Phase I / II Study of Enadenotucirev by Sub-acute Fractionated IV Dosing in Cancer Patients
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ABSTRACT: This is a multicentre, open-label, Phase I/II study of enadenotucirev in patients with either solid tumour of epithelial origin not responding to standard therapy or for whom no standard treatment exists (Phase I dose escalation stage Single cycle), mCRC not responding to standard therapy (Phase I dose escalation Repeat cycle cohort expansion stage ), mCRC not responding to standard therapy or advanced or metastatic bladder cancer not candidate for chemotherapy (Phase Ib) or mCRC in stable disease or partial response after 3-4 months of first line standard of care chemotherapy (Phase II).
DISEASE(S): Metastatic Colorectal Cancer,Solid Tumours Of Epithelial Origin,Colorectal Neoplasms,Metastatic Bladder Cancer
Project description:Primary objectives: Phase I: - To evaluate the safety and tolerability of ColoAd1, when administered by sub-acute fractionated IV injection to patients with advanced or metastatic epithelial solid tumours not responding to standard therapy or for whom no standard treatment exists- To determine the maximally-tolerated dose (MTD) and/or maximum-feasible dose (MFD) of ColoAd1 when administered by sub-acute fractionated intravenous (IV) injection to patients with advanced or metastatic epithelial solid tumours not responding to standard therapy or for whom no standard treatment exists, and to recommend a dose for phase II studies.
Phase II:- To evaluate the progression free survival (PFS) in patients with metastatic colorectal cancer, who receive ColoAd1 administered by sub-acute fractionated IV injection as an intensification of first line chemotherapy compared with first line chemotherapy alone.
Primary endpoints: Phase 1: Safety and tolerabilityDetermine a maximum tolerated dose (MTD) / maximum feasible dose (MFD) of ColoAd1 when administered by sub-acute fractionated IV injection (phase I Dose Escalation) and a recommended dose for phase II studies
Phase 2: Rate of Progression-Free Survival (PFS) at 24 weeks, defined as the rate of patients being free from clinical/radiological progression and alive within the week 24 time window from randomisation as determined by an independent review committee.
Project description:This is a Phase I multicenter, open label, nonrandomized study of enadenotucirev administered in combination with nivolumab in subjects with metastatic or advanced epithelial tumors (with focus on CRC, SCCHN, escalation phase), not responding to standard therapy.
Project description:Stable cisplatin- and vincristine-tolerant Group 3 and SHH cell lines were generated by continuous drug exposure with dose escalation to identify mechanisms driving resistance to standard-of-care medulloblastoma therapy. Next-generation sequencing revealed a vastly different transcriptomic landscape following chronic drug exposure, including a drug-tolerant gene expression signature, common to all sequenced drug-tolerant cell lines.
Project description:The aim of our study was to investigate whether miRNAs could serve as predictive biomarkers to anti-EGFR therapy (cetuximab, panitumumab) in patients with KRAS wild-type (wt-KRAS) metastatic colorectal cancer (mCRC). In our study, historical cohort of 96 patiens with wt-KRAS mCRC (2006-2009) was included and further divided into exploratory and validation cohorts. Large-scale miRNAs expression profiling was performed on the exploratory cohort of 41 wt-KRAS mCRC patients treated with cetuximab to identify miRNAs associated with time to progression (TTP). The validation was performed on two independent cohorts: 30 patients of wt-KRAS mCRC treated with cetuximab and 25 patients of wt-KRAS mCRC treated with panitumumab.
Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 metastisized colorectal cancer patients in a phase III trial (CKTO 2005-02; ClinTrials.gov NCT00208546) of the Dutch Colorectal Cancer Group (DCCG), who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab.
Project description:Peripheral blood was collected into PAXgene tubes from 7 patients with follicular lymphoma, in a phase 2 clinical trial of lenalidomide plus rituximab as initial therapy for advanced-stage indolent non-Hodgkin's lymphoma. Blood was collected at baseline and on Day 15 of the second 28-day cycle, for determination of the gene expression profile after globin mRNA reduction.
Project description:MicroRNA profiling was performed on baseline bloods using the NanoString nCounter platform in a serial liquid biopsies obtained at baseline in chemo-refractory mCRC patients treated with regorafenib in a phase II clinical trial (PROSPECT-R n=40; NCT03010722).
Project description:A Phase I study was conducted to determine the tolerability, activity, and immune responses of JEN-101 in dogs with advanced melanoma. A 3+3 dose escalation design was used to evaluate intratumoral injection of JEN-101 at 1, 3, 10, or 20 μg/kg every three weeks for four cycles. A second course was allowable in the absence of disease progression or toxicity. Peripheral blood, serum, and tumor biopsies were collected at baseline and at pre-specified timepoints for pharmacokinetic and immune analyses, which included serum cytokines, immunohistochemistry, and gene expression assessment. JEN-101 was well tolerated with adverse events being fever, lethargy, and isolated elevated liver enzymes. Five dogs experienced grade 3 events and no grade 4 events were observed. Pharmacokinetic analysis showed a trend towards dose-related Cmax within 8 hours of injection. Responding dogs demonstrated increased systemic interferon-γ and IL-10 AUC levels and local recruitment of CD3+ T cells. Increased pro-inflammatory and antigen processing gene expressions were identified in responding lesions.
Project description:KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. Here, we assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Good response was associated with 12p12.1 copy number loss, even in patients with a KRAS mutation, while copy number gain in wild-type KRAS patients was correlated with a poor response. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good response. In wild-type KRAS patients, miRNA expression did not predict response in a multivariate model. Thus, assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of patients eligible for anti-EGFR therapy. Copy number detection was performed using NimbleScan and Nexus software