Randomized phase II study of valproic acid in combination with bevacizumab and oxaliplatin/fluoropyrimidine regimens in patients with RAS-mutated metastatic colorectal cancer: the REVOLUTION study protocol.

BACKGROUND: Despite effective treatments, metastatic colorectal cancer (mCRC) prognosis is still poor, mostly in RAS-mutated tumors, thus suggesting the need for novel combinatorial therapies. Epigenetic alterations play an important role in initiation and progression of cancers, including CRC. Histone-deacetylase inhibitors (HDACi) have shown activity in combination with chemotherapy in the treatment of solid tumors. Owing to its HDACi activity and its safe use for epileptic disorders, valproic acid (VPA) is a good candidate for anticancer therapy that we have largely explored preclinically translating our findings in currently ongoing clinical studies. We have shown in CRC models that HDACi, including VPA, induces synergistic antitumor effects in combination with fluoropyrimidines. Furthermore, unpublished results from our group demonstrated that VPA induces differentiation and sensitization of CRC stem cells to oxaliplatin. Moreover, preclinical and clinical data suggest that HDACi may prevent/reverse anti-angiogenic resistance. METHODS/DESIGN: A randomized, open-label, two-arm, multicenter phase-II study will be performed to explore whether the addition of VPA to first line bevacizumab/oxaliplatin/fluoropyrimidine regimens (mFOLFOX-6/mOXXEL) might improve progression-free survival (PFS) in RAS-mutated mCRC patients. A sample size of 200 patients was calculated under the hypothesis that the addition of VPA to chemotherapy/bevacizumab can improve PFS from 9 to 12 months, with one-sided alpha of 0.20 and a power of 0.80. Secondary endpoints are overall survival, objective response rate, metastases resection rate, toxicity, and quality of life. Moreover, the study will explore several prognostic and predictive biomarkers on blood samples, primary tumors, and on resected metastases. DISCUSSION: The "Revolution" study aims to improve the treatment efficacy of RAS-mutated mCRC through an attractive strategy evaluating the combination of VPA with standard cancer treatment. Correlative studies could identify novel biomarkers and could add new insight in the mechanism of interaction between VPA, fluoropyrimidine, oxaliplatin, and bevacizumab. TRIAL REGISTRATION: EudraCT: 2018-001414-15; ClinicalTrials.gov identifier: NCT04310176.

First line nab-paclitaxel plus gemcitabine in elderly metastatic pancreatic patients: a good choice beyond age.

BACKGROUND: Nab-paclitaxel plus gemcitabine represents one of the standard regimens for first line treatment of metastatic pancreatic cancer (mPC). Few data are available on nab-paclitaxel plus gemcitabine in geriatric population. Our study aims to show whether this schedule can be feasible in the elderly as first-line treatment for mPC. METHODS: We retrospectively analyzed the data of 64 mPC patients (≥65 years old) treated according to the MPACT schedule. RESULTS: Median age was 69.5 years (range, 65-80 years); after a median of 5 cycles administered (range, 1-12), the most common adverse events (AEs) were grade 2 alopecia (46.9%), anemia (17.2%) and hypertransaminasemia (10.9%); all grades neutropenia occurred in 20.3% of pts. Global incidence of grade 3 and 4 toxicities were 26.5% and 0%, respectively, and no patients stopped treatment due to unacceptable toxicity. Stable disease (SD) was observed in 31.2% of patients, with a disease control rate (DCR) and overall response rate of 57.8% and 26.6%, respectively. After a median follow-up of 18 months, median progression free survival (PFS) was 8 months (95% CI: 6.3-9.6) and median OS was 12.0 months (95% CI: 8.4-15.6). The univariate analysis for overall survival (OS) showed that only ECOG performance status was an independent prognostic factor for survival. CONCLUSIONS: Nab-paclitaxel plus gemcitabine schedule is feasible and effective in the "daily clinical practice" geriatric population.

Exploratory findings from a prematurely closed international, multicentre, academic trial: RAVELLO, a phase III study of regorafenib versus placebo as maintenance therapy after first-line treatment in RAS wild-type metastatic colorectal cancer.

BACKGROUND: In patients with RAS wild-type (WT) metastatic colorectal cancer (mCRC), the role of maintenance therapy after first-line treatment with chemotherapy plus antiepidermal growth factor receptor (EGFR) monoclonal antibodies (MoAb) is still an object of debate. METHODS: We assessed the efficacy and safety of regorafenib as a switch maintenance strategy after upfront 5-fluorouracil-based chemotherapy plus an anti-EGFR MoAb in patients with RAS WT mCRC. RAVELLO was a phase III, international, double-blind, placebo-controlled, academic trial. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival and toxicity. Regorafenib or placebo were administered daily for 3 weeks of 4-week cycle until disease progression or unacceptable toxicity, up to 24 months. RESULTS: The study was stopped prematurely due to slow accrual and lack of funding after the randomisation of 21 patients: 11 in the regorafenib arm and 10 in the placebo arm. The small sample size precludes any statistical analysis. Toxicity was acceptable and consistent with the known regorafenib safety profile. Median PFS was similar in the two arms. However, a subgroup of patients treated with regorafenib experienced a remarkably long PFS. Three patients were progression free at 9 months in the regorafenib arm versus one patient in the placebo arm, whereas at 12 months two regorafenib-treated patients were still progression free versus none in the placebo arm. CONCLUSION: RAVELLO trial demonstrated that growing financial and bureaucratic hurdles affect the feasibility of independent academic research. Although stopped prematurely and within the limited sample size, RAVELLO suggests that regorafenib has not a major activity in maintenance setting after upfront chemotherapy and anti-EGFR MoAb. However, a subgroup of patients experienced a remarkable long PFS, indicating that a better refinement of the patient population would help to identify subjects that might benefit from a regorafenib personalised approach in the switch maintenance setting.

Nab-paclitaxel plus gemcitabine as first line therapy in metastatic pancreatic cancer patients relapsed after gemcitabine adjuvant treatment.

Nab-paclitaxel plus gemcitabine (Nab-Gem) represents one of the standard regimen for first-line treatment of metastatic pancreatic adenocarcinoma (mPDAC). However, few data are available in mPDAC relapsed after gemcitabine as adjuvant treatment. Our study aims to evaluate the efficacy and feasibility of Nab-Gem as first-line treatment for mPDAC patients previously treated with adjuvant treatment. We retrospectively analyzed the safety and efficacy data of 36 patients, who received first-line Nab-Gem after gemcitabine as adjuvant treatment. All patients received gemcitabine after radical surgery. Median disease-free survival was 12 months (95% CI 9.7-14.3); at relapse, all patients received Nab-Gem. We observed an objective response rate and disease control rate of 11.1% and 63.9%, respectively. With a median follow-up of 47 months, median progression-free survival was 5 months (95% CI 1.0-9.0), whereas median overall survival (OS) was 13 months (95% CI 5.5-20.5). Median OS was higher in patients with a relapse ≥ 7 months after the end of adjuvant treatment than in patients relapsed < 7 months (14 vs. 8 months, respectively, p: 0.52). Our results show that first-line Nab-Gem is feasible and effective in patients previously treated with gemcitabine as adjuvant treatment.

Capecitabine plus gemcitabine in thymic epithelial tumors: final analysis of a Phase II trial.

BACKGROUND: A multi-institutional Phase II trial was initiated in 2005 to test the combination gemcitabine and capecitabine in patients with thymic epithelial malignancies (TETs). PATIENTS & METHODS: Patients with histologic confirmation of TET diagnosis by central review who had received >1 systemic chemotherapy treatment were included. Patients received oral capecitabine (650 mg/mq twice daily on days 1-14) and intravenous gemcitabine (1000 mg/mq on days 1 and 8 every 3 weeks). RESULTS: Of the 30 patients included (18 men, 12 women; median age: 57 years, range: 48-61 years), the majority (73%) had thymoma, and the remaining thymic carcinoma. Eight patients developed grade 3-4 neutropenia. A total of 12 patients had a response. Median progression-free survival was 11 months (range: 6.5-16.5). CONCLUSION: Capecitabine and gemcitabine is highly active in TETs.

Tumor-to-tumor metastasis: breast cancer metastatic to thymic epithelial tumor.

Tumor-to-tumor metastasis is a rare phenomenon, with around 150 cases being reported in the literature. Breast cancer is the second most commonly reported donor tumor after lung cancer, but thymic epithelial tumors have never been reported as recipient tumors. Furthermore, the thymus is rarely affected by metastases. To our knowledge, the present report is the first case of breast cancer metastatic to thymic epithelial tumor.