB4, PDGFRα and c-Ret, several of which are key pathways for MPC pathogenesis. G prevents Hsp90 binding to client proteins leading to inactivation and degradation, disrupting signaling that promotes cancer progression. This phase II study is designed to evaluate the efficacy of G in patients (pts) with refractory MPC. Methods: Pts with MPC in the 2nd or 3rd line setting, with PS 0-1, received G 175 mg/m2intravenously once weekly for 3 weeks out of a 4 week cycle. Primary endpoint was disease control rate (DCR) at 8 weeks, with a goal of 70% DCR. Secondary endpoints were response rate (RR), overall survival (OS), and safety. 43 pts were planned for initial accrual. Simon’s optimal two-stage design was used to assess 8 week DCR. G was considered inactive if 8 or fewer pts among the first 15 treated had disease control after 8 weeks of treatment (tx). Results: Seventeen pts were enrolled, and 14 received G. Median age was 65 (range 33-77), 4 female and 10 male. Eight received 1 prior line of therapy, and 6 received 2 prior lines of therapy. Grade 3 related toxicities include abdominal pain (4), fatigue (4), diarrhea (4), hyponatremia (9), nausea (1) and vomiting (1). There were no Grade 4-5 related events. DCR at 8 weeks was 21%, and OS was 2.5 months. Three pts didn’t complete tx; 1 due to disease progression after first cycle, 1 due to tx related toxicity, and 1 withdrew after 2 tx’s. Early stopping rules for lack of clinical efficacy led to study closure. Conclusions: Single agent G was tolerable with modest disease control when used as a single agent in refractory MPC. This disease is resistant to chemotherapy, and given the emerging data in both lung and breast cancer suggesting improved activity of G in combination with cytotoxic agents, studies combining this agent with chemotherapy in MPC are under development. Supported by Vanderbilt-Ingram Cancer Center CCSG (P30CA68485) and Synta. Clinical trial information: NCT01227018.

Phase II study of regorafenib (Reg) in patients with previously treated advanced pancreatic cancer (APC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15751-e15751 ◽  
Author(s):  
John Stuart Salmon ◽  
Jimmy J. Hwang ◽  
Myra M. Robinson ◽  
James Thomas Symanowski ◽  
Lloye M Dillon ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Disease Control ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Single Agent ◽  
Advanced Pancreatic Cancer ◽  
Radiographic Evaluation ◽  
Treatment Approaches ◽  
Dismal Prognosis ◽  
Line Of Therapy

e15751 Background: APC that has progressed after treatment with gemcitabine has a dismal prognosis and novel treatment approaches are needed. Reg is a potent oral inhibitor of VEGFR 1-3, PDGFR, TIE-2, FGFR-1, KIT, and the RAF kinases, and has activity in pancreatic xenograft models. We tested the activity of Reg in patients (pts) with refractory APC. Methods: This single arm, single center phase II study evaluated Reg (120mg/d, for 21 days, followed by 7-day break, with escalation to 160mg after the 1st cycle if tolerated) in pts with metastatic pancreatic cancer whose disease had progressed after at least one prior line of therapy and treatment with gemcitabine. Pts underwent radiographic evaluation every 2 cycles. The primary endpoint was 16-wk PFS. Kaplan Meier techniques were used to estimate PFS and OS. Serum tumor MUC1 antigen (tMUC1) concentrations were measured at baseline, end of cycle 1, and off-treatment using the TAB 004 antibody (Agkura Personal Score blood test, OncoTAb, Inc). Relative change of tMUC1 from baseline to end of cycle 1 was compared between those with and without 16-wk disease control. Results: 20 pts were enrolled into the study. Median age = 65 (47-79), and 80% (16/20) had 2 or more prior lines of therapy for advanced disease. Landmark 16 wk PFS = 10% (2/20), crossing a predefined futility boundary to demonstrate 20% improvement over historical controls with BSC. ORR was 5% (1/20), and DCR at 8 wks was 20% (4/20). Median PFS was 6.1 wks (95% CI: 2.9 – 7.1), and median OS was 9.4 wks (95% CI: 8.1 – 17.0). 10% of pts (2/20) had protocol defined Reg dose escalation to 160mg, and 30% (6/20) had dose reduction to 80mg. The most frequent grade 3-4 adverse events included hyponatremia (35%), fatigue (20%), and hypoalbuminemia (20%). Baseline tMUC1 varied substantially, mean 69.6ug/mL, median 51.3ug/mL (10.8 – 310.5). Serum tMUC1 decreased by a mean of 20.8% in the pts with disease control at 16 wks (n = 2), but increased by 65% (mean) in pts with disease progression or death within 16 wks (n = 13, p = 0.048). Conclusions: Reg has minimal activity as a single agent in pts with heavily treated APC. Serum tMUC1 levels measured by TAB 004 antibody may be a novel tumor marker in this disease. Different treatment approaches are needed. Clinical trial information: NCT02080260.

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.

scholarly journals Pembrolizumab in vaginal and vulvar squamous cell carcinoma: a case series from a phase II basket trial

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jeffrey A. How ◽  
Amir A. Jazaeri ◽  
Pamela T. Soliman ◽  
Nicole D. Fleming ◽  
Jing Gong ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Phase Ii ◽  
Squamous Cell ◽  
Single Agent ◽  
Case Series ◽  
Predictive Biomarkers ◽  
Vulvar Squamous Cell Carcinoma ◽  
Metastatic Setting ◽  
Progression Of Disease

AbstractVaginal and vulvar squamous cell carcinoma (SCC) are rare tumors that can be challenging to treat in the recurrent or metastatic setting. We present a case series of patients with vaginal or vulvar SCC who were treated with single-agent pembrolizumab as part of a phase II basket clinical trial to evaluate efficacy and safety. Two cases of recurrent and metastatic vaginal SCC, with multiple prior lines of systemic chemotherapy and radiation, received pembrolizumab. One patient had significant reduction (81%) in target tumor lesions prior to treatment discontinuation at cycle 10 following confirmed progression of disease with new metastatic lesions (stable disease by irRECIST criteria). In contrast, the other patient with vaginal SCC discontinued treatment after cycle 3 due to disease progression. Both patients had PD-L1 positive vaginal tumors and tolerated treatment well. One case of recurrent vulvar SCC with multiple surgical resections and prior progression on systemic carboplatin had a 30% reduction in her target tumor lesions following pembrolizumab treatment with a PD-L1 positive tumor. Treatment was discontinued for grade 3 mucositis after cycle 5. Pembrolizumab may provide some clinical benefit to some patients with vaginal or vulvar SCC and is overall safe to utilize in this population. Future studies are needed to evaluate the efficacy of pembrolizumab in these rare tumor types and to identify predictive biomarkers of response.

Phase II Study: Adjuvant Single-Agent Carboplatin Therapy for Clinical Stage I Seminoma

1997 ◽  
Vol 31 (4) ◽  
pp. 405-407 ◽  
Author(s):  
S. Krege ◽  
G. Kalund ◽  
T. Otto ◽  
M. Goepel ◽  
H. Rübben
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Clinical Stage ◽  
Single Agent ◽  
Stage I ◽  
Stage I Seminoma

scholarly journals CTIM-15. PRELIMINARY RESULTS OF A PHASE II STUDY OF NIVOLUMAB WITH HYPOFRACTIONATED RE-RADIATION AND BEVACIZUMAB FOR RECURRENT MGMT METHYLATED GLIOBLASTOMA

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii36-ii36
Author(s):  
Christian Grommes ◽  
Minesh Mehta ◽  
Alexandra Miller ◽  
Mariza Daras ◽  
Anna Piotrowski ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Disease Recurrence ◽  
Primary Objective ◽  
Significant Finding ◽  
Trial Treatment

Abstract Standard of standard of care for glioblastoma (GBM) remains unsatisfactory with universal disease recurrence and a median survival of < 2 years. Immune checkpoint inhibitors (ICI) have shown limited single-agent activity in GBM thus far. GBMs with methylated MGMT promoter and no baseline corticosteroid dependence may be most likely to derive benefit from ICI. The combination of ICIs with radiation has shown promising activity in other human cancers. Combining nivolumab and re-RT/bevacizumab in GBM may augment ICI activity through immunogenic effects of radiation, may reduce the risk of radiation necrosis by addition of bevacizumab at the time of radiation, and may reduce the need for corticosteroids. In this multicenter phase II study, nivolumab is combined with re-irradiation and optional concurrent bevacizumab followed by nivolumab in patients with first recurrence of IDH-wildtype and MGMT methylated glioblastoma. Primary objective is to improve 1-year overall survival (OS) from 33 (based on EORTC 26101) to 50%. Nine-three patients are required to show a significant finding with an α of 0.05 and 81% power. Thirteen of 93 patient (14%) have been enrolled with a median age of 59 (range 42–71) with a median KPS of 90 (range 70–90). Treatment has been tolerated well without any grade ≥ 4 toxicities and only one grade 3 (amylase elevation). The most common adverse events were pruritus and hypothyroidism in 3/13 (23%). The median progression-free survival (PFS) is 7 months with a 6months PFS of 55.6%. The 12months OS is 66.7%. Patients with recurrent MGMT methylated, IDH-wildtype glioblastoma tolerate trial treatment with acceptable toxicities. Clinical efficacy in the first patients enrolled shows a promising effect. Enrollment is ongoing.

Denosumab and pembrolizumab in clear cell renal carcinoma (KEYPAD): A phase II trial (ANZUP1601).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS367-TPS367
Author(s):  
Craig Gedye ◽  
Abhishek Jagdish Joshi ◽  
Alison Yan Zhang ◽  
Andrew James Martin ◽  
Anthony M. Joshua ◽  
...  
Keyword(s):  
Disease Progression ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Clear Cell ◽  
Phase Ii Trial ◽  
Case Reports ◽  
Cell Cancer ◽  
Tumour Response ◽  
Predictive Biomarkers ◽  
Progression Free Survival

TPS367 Background: Inhibitors of the programmed death-1 pathway (PD-1) are effective in clear cell renal cell cancer (ccRCC). Preclinical data and case reports suggest that denosumab, an inhibitor of Receptor Activator of Nuclear Factor κ-B Ligand (RANKL) signaling, could potentiate the anti-tumour effects of anti-PD1 inhibitors without overlapping toxicities. We aim to determine the activity and safety of combining denosumab and pembrolizumab in advanced ccRCC. Methods: This single arm, multi-center, phase II trial will recruit 70 participants with metastatic or unresectable ccRCC, progressing during or after treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors, and with no prior treatment with immunotherapy or denosumab. Participants will receive pembrolizumab 200mg IV every 3 weeks plus denosumab 120mg SC on days 1, 8 and 22 and then every 3 weeks until disease progression, prohibitive toxicity or maximum treatment of 24 months. Response will be assessed at weeks 12, 18, 24, then every 12 weeks until disease progression. Bloods for translational studies are collected at baseline, week 6 and on disease progression. The primary endpoint is objective tumour response rate (OTRR) per RECIST 1.1. Secondary endpoints include OTRR per iRECIST, progression free survival (PFS), time to OTRR, time to first skeletal related event, adverse events, and frequency of treatment delays/discontinuations. Correlative studies will include identification of prognostic and/or predictive biomarkers relating to immune and RANKL signaling. A sample size of 70 provides 90% power with a 1-sided type 1 error rate of 10% to distinguish the observed OTRR (and PFS at 6 months) from an OTRR of 40% (worthy of pursuit) versus 25% (not worthy of pursuit). 15 sites are open across Australia. As of September 23, 2020, 40 patients have been recruited. Clinical trial information: NCT03280667 .

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