scholarly journals RARE-24. OBJECTIVE RESPONSE AND CLINICAL BENEFIT IN RECURRENT EPENDYMOMA IN ADULTS: FINAL REPORT OF CERN 08-02: A PHASE II STUDY OF DOSE-DENSE TEMOZOLOMIDE AND LAPATINIB

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi241-vi241 ◽  
Author(s):  
Terri Armstrong ◽  
Ying Yuan ◽  
Jimin Wu ◽  
Tito Mendoza ◽  
Elizabeth Vera ◽  
...  
Keyword(s):  
Phase Ii ◽  
Clinical Benefit ◽  
Phase Ii Study ◽  
Objective Response ◽  
Final Report ◽  
Recurrent Ependymoma ◽  
Dose Dense

scholarly journals A Phase II Study of Dose-Dense Temozolomide and Lapatinib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma

2020 ◽  
Author(s):  
Mark R Gilbert ◽  
Ying Yuan ◽  
Jimin Wu ◽  
Tito Mendoza ◽  
Elizabeth Vera ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Phase Ii ◽  
Objective Response ◽  
Symptom Burden ◽  
Adult Patients ◽  
Research Network ◽  
Clinical Activity ◽  
Low Grade ◽  
Recurrent Ependymoma ◽  
Dose Dense

Abstract Background No standard medical treatment exists for adult patients with recurrent ependymoma and prospective clinical trials in this population have not succeeded because of its rarity and challenges in accruing patients. The Collaborative Ependymoma Research Network (CERN) conducted a prospective phase II clinical trial of dose-dense temozolomide and lapatinib, targeting the unmethylated MGMT promoter status and increased expression of ErbB2 (HER2) and ErbB1 (EGFR) in ependymomas. Methods Patients age 18 or older with histologically proven and progressive ependymoma or anaplastic ependymoma were eligible and received dose-dense temozolomide and daily lapatinib. The primary outcome measure was median progression-free survival (PFS). Landmark 6- and 12-month PFS and objective response were measured. Serial assessments of symptom burden using the MDASI-BT/MDASI-SP were collected. Results The 50 patients enrolled had a median age of 43.5 years, median Karnofsky Performance Status of 90, and a median of 2 prior relapses. Twenty patients had grade III, 16 grade II, and 8 grade I ependymoma. Half had spinal cord tumors; 15 had a supratentorial tumor, 8 infratentorial, and 2 had disseminated disease. Treatment was well tolerated. The median PFS was 7.8 months (95% CI 5.5,12.2); the 6-and 12-month PFS rates were 55% and 38%; with 2 complete and 6 partial responses. Measures of symptom burden showed reduction in moderate-severe pain and other disease-related symptoms in most patients. Conclusions This treatment, with demonstrated clinical activity with objective responses and prolonged disease control associated with disease-related symptom improvements is an option as a salvage regimen for adult patients with recurrent ependymoma.

scholarly journals AT-23 * A PHASE II STUDY OF LAPATINIB AND DOSE-DENSE TEMOZOLOMIDE (TMZ) FOR ADULTS WITH RECURRENT EPENDYMOMA: A CERN CLINICAL TRIAL

2014 ◽  
Vol 16 (suppl 5) ◽  
pp. v13-v13 ◽  
Author(s):  
M. Gilbert ◽  
Y. Yuan ◽  
K. Wani ◽  
J. Wu ◽  
A. Omuro ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Recurrent Ependymoma ◽  
Dose Dense

Analysis of serum biomarkers and tumor genetic alterations from a phase II study of lenvatinib in patients with advanced BRAF wild-type melanoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 9058-9058 ◽  
Author(s):  
Pallavi Sachdev ◽  
Omid Hamid ◽  
Kevin Kim ◽  
Axel Hauschild ◽  
Steven O'Day ◽  
...  
Keyword(s):  
Clinical Outcome ◽  
Phase I ◽  
Phase Ii ◽  
Clinical Benefit ◽  
Phase Ii Study ◽  
Objective Response ◽  
Genetic Alterations ◽  
Advanced Melanoma ◽  
Wild Type ◽  
Biomarker Analysis

9058 Background: Lenvatinib is an oral receptor tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. Phase I and II studies of lenvatinib demonstrate that a subset of advanced melanoma patients (pts) appears to derive benefit from lenvatinib treatment (tx), prompting a need to identify predictive biomarkers for response to lenvatinib. Methods: Serum and archival tumor samples were collected from 93 enrolled pts in the BRAF wild-type (wt) cohort of the lenvatinib phase II study of advanced melanoma. Concentrations of 50 factors were measured in pre- and post-tx serum samples; 58 archival tumor tissues were obtained and gene mutation (mut) (n=53) and gene expression profiling (GEP) (n=39) analyses were performed. For mut analysis, targeted resequencing was performed on a select panel of genes using the Ion PGM Sequencer and mut validation studies were performed. For GEP analysis, the nCounterAnalysis System was used to measure the expression level of 330 genes. Results: Clinical benefit rate (32%) and objective response rate (9%) by independent radiologic review were observed in the BRAF wt cohort. In serum biomarker analysis, lenvatinib tx resulted in a decrease in soluble VEGFR2 and increase in VEGF and PlGF levels consistent with target engagement. Correlation with clinical outcome demonstrated that baseline (BL) levels of Ang-2, IL8, PlGF, and PDGFBB associated with OS, but only pts with low BL Ang-2 levels also demonstrated improved response. High BL levels of FLT3LG and eotaxin associated with longer OS and improved response. In GEP analysis, expression levels of a set of genes including TARBP2, ZNF544, and NF1 (targets identified in phase I and preclinical studies) associated with OS. In gene mut analysis, NRAS mut showed a trend towards longer OS. Pts with NRAS mut along with wt PIK3CA status demonstrated longer OS. Conclusions: Lenvatinib demonstrated limited response in BRAF wt advanced melanoma pts. A subset of pts may derive extended clinical benefit. NRAS mut/PIK3CA wt status and low BL Ang-2 levels appear to associate with improved clinical outcome in this pt population and require further study to assess their predictive value. Clinical trial information: NCT01136967.

Phase II study of docetaxel and cisplatin in advanced non-small-cell lung cancer.

1998 ◽  
Vol 16 (5) ◽  
pp. 1948-1953 ◽  
Author(s):  
J Zalcberg ◽  
M Millward ◽  
J Bishop ◽  
M McKeage ◽  
A Zimet ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase Ii ◽  
Advanced Nsclc ◽  
Response Rate ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE Docetaxel (Taxotere, Rhone-Poulenc Rorer, Antony, France) and cisplatin are two of the most active single agents used in the treatment of non-small-cell lung cancer (NSCLC). A recently reported phase I study of the combination of docetaxel and cisplatin recommended a dose of 75 mg/m2 of both drugs every 3 weeks for subsequent phase II study. PATIENTS AND METHODS Eligible patients were aged 18 to 75 years with a World Health Organization (WHO) performance status < or = 2 and life expectancy > or = 12 weeks, with metastatic and/or locally advanced NSCLC proven histologically or cytologically. Patients were not permitted to have received prior chemotherapy, extensive radiotherapy, or any radiotherapy to the target lesion and must have had measurable disease. Concurrent treatment with colony-stimulating factors (CSFs) or prophylactic antibiotics was not permitted. Docetaxel (75 mg/m2) in 250 mL 5% dextrose was given intravenously (i.v.) over 1 hour immediately before cisplatin (75 mg/m2) in 500 mL normal saline given i.v. over 1 hour in 3-week cycles. Premedication included ondansetron, dexamethasone, promethazine, and standard hyperhydration with magnesium supplementation. RESULTS A total of 47 patients, two thirds of whom had metastatic disease, were entered onto this phase II study. The majority of patients were male (72%) and of good (WHO 0 to 1) performance status (85%). All 47 patients were assessable for toxicity and 36 were for response. Three patients were ineligible and eight (17%) discontinued treatment because of significant toxicity. In assessable patients, the overall objective response rate was 38.9% (95% confidence limits [CL], 23.1% to 56.5%), 36.1% had stable disease, and 25% progressive disease. On an intention-to-treat analysis, the objective response rate was 29.8%. Median survival was 9.6 months and estimated 1-year survival was 33%. Significant (grade 3/4) toxicities included nausea (26%), hypotension (15%), diarrhea (13%), and dyspnea mainly related to chest infection (13%). One patient experienced National Cancer Institute (NCI) grade 3 neurosensory toxicity after eight cycles. Grade 3/4 neutropenia was common and occurred in 87% of patients, but thrombocytopenia > or = grade 3 was rare (one patient). Significant (grade 3/4) abnormalities of magnesium levels were common (24%). Febrile neutropenia occurred in 13% of patients and neutropenic infection in 11%, contributing to two treatment-related deaths. No neutropenic enterocolitis or severe fluid retention was reported. CONCLUSION Compared with other active regimens used in this setting, the combination of docetaxel and cisplatin in advanced NSCLC is an active regimen with a similar toxicity profile to other combination regimens.

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.

NCT04552223: A phase II study of nivolumab plus BMS-986016 (relatlimab) in patients with metastatic uveal melanoma (UM) (CA224-094).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9590-TPS9590
Author(s):  
Jose Lutzky ◽  
Lynn G. Feun ◽  
Norma Magallanes ◽  
Deukwoo Kwon ◽  
J. William Harbour
Keyword(s):  
T Cells ◽  
Mhc Class Ii ◽  
Uveal Melanoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Type I ◽  
Tumor Escape ◽  
Potential Candidate

TPS9590 Background: Uveal melanoma (UM) is a rare disease but 50% of patients will eventually develop metastatic disease, for which not effective therapy is available. Liver-directed therapies, immunotherapy, targeted therapy and chemotherapy have limited activity [1]. Lymphocyte activation gene 3(LAG-3) is an immune checkpoint receptor associated with decreased T-cell effector function and tumor escape. Preclinical models have shown that dual inhibition of LAG-3 and PD-1 blockade generates synergistic anti-tumor activity [2]. Recent preclinical data indicates that uveal melanoma CD8+ T cells express the checkpoint receptor LAG3 to a greater extent than PD1 or CTLA4 [3,4]. Therefore, LAG3 is a potential candidate for checkpoint inhibitor immunotherapy in UM. Relatlimab is a human LAG-3-specific antibody isolated from immunized transgenic mice which binds to a defined epitope on LAG-3 with high affinity and specificity and potently blocks the interaction of LAG-3 with its ligand, MHC Class II. Methods: This is an open-label, single arm, single site investigator-initiated phase II study, NCT04552223. Based on Simon two-stage minimax design, 13 patients will be enrolled in Stage 1. If at least one response is noted, the study will proceed to Stage 2 and enroll an additional 14 patients. The null hypothesis will be rejected if 4 or more responses are observed among 27 patients. This design achieves 5% type I error and 80% power when the true ORR is 20%. The trial opened to accrual in December 2020. As of February 15, 2021 four patients had been enrolled the first stage of accrual. Main eligibility criteria include patients with biopsy proven metastatic uveal melanoma, previously untreated with PD-1, CTLA-4 and/or LAG-3 blocking antibodies and in good performance status. Enrolled patients are treated in the outpatient setting. Nivolumab 480 mg is mixed in the same bag with relatlimab 160 mg and administered intravenously over 60 minutes every 4 weeks until disease progression or intolerable toxicity for up to 24 months. The primary endpoint is best objective response rate (ORR). Secondary endpoints include disease control rate (DCR), progression-free survival (PFS), overall survival (OS), median duration of response (mDOR), and adverse events (AEs). Correlative studies will evaluate pre- and post-treatment characteristics of T cells in the tumor microenvironment and blood. Clinical trial information: NCT04552223.

Phase II study of binimetinib with imatinib in patients with unresectable KIT-mutant melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9594-TPS9594
Author(s):  
Katy K. Tsai ◽  
Iwei Yeh ◽  
Adil Daud ◽  
Ari Oglesby
Keyword(s):  
Phase Ii ◽  
Null Hypothesis ◽  
Response Rate ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Specific Treatment ◽  
Type I ◽  
True Response ◽  
Phase Ii Studies

TPS9594 Background: Immune checkpoint inhibitors (ICI) have transformed treatment for patients (pts) with advanced melanoma, as have BRAF/MEK inhibitors for pts with BRAF V600-mutant melanoma. However, pts with acral or mucosal melanomas are in particular need of more options given a lower objective response rate (ORR) to ICI, and lower incidence of BRAF V600 driver mutation. Such BRAF mutations are found in only 5-10% of acral/mucosal melanomas, while KIT mutations/amplifications are found in 10-20%. Even when present, a KIT alteration does not guarantee response to KIT inhibition, with only about one-third responding as previously shown in 3 phase II studies. A significant number of KIT-mutant melanomas have been shown to demonstrate NF1 or SPRED1 loss, with recent preclinical work showing that such alterations are associated with the loss of negative suppression of RAS, resulting in RAS activation and MEK dependence. We hypothesize that NF1 or SPRED1 loss cooperates with KIT mutations to drive melanomagenesis and resistance to KIT inhibition, and propose to target this vulnerability with a combination approach to targeted therapy. This phase II study will be the first to evaluate the efficacy and safety of binimetinib plus imatinib in pts with KIT-mutant melanoma. Methods: This is an investigator-initiated phase II study of binimetinib in combination with imatinib in pts with BRAF V600 WT, KIT-mutant unresectable melanoma who have progressed on or who are ineligible for ICI (NCT04598009). Pts will be ≥18 yo with performance status ECOG 0-2, and have unresectable Stage IIIB/C/D or Stage IV melanoma that is BRAF V600 WT and KIT-mutant by CLIA-certified testing platform. Pts will have progressed on prior ICI or other standard-of-care (SOC) therapies, or be ineligible for or unable to tolerate SOC therapies. Pts with brain metastasis will be eligible if clinically stable and determination made that no CNS-specific treatment is required prior to study start. Pts previously treated with a MEK inhibitor will be excluded. A Simon 2-stage Minimax design will be used; the null hypothesis that the true response rate is 0.1 will be tested against a one-sided alternative. 15 pts will be accrued in the first stage. If there are £1 responses, the study will be stopped. Otherwise, 10 additional pts will be accrued for a total of 25. The null hypothesis that the true response rate is 0.1 will be rejected if ≥6 responses are observed. This yields a type I error rate of 0.05 and power of 0.8017 when the true response rate is 0.3.Primary endpoint: ORR (RECIST). Secondary endpoints: duration of response, progression-free survival, overall survival, clinical benefit rate (CR, PR, or SD ≥16 weeks), safety profile (CTCAE). Exploratory objectives to include investigations of association between clinical response and baseline NF1 and SPRED1 status, and of pathologic correlates of acquired resistance. Study began enrolling pts in December 2020 and is ongoing. Clinical trial information: NCT04598009.

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