Dataset Information

EVICT: The erlotinib and vemurafenib in combination trial.A Phase I/II Trial of the combination of BRAF and EGFR inhibition in BRAF V600E mutant colorectal, advanced or metastatic lung adenocarcinoma and other cancers.

ABSTRACT: Interventions: Tarceva (erlotinib) and Zelboraf (vemurafenib) are the intervention being studied. Both are provided in tablet form and are taken orally everyday until disease progression or unacceptable toxicity (anticipated this will be for approximately 6 months). There will be 3 dose levels: a) Dose level D-1 = erlotinib (100 mg/day) and vemurafenib (720 mg twice a day) b) Dose level D1 = erlotinib (100 mg/day) and vemurafenib (960 mg twice a day) c) Dose level D2 = erlotinib (150 mg/day) and vemurafenib (960 mg twice a day). Please note; this is a dose escalation study in the first phase, proceeding to dose expansion in the second phase. Strategies used to monitor adherence will be via a patient diary, where patients are asked to complete a daily diary entry recording drug use, as well as, standard drug tablet return and accountability logs. Primary outcome is to determine the safety of the combination of vemurafenib and erlotinib in the first 4 weeks of treatment in BRAF V600E mutant metastatic CRC and identify the dosing regimen to be evaluated in Phase II. This outcome will be assessed via the incidence of dose-limiting toxicities (DLTs) reported within the first 4 weeks of treatment with the combination of erlotinib and vemurafenib in a cohort of 3 patients. After each cohort of 3 patients completes the DLT observation period, a clinical synthesis of the available toxicity information will be reviewed by the trials safety monitoring committee.[Post first 4 weeks of treatment.];Secondary primary outcome is to evaluate the clinical efficacy of the combination of vemurafenib and erlotinib in BRAF V600E mutant metastatic CRC as measured by the proportion of patients achieving a complete or partial response (CR or PR) within the first 24 weeks of treatment. This outcome will be assessed using the Response Evaluation Criteria in Solid Tumours (RECIST) v1.1 within the first 24 weeks of treatment with the combination of erlotinib and vemurafenib.[Post the first 24 weeks of treatment.] Study Design: Purpose: Treatment; Allocation: Non-randomised trial; Masking: Open (masking not used);Assignment: Single group;Type of endpoint: Safety/efficacy

DISEASE(S): Lung Cancer (metastatic),Cancer-bowel-back Passage (rectum) Or Large Bowel (colon),Colorectal Cancer (metastatic),Cancer-lung-non Small Cell

PROVIDER: 2460852 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Gene-expression profiles of rat liver cirrhosis induced by diethylnitrosamine and the effect of erlotinib on liver fibrogenesis and liver cancer development Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level. Keywords: Cirrhotic liver, Expression array, Illumina, Signatures, Outcome prediction Animals received humane care according to the criteria outlined in the M-bM-^@M-^\Guide for the Care and Use of Laboratory AnimalsM-bM-^@M-^] of the National Academy of Sciences. All animals were maintained in accordance with the institutional guidelines of the Massachusetts General Hospital Subcommittee on Research Animal Care. Male Wistar rats received weekly IP injections of diethylnitrosamine (DEN) at 50 mg/kg, 100mg/kg, or vehicle control (PBS) for 18 weeks. A subset of rats received either daily (5X a week) IP injections of 2 mg/kg erlotinib or vehicle control during weeks 13 - 18. In a separate study, the erlotinib dose was lowered to 0.5 mg/kg. The vehicle groups from the two studies were not significantly different so they were combined together for analysis. Rats were weighed at the end of each week. Animals were sacrificed at 9, 13 and 19 weeks after a one-week washout period to eliminate acute effects of DEN. At the time of sacrifice, the non-tumor liver tissues were collected in RNase-free tubes and snap-frozen in liquid nitrogen. Frozen tissues were stored at -80M-BM-0C until RNA extraction.

Project description:Gene-expression profiles of rat hepatocellular carcinoma induced by diethylnitrosamine (DEN) and the effect of erlotinib Hepatocellular carcinoma (HCC) is the sixth most common solid tumor worldwide and the third leading cause of cancer-related death. Given the lack of successful treatment options, chemoprevention in high-risk patients has been proposed as an alternative strategy. Mounting evidence supports a role for epidermal growth factor (EGF) during chronic liver disease and hepatocellular transformation. We address the hypothesis that blocking the EGF-EGF receptor (EGFR) pathway may be an effective strategy for inhibiting fibrogenesis and hepatocarcinogenesis. A rat model of diethylnitrosamine (DEN)-induced cirrhosis was used to examine the effects of erlotinib on underlying chronic liver disease and HCC formation. The DEN-induced rat model closely resembles disease progression in humans both pathologically and molecularly. Erlotinib significantly prevented the development of HCC tumor nodules in a dose-dependent fashion. Further, erlotinib inhibited the activation of hepatic stellate cells and prevented fibrogenesis. Erlotinib also reduced hepatotoxicity and improved liver function. Finally, a gene expression signature predictive of poor survival in human cirrhosis patients was reversed in response to erlotinib. Our data demonstrate for the first time that EGFR inhibition prevents liver fibrogenesis. Further, our results suggest that erlotinib is a potentially effective HCC chemoprevention strategy through inhibition of cirrhosis progression which can be monitored at the molecular level. Animals received humane care according to the criteria outlined in the M-bM-^@M-^\Guide for the Care and Use of Laboratory AnimalsM-bM-^@M-^] of the National Academy of Sciences. All animals were maintained in accordance with the institutional guidelines of the Massachusetts General Hospital Subcommittee on Research Animal Care. Male Wistar rats received weekly IP injections of diethylnitrosamine (DEN) at 50 mg/kg, 100mg/kg, or vehicle control (PBS) for 18 weeks. A subset of rats received either daily (5X a week) IP injections of 2 mg/kg erlotinib or vehicle control during weeks 13 - 18. In a separate study, the erlotinib dose was lowered to 0.5 mg/kg. The vehicle groups from the two studies were not significantly different so they were combined together for analysis. Rats were weighed at the end of each week. Animals were sacrificed at 9, 13 and 19 weeks after a one-week washout period to eliminate acute effects of DEN. At the time of sacrifice, the non-tumor liver tissues were collected in RNase-free tubes and snap-frozen in liquid nitrogen. Frozen tissues were stored at -80M-BM-0C until RNA extraction.

Dataset Information

EVICT: The erlotinib and vemurafenib in combination trial.A Phase I/II Trial of the combination of BRAF and EGFR inhibition in BRAF V600E mutant colorectal, advanced or metastatic lung adenocarcinoma and other cancers.

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