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Tocotrienol and Bevacizumab in Metastatic Colorectal Cancer

ABSTRACT: This double blind, randomized phase II trial will investigate whether the addition of tocotrienol will improve the effect and lower the toxicity of standard chemotherapy and bevacizumab. Half of the patients will receive tocotrienol and the other half placebo. Treatment is planned for a period of maximum six months and will be discontinued earlier in case of progression or unacceptable toxicity.

DISEASE(S): Metastatic Colorectal Cancer,Colorectal Cancer,Colorectal Neoplasms,Colorectal Cancer Metastatic

PROVIDER: 2328288 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Growth factor signaling and angiogenesis may promote endocrine-resistance in breast cancer and blocking these pathways can overcome resistance in preclinical models. We conducted a phase-II study of adding the VEGFR/Ras/Raf/MAPK inhibitor sorafenib to endocrine therapy in metastatic ER-positive breast cancer, either upon progression or after maximal response with measurable residual disease. Tumor biopsies and serum were collected on days 1 and 28. Primary endpoint was response by RECIST after 3 months and secondary endpoints included safety, time to progression (TTP), and biomarker assessment. Planned sample size was 43 patients but the study closed after 11 patients because of slow accrual. 8 patients had progressive disease (PD) on entry and 3 had stable disease (SD). One patient with SD discontinued sorafenib after 2-weeks because of grade 3 rash. Of the 10 remaining patients after adding sorafenib, 7 had SD (70%), 3 had PD (30%) and median TTP was 6.1-months. Of the 8 patients who entered the study with PD on endocrine therapy, 5 converted to SD (62%) with a median TTP of 6.4-months. Notably, patients on tamoxifen had a median TTP of 8.4-months. The most common adverse events were hypophosphatemia, hypokalemia, and rash, and the majority were grade 1&2 with no grade 4 toxicities. There was a significant reduction in serum VEGFR2 and PDGFR-α on day-28 (p-values 0.0035 and 0.017, respectively). Both serum VEGF and sVEGFR-1 were increased on day-28, but the differences were not statistically significant (p-values 0.3223 and 0.084, respectively). Microarray analysis identified 32 suppressed genes with an FDR of <0.20 and at least a 2-fold change with no induced genes and 29 KEGG pathways were enriched on day-28. Our study suggests that sorafenib can restore endocrine sensitivity, particularly tamoxifen, and this strategy of adding novel agents in patients progressing on endocrine therapy should be examined in future trials. This was a single-institution, phase II study of adding sorafenib to existing endocrine therapy. On study entry, eligible patients underwent serum sample collection and core biopsy of accessible disease (if applicable) on endocrine therapy and prior to starting sorafenib. Serum and a second biopsy were then collected on day 28. Sorafenib dose was 400mg orally twice daily along with continuing the same endocrine agent. Patients were followed monthly for clinical and toxicity evaluation. Disease response by RECIST criteria was assessed after 3 months by appropriate scans and these were obtained every 2 months thereafter until progression. Sorafenib and the endocrine agent were continued until disease progression or unacceptable toxicity

Project description:<p>LGL leukemia can be divided into three subsets including the following: αβ or γδT-LGL and NK-LGL leukemia. All three subtypes will be enrolled using a two-stage design. The primary endpoint of the study is assessment of overall clinical response. Correlative laboratory studies will be performed aimed at determining the mechanism of response to treatment. Thirteen participants will be accrued in the first stage at a dose of 300 mg BID administered intermittently every other week (i.e., 7 days on and 7 days off). If there are two or more responders, the protocol will be extended to a second stage of the study and accrual will be extended to 25 evaluable participants. Allowing for 10% rate of ineligibility due to unexpected events and dropout, we will accrue 14 patients in the first stage and 27 patients in total. Participants that withdraw from the study for reason unrelated to toxicity, will be replaced. There are two potential stopping rules for toxicity.</p> <p>If 3 or more participants out of the 13 enrolled in the first stage experiences grade IV neurotoxicity, the study will be stopped due to excessive toxicity. Dose reductions have been incorporated for hematologic toxicity. Treatment of T and NK LGL leukemia with immunosuppressive agents such as low-dose methotrexate generally require from four to six months for a clinical response and sometimes much longer. Therefore, in participants who show clinical improvement with less than grade three toxicity, tipifarnib treatment will be continued for as many as four additional months (12 months total). After the first 8 months, response will be assessed. The protocol treatment will be discontinued in participants with progression of disease. A long-term follow up will be performed for five years in patients that receive a complete clinical response. The long-term follow up will consist of vital signs, weight, CBCs, serum chemistries, and physical examination at six month intervals.</p>

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Tocotrienol and Bevacizumab in Metastatic Colorectal Cancer

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