Phase I-II study of sequential combination of XELOX and bevacizumab plus erlotinib (XELOX-TARAV) in first line colorectal patients:Run in phase I part

Methods: Chemonaive mCRC patients were treated with OX, 130 mg/m2 day 1 plus XEL, 1625 mg/m2/day days 1 to 14; B 7.5 mg/kg day 1; E, orally days 2 to 18 at 100 mg (I dose level) and 150 mg (II level), every 3 weeks. Treatment was administered for a maximum of 9 cycles or until PD or unacceptable toxicity (UT). The maximum tolerated dose (MTD) was defined as the dose level immediately preceding that in which dose-limiting toxicity (DLT) has been identified. DLT was the dose causing UT (defined with conventional NCI criteria) in ‡2 patients within a 3-6 patients cohort during the first cycle. Pharmacodynamic studies were conducted to evaluate tissue and circulating biologic factors. Results: To date 9 patients were enrolled. During the first cycle of therapy, according to the phase I objective definition, DLT was recorded in 1 patient at dose level I (diarrhea G3) and 2 patients at dose level II (diarrhea G3-4). Therefore, dose level II was defined as the DLT and 3 additional patients were treated at I dose level and no further UT was experienced. Overall, 43 complete cycles were administered (median 3; range 1-12). Overall toxicity is reported in the following table. Tumor shrinkage (5 pts) or stabilization (1 pt) were observed in 6/8 patients evaluable for response assessment. Conclusion: Diarrhea was responsible of DLT at II dose level (E 150 mg). E 100 mg is the recommended dose to be combined with chemotherapy and B for the Phase II part of the study. Pharmacodynamic correlative studies are ongoing

PRECLINICAL AND PHASE I STUDY OF OXALIPLATIN AND TOPOTECAN IN COMBINATION IN HUMAN CANCER.

BACKGROUND: DNA damage caused by platinum agents is frequently followed by induction of topoisomerase I, providing a rationale for use of platinum-based compounds with topoisomerase I inhibitors. MATERIALS AND METHODS: We studied the effect of a sequential schedule of oxaliplatin on day I and topotecan on days 2-5, in human colon and ovarian cancer cells in vitro, in nude mice bearing human cancer xenografts and finally in cancer patients in a phase I trial. RESULTS: We demonstrated a supra-additive effect of this combination on inhibition of colony formation and induction of apoptosis in vitro. We then demonstrated that the two agents in combination markedly inhibit tumor growth in nude mice. We translated these results into a clinical setting, conducting a phase I study in cancer patients with oxaliplatin 85 mg/m2 on day 1 and topotecan at doses escalating from 0.5 to 1.5 mg/m2 on days 2-5. Sixty cycles of treatment were administered to 18 patients affected prevalently by ovarian and colorectal cancer. Combination with topotecan 1.5 mg/m2 caused a dose-limiting toxicity. Therefore the maximum tolerated dose of topotecan was 1.25 mg/m2, at which six patients experienced a mild hematological and gastrointestinal toxicity. We also obtained evidence of clinical activity, particularly in ovarian cancer. CONCLUSIONS: Our results provide a solid biological and clinical rationale for a phase II trial at the recommended doses of oxaliplatin 85 mg/m2 and topotecan 1.25 mg/m2, possibly in ovarian cancer patients

Predictive factors of response to neoadjuvant chemoradiotherapy in rectal cancer patirnts.

Background: Pre-operative chemo-radiotherapy (CT-RT) produces a high rate of response in rectal cancer patients (pts). Several evidences suggests that using 2 drugs correlates with best responses and that complete pathologic response (cPR) induces prolonged survival. The aim of the present analysis was the evaluation of the effect of some biologic characteristics of the primary tumor on PR, as scored according to Tumor Regression Grade (TRG) scale. Methods: 45 pts, enrolled in a phase II trial, were treated with 2 cycles of CAP-OX concomitantly with pelvic conformal radiotherapy (45 Gy). EGFR, p53, PARP, XRCC, VEGFR and TS expression was determined by immunohistochemistry on rectal biopsies obtained prior CT-RT initiation, and scored as percentage of positive cells. The Spearman’s correlation test, t-test and logistic regression analysis were used to explore the correlation between these biological factors and the TRG (SPSS software). Biological factors expression was considered as a continuous variable. TRG was both considered as 4 categories and coded as TRG1 (cPR) vs TRG >=2. Results: Among the 42 operated pts, cPR (TRG-1) was observed in 10 (23.8%); TRG-2 in 18 (42.9%); TRG-3 in 11 (26.2%); TRG-4 in 3 pts (7.1%). Paraffin embedded biConclusions: A statistically significant inverse association was observed between TRG and TS expression; a weak correlation was suggested between cPR and low EGFR, VEGFR and PARP expression. Neither gender nor age significantly affected cPR.opsies from primary tumor were available for all pts

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FLFOX-4) as first-line treatment of advanced gastric cancer patients.

Background: The purpose of this study was to assess the toxicity and clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil and folinic acid administered every 2 weeks (FOLFOX4 regimen) in patients with advanced gastric cancer (AGC). Patients and methods: Sixty-one previously untreated AGC patients were treated with oxaliplatin 85mg/m2 on day 1, folinic acid (FA) 200mg/m2 as a 2-h infusion followed by bolus 5-fluorouracil (5-FU), 400 mg/m2 and a 22-h infusion of 5-FU, 600 mg/m2, repeated for two consecutive days every 2 weeks. Results: All patients were assessable for toxicity and response to treatment. Patient characteristic were: sex (male, 38; female, 23); median age, 64 years (range, 47–75 years); Eastern Cooperative Oncology Group (ECOG) performance status (PS): 0, nine patients; 1, 39 patients; 2, 13 patients; metastatic disease, 56 patients; locally advanced disease, five patients. Four (7%) complete responses (CR) and 19 partial responses (PR) were observed (overall response rate, 38%). Stable disease (SD) was observed in 22 (36%) patients, with progressive disease (PD) in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. NCI common toxicity criteria grade 3 and 4 hematologic toxic effects were neutropenia, anemia and thrombocytopenia in 36%, 10% and 5% patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. No treatment-related deaths were observed. Conclusion: FOLFOX-4 is an active and well tolerated chemotherapy. RR, TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer

Manuale di Oncologia Clinica

Manuale di Oncologia Clinica rivolto agli studenti delle Facolt\ue0 di Medicina e Chirurgia e agli specializzandi in Oncologia Medic