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A clinical trial to study the effects of Bevacizumab injection (Hetero) against Reference Medicinal Product (Reference product, Roche) in patients suffering from metastatic colorectal cancer

ABSTRACT: Intervention1: Bevacizumab (Hetero): Bevacizumab is given at the dose of 7.5mg/kg, every 3 weeks for up to 08 cycles along with standard chemotherapy. Bevacizumab is given at the dose of 5mg/kg, every 2 weeks for up to 12 cycles along with standard chemotherapy. Control Intervention1: Bevacizumab (Roche): Bevacizumab is given at the dose of 7.5mg/kg, every 3 weeks for up to 08 cycles along with standard chemotherapy. Bevacizumab is given at the dose of 5mg/kg, every 2 weeks for up to 12 cycles along with standard chemotherapy. Primary outcome(s): Disease control rate as per RECIST 1.1 criteriaTimepoint: At baseline and end of treatment cycles Study Design: Randomized, Parallel Group, Active Controlled Trial Method of generating randomization sequence:Permuted block randomization, fixed Method of allocation concealment:Centralized Blinding and masking:Open Label

DISEASE(S): Malignant Neoplasm Of Colon, Unspecified

PROVIDER: 2576589 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Intervention1: DRL_BZ (Bevacizumab): Part A: DRL_BZ, 5 mg/kg administered intravenously (i.v.) on day 1 as a 90 min infusion with the needed adjustments every two weeks in conjunction with mFOLFOX6. Patients will continue to be treated with their assigned treatment until documented progressive disease, death, unacceptable toxicity, withdrawal of consent or Investigator decision to discontinue in the best interest of patient or for 9 months, whichever occurs earlier. Part B: DRL_BZ; 15 mg/kg administered intravenously (i.v.) on day 1 every three weeks plus pemetrexed+carboplatin chemotherapy for 4 cycles. After 4 cycles, treatment will be continued with bevacizumab and pemetrexed only. Patients need to be premedicated with folic acid, vitamin B12 and dexamethasone as per institutional practice. Patients will be treated until documented progressive disease, death, unacceptable toxicity, patient withdrawal or Investigator decision to discontinue in the best interest of patient or up to 6 months Control Intervention1: AvastinÂ (Bevacizumab): AvastinÂ, 5 mg/kg administered intravenously (i.v.) on day 1 as a 90 min infusion with the needed adjustments every two weeks in conjunction with mFOLFOX6. Patients will continue to be treated with their assigned treatment until documented progressive disease, death, unacceptable toxicity, withdrawal of consent or Investigator decision to discontinue in the best interest of patient or for 9 months, whichever occurs earlier. Part B: AvastinÂ; 15 mg/kg administered intravenously (i.v.) on day 1 every three weeks plus pemetrexed+carboplatin chemotherapy for 4 cycles. After 4 cycles, treatment will be continued with bevacizumab and pemetrexed only. Patients need to be premedicated with folic acid, vitamin B12 and dexamethasone as per in Primary outcome(s): PART A: To compare the efficacy measured in terms of progression free survival at 9 months (PFS9) of two anti-VEGF antibodies administered in combination with chemotherapy for mCRC (stage IV) as first-line treatment for metastatic disease. PART B: To compare the efficacy measured in terms of progression free survival at 6 months (PFS6) of two anti-VEGF antibodies administered in combination with chemotherapy for recurrent or advanced non-squamous NSCLC not previously treated with chemotherapy.Timepoint: 9 months Study Design: Randomized, Parallel Group, Multiple Arm Trial Method of generating randomization sequence:Stratified block randomization Method of allocation concealment:Centralized Blinding and masking:Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded

Project description:The VEGF targeted antiangiogenic drug bevacizumab has shown varying results in clinical trials of breast cancer. Identifying robust biomarkers for selecting patients that may benefit from bevacizumab treatment and for monitoring of response is important for the future use of this drug. Two established xenograft models representing basal-like and luminal-like breast cancer were used to study bevacizumab treatment response on the metabolic and gene expression levels. Mice given no treatment or treated with bevacizumab, doxorubicin or the combination of these two drugs were sacrificed at day 3 or 10. High resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS) and gene expression microarray analysis was performed on all tumor samples. Combination treatment with bevacizumab had the strongest growth inhibiting effect in the basal-like tumors, and this was reflected in a significant response in the metabolomic and transcriptomic profiles. In the luminal-like xenografts, addition of bevacizumab did not improve the effect of doxorubicin. On the global transcriptomic level, the largest changes in gene expression were observed for the most efficient treatment in each of the two xenograft models. The metabolite glycerophosphocholine (GPC) showed opposite response in the treated xenografts compared with untreated controls: lower in basal-like tumors and higher in luminal-like tumors. Lower levels of creatine, taurine and glycine were observed in the basal-like xenografts given bevacizumab as monotherapy compared with untreated xenografts. Comparing combination therapy with doxorubicin monotherapy in basal-like xenografts, 14 genes showed significant differential expression, including higher expression of very low density lipoprotein receptor (VLDLR), and lower expression of hemoglobin, theta 1 (HBQ1). Using published gene expression signatures, bevacizumab treated tumors were associated with a more hypoxic phenotype, while no evidence was found for associations between bevacizumab treatment and vascular invasion or increasing tumor grade. This study underlines the importance of characterizing biological differences between subtypes of breast cancer to identify personalized biomarkers for selecting patients for bevacizumab treatment and evaluating response to therapy. 60 samples are analyzed. For each of the two xenograft models, tumors were collected from animals that were untreated or treated with bevacizumab (5 mg/kg), doxorubicin (8 mg/kg) or a combination of the two therapies (n = 6 tumors for each group). Bevacizumab treatment was repeated at day 4 and day 7. Animals were sacrificed and tissue harvested at either day 3 or 10 after treatment, in triplicates within each treatment group. This resulted in 24 tumor samples from each of the models. In addition, untreated and bevacizumab treated luminal-like xenografts not fed with estradiol were included for comparison (n = 12). Note that the untreated controls are overlapping with the samples in the GEO series with accession number: GSE25915.

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A clinical trial to study the effects of Bevacizumab injection (Hetero) against Reference Medicinal Product (Reference product, Roche) in patients suffering from metastatic colorectal cancer

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