FOLFOX In Patients Research Articles

Treatment of oxaliplatin-induced peripheral neuropathy with oxycodone and extension of FOLFOX in patients with advanced colorectal cancer.

e19534 Background: FOLFOX is a combination chemotherapeutic regimen that incorporates folinic acid (FOL), 5-fluorouracil (F), and oxaliplatin (OX). FOLFOX is the standard adjuvant and metastatic therapy for advanced colorectal cancer. Peripheral neuropathy (PN) is the most frequent dose-limiting toxicity of oxaliplatin. It is crucial to prevent chemotherapy-induced PN or reduce its severity for optimal treatment delivery and prolongation of survival. We retrospectively evaluated the efficacy of oxycodone in patients with oxaliplatin-induced PN. Methods: The medical records of 56 eligible patients (range 48-74 y.o.) treated at Toho University Medical Center Sakura Hospital were reviewed; of these 56 patients, 27 received oxycodone (range 10-60 mg/day, average 17.8 mg) for oxaliplatin-induced PN (OXC (+) group). Treatment was continued until disease progression, unacceptable toxicity occurred, or until patient withdrawal. Results: One patient in the OXC (-) group showed Grade 3 PN (CTCAE v4.0), other patients showed Grade 1 or Grade 2 symptoms. Chemotherapy was suspended due to PN in 2 patients of the OXC (-) group, while it was not discontinued due to PN in any patient of the OXC (+) group. The number of mFOLFOX6 or mFOLFOX6+B-mab cycles was 15.6±1.5 (AVG±SE) (range 6-36 courses) in the OXC (+) group, and 7.4±0.5 (range 2-15 courses) in the OXC (-) group (P<0.05). The total dose of oxaliplatin was 1172.4±110.5 mg/m2 (range 408.7-2579.9 mg) in the OXC (+) group, and 537.9±43.5 mg/m2 (range 76.2-1235.9 mg) in the OXC (-) group (P<0.05). Conclusions: Treatment with oxycodone reduced the severity of oxaliplatin-induced peripheral neuropathy and contributed to the good performance status of patients receiving FOLFOX chemotherapy. Preventing oxaliplatin-induced PN with oxycodone made it possible to continue the FOLFOX regimen during its effective term and might improve the treatment outcome in patients with advanced colorectal cancer. Distribution of patients Total OXC(+) OXC(-) No. of patients 56 27 29 Stage III 16 3 13 Stage IV 40 24 16 mFOLFOX6 32 10 22 mFOLFOX6-B-mab 24 17 7

A multicenter, randomized, open-label study to assess the steady-state pharmacokinetics of bevacizumab given with either XELOX or FOLFOX-4 in patients with metastatic colorectal cancer

To compare the pharmacokinetics (PK) of bevacizumab (BV) at steady-state under two different dosing regimens, 7.5mg/kg q3w and 5.0mg/kg q2w, concomitantly with a combination of capecitabine and oxaliplatin (XELOX) and FOLFOX-4 (oxaliplatin in combination with infusional 5-FU/LV), respectively, in patients with metastatic colorectal cancer (mCRC). Patients were randomized in a 1:1 ratio to either XELOX+BV or FOLFOX-4+BV. Blood samples for steady-state PK of BV were collected on day 1 of cycle 5 (at the earliest) for XELOX+BV treatment and day 1 of cycle 7 (at the earliest) for FOLFOX-4+BV treatment. A total of 64 patients were enrolled, of which 37 were eligible for PK analyses. The primary PK parameter of BV, AUC(ss(per week)), was statistically similar between the two dosing regimens with the 90% confidence interval in the commonly used no-effect boundaries of 0.8 and 1.25. The V (ss) and CL did not differ between the two regimens; t (½) during the PK cycle was also similar for both arms at approximately 16days. These results demonstrated no clinically relevant change in BV PK when co-administered with either XELOX or FOLFOX-4. BV in combination with XELOX and FOLFOX-4 was generally well tolerated with no unexpected safety signals and no deaths. Nine patients in the XELOX+BV arm and 15 patients in the FOLFOX-4+BV arm experienced at least one SAE (most commonly gastrointestinal disorders) which led to dose modification in 7 and 2 patients, respectively, and to premature withdrawal in 9 and 5 patients, respectively. All 64 patients experienced at least one non-serious AE. Laboratory tests and vital signs were unremarkable. No clinically relevant differences in overall steady-state exposure of BV occurred when BV was given 7.5mg/kg q3w in combination with XELOX or 5.0mg/kg q2w with FOLFOX-4 in patients with mCRC, and the pharmacokinetics of BV were very similar between the two regimens. No unexpected adverse events or deaths were identified.

A phase Ib, open-label, dose-escalation study of tivozanib and FOLFOX6 in patients (pts) with advanced gastrointestinal (GI) tumors.

549 Background: Tivozanib (AV-951), a highly potent and selective tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, -2, and -3, has shown additive antitumor activity with fluorouracil (5-FU) in preclinical studies. An open-label phase Ib study was conducted to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PK), and antitumor activity of escalating doses of tivozanib combined with standard-dose FOLFOX6 (i.e., oxaliplatin, leucovorin, and 5-FU) in pts with advanced GI tumors. Methods: Tivozanib was administered orally once daily in 4-week cycles (3 weeks on, 1 week off), with FOLFOX6 administered on days 1 and 15 of each cycle. Pts were allowed to continue tivozanib following discontinuation of FOLFOX6. Results: 22 pts (14 male/8 female; median age of 58 years [range, 40-75]) received 0.5 mg (n = 9), 1.0 mg (n = 3), or 1.5 mg (n = 10) tivozanib plus FOLFOX6. Pts received a median of 8.1 weeks (range, 0.1 - 43.1) of treatment. DLTs were observed in 2 pts receiving 0.5 mg tivozanib (reversible grade 3 diarrhea and grade 3 and 4 transaminase elevations, respectively) and in 2 pts receiving 1.5 mg tivozanib (reversible grade 3 seizures and grade 3 vertigo, respectively). Other grade 3/4 drug-related adverse events (AEs) included neutropenia, fatigue, and hypertension (n = 2 each); and pyrexia, pulmonary embolism, and thrombosis (n = 1 each). There was no indication that drug-related AEs in this study were more frequent or severe than those observed with tivozanib or FOLFOX6 alone. The MTD was 1.5 mg tivozanib with full dose FOLFOX6. The PK profiles of tivozanib, oxaliplatin, and 5-FU will be presented. Several durable partial responses were observed. Additional safety and efficacy data are being obtained in 8 pts currently being treated at the 1.5-mg dose level. Conclusions: The combination of tivozanib and FOLFOX6 is tolerable and safe, with tivozanib given at its recommended dose of 1.5 mg. Observed clinical activity merits further exploration in several GI tumors, and these studies are being planned. [Table: see text]

A multicenter phase II clinical study of oxaliplatin, folinic acid, and 5-fluorouracil combination chemotherapy as second-line treatment for advanced colorectal cancer: A Japanese experience

This multicenter phase II study was designed to determine the efficacy and tolerability of oxaliplatin, levoforinate, and infusional 5-fluorouracil (FOLFOX4) as a second-line therapy for Japanese patients with unresectable advanced or metastatic colorectal cancer. A total of 53 patients with progressive disease after first-line chemotherapy were enrolled in the study. The treatment was repeated every 2 weeks until disease progression or unacceptable toxicity occurred, or the patient chose to discontinue the treatment. Four patients were ineligible and one did not receive the protocol therapy. Therefore, the response rate, overall survival (OS), and progression-free survival (PFS) were evaluated in 48 patients; toxicity was evaluated in 52 patients, excluding the patient who had not received the protocol therapy. A partial response was observed in 10 patients. The overall response rate was 20.8% (95% confidence interval [CI], 10.5%-35.0%). The median PFS was 5.6 months (95% CI, 4.1-7.0 months) and the median OS was 19.6 months (95% CI, 11.4-24.3 months). The most frequently encountered grade 3/4 hematological symptom was neutropenia (43.1%). The toxicity profile was generally predictable and manageable. The results showed good tolerability and efficacy for second-line FOLFOX4 in patients with advanced colorectal cancer, thus indicating the promise of this regimen as an effective second-line therapy for advanced colorectal cancer in the Japanese population.

370 A phase Ib study of escalating doses of Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitor Tivozanib and FOLFOX6 in patients with advanced gastrointestinal (GI) tumors

370 A phase Ib study of escalating doses of Vascular Endothelial Growth Factor (VEGF) tyrosine kinase inhibitor Tivozanib and FOLFOX6 in patients with advanced gastrointestinal (GI) tumors

5-fluorouracil, leucovorin and oxaliplatin (FOLFOX4) as postoperative adjuvant chemotherapy (CT) for node positive rectal cancer after radiochemotherapy (R-CT) and surgery

Aims: To evaluate the activity and safety of postoperative adjuvant CT of 8 cycles FOLFOX4 in patients with node-positive rectal cancer after neoadjuvant R-CT and surgery.

5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) as postoperative adjuvant chemotherapy (CT) for node-positive rectal cancer after radiochemotherapy (R-CT) and surgery.

e14125 Background: To evaluate the activity and safety of postoperative adjuvant CT of 8 cycles FOLFOX4 in patients with node-positive rectal cancer after neoadjuvant R-CT and surgery. Methods: We ...

Adjuvant FOLFOX-4 in patients with radically resected gastric cancer: Tolerability and prognostic factors

The aim of the present study was to evaluate the toxicity and efficacy of the FOLFOX-4 regimen as adjuvant chemotherapy in patients with gastric cancer after radical surgery. Fifty-four patients (1 stage Ib, 6 stage II, 22 stage IIIa, 14 stage IIIb and 11 stage IV) received 8-12 cycles of FOLFOX-4 (oxaliplatin 85 mg/m(2), Day 1; leucovorin 100 mg/m(2) i.v., Days 1 and 2; 5-fluorouracil 400 mg/m(2) i.v. bolus, Days 1 and 2 and 600 mg/m(2) in 22 h i.v. continuous infusion, Days 1 and 2; every 14 days). Toxicity was recorded at each cycle according to the National Cancer Institute Common Toxicity Criteria. Disease-free (DFS) and overall survival (OS) were calculated according to the Kaplan-Meier method. Thirty-eight patients (70.4%) completed the prescribed number of cycles of chemotherapy. The toxicity was mild. Grade 3-4 neutropenia occurred in 57% of patients, thrombocytopenia and anemia in 2% of cases. Peripheral neuropathy was experienced by 46% of the patients (grade 4 in 2% of cases). Five patients experienced grade 3 gastrointestinal toxicity. After a median follow-up of 33.1 months, 17 patients relapsed and 17 succumbed to the disease. The mean observed DFS and OS were 49.7 months (range 40.7-58.8) and 57.9 months (range 49.6-66.2), respectively. At univariate analysis, females and patients who had received <8 cycles of chemotherapy had a significantly worse probability of DFS and OS. The Cox model showed gender to be independent of the factors affecting DFS. Adjuvant FOLFOX-4 is feasible and well-tolerated in patients radically resected for gastric cancer. Receiving <4 months of adjuvant FOLFOX-4 could be detrimental to prognosis.

FOLFOX in patients with metastatic colorectal cancer and high alkaline phosphatase level: an exploratory cohort of the GERCOR OPTIMOX1 study

BackgroundAlkaline phosphatase (ALP) is a strong prognostic factor in patients with metastatic colorectal cancer (MCRC). Patients with ALP more than three times the upper limit of normal (ULN) were excluded from our previous studies evaluating chemotherapy. An exploratory cohort of patients with ALP >3 ULN was included in the OPTIMOX1 study. Patients and methodsPreviously untreated patients with MCRC were randomized to FOLFOX4 until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles and reintroduction of FOLFOX7 (arm B). Patients were stratified according to ALP level ≤3 ULN versus 3–5 ULN. ResultsAmong the 620 patients in OPTIMOX1 study, 63 had ALP 3–5 ULN; 33 in arm A and 30 in arm B. The response rate in these patients was 56% versus 59% in patients with ALP ≤3 ULN. Median progression-free survival and overall survival were, respectively, 6.4 and 11.5 months in patients with ALP 3–5 ULN and 9.0 and 21.1 months in patients with ALP ≤3 ULN. Thirty-three percent of the patients in the cohort experienced grade 3/4 toxicity. ConclusionBoth FOLFOX regimens achieved high tumor response rates and offer good palliation in MCRC patients with a poor prognosis.

Efficacy of FOLFOX4 in patients with hypoalbuminemia or immune impairment

e15141 Background: The effects of chemotherapeutic agents are understood to be regulated by many factors including tumor factors such as sensitivity to drugs and host factors. Among these host factors, nutritional conditions and immune function of cancer-bearing host has been told to relate the effects of chemotherapy, however, it has not been clarified yet. Methods: We have analysed the relationships between the effects of FOLFOX4 and nutritional markers such as serum albumin concentrations and immunology markers including counts of lymphocytes and neutrophils, the ratios of these counts G/L: granulocytes/lymphocytes) and serum concentrations of immunosuppressive acidic protein (IAP) in the patients with disseminated colorectal cancer who have received FOLFOX4. All these blood examinations were performed before the first administration of FOLFOX4 as a first line chemotherapy in 18 patients with disseminated colorectal cancer. Results: Firstly serum albumin levels have shown significant correlation to lymphocyte counts and did inverse correlation to neutrophil counts and G/L ratios. The albumin levels in the patients with PD of FOLFOX outcome was significantly lower than in the patients with PR(p&lt;0.05) and SD (p&lt;0.05). The lymphocytes counts in the patients with PD were significantly lower than in those with PR (p&lt;0.05) and SD (p&lt;0.05). Neutrophil counts, on the other hand, was significantly higher in the patients with PD than in those with PR (p&lt;0.01) and SD (p&lt;0.05). IAP, have been recognized as a marker of immune-suppression in patients with cancer was higher in the patients with PD. Conclusions: Thus the nutritional status is closely related to the immune status in patients with cancer, and the markers of these conditions may present important informations in prediction of results of cancer chemotherapy. No significant financial relationships to disclose.

A phase II, double-blind, randomized multicenter study of cediranib with FOLFOX versus bevacizumab with FOLFOX in patients with previously treated metastatic colorectal cancer (mCRC): Final PFS results

4028 Background: Cediranib (AZD2171) is an oral, highly potent and selective inhibitor of VEGF signaling, with activity against VEGFR-1, -2, and -3. Recent trials have shown that the combination of...

A phase I dose escalation and pharmacokinetic (PK) study of intravenous (iv) aflibercept (VEGF Trap) plus FOLFOX4 in patients (pts) with advanced solid tumors: Preliminary results

3556 Background: Aflibercept (AF) is a recombinant fusion protein that is a potent inhibitor of vascular endothelial growth factor (VEGF). This study was designed to assess the safety/tolerability, dose-limiting toxicities (DLTs), recommended Phase II dose, and PK of AF + FOLFOX4. Methods: This combination trial explored escalating iv doses of AF followed by standard fixed FOLFOX4 regimen, every 2 weeks. Results: 32 pts (M/F 9/23, median age 59 [25–79], ECOG-PS 0/1: 11/21) were enrolled in 3 AF dose levels: 2.0 (n = 4), 4.0 (n = 18) and 5.0 (n = 10) mg/kg. Primary tumors were mostly gastro-intestinal (16, including 8 pancreas, 3 cholangiocarcinoma and 3 gastric), breast (5), ovarian (4), and others (7). Most (75%) pts were heavily pre-treated, with a median number of prior lines of 3[1–9]. Pts received a median number of 4.5 [1–20] treatment cycles (cy). During the dose escalation phase, no AF-related DLT (first 2 cy) was observed. Gr > 3 NCI-CTCAE v3.0 toxicity observed included: neutropenia (69%), thrombocytopenia (13%), hypertension (13%), proteinuria (13%), hemorrhagic events (9%, including one G5 hemorrhagic stroke at 4 mg/kg), febrile neutropenia (3%), deep vein thrombosis (3%). A G5 posterior leukoencephalopathy syndrome was reported at 5 mg/kg. Five partial responses were noted (pancreas, cholangiocarcinoma, colo-rectal; all at doses > 4 mg/kg) and 10 pts had stable disease. Free and bound AF drug concentrations in combination with FOLFOX4 are comparable to those observed with AF as monotherapy. At doses > 4 mg/kg, free AF exceeds bound AF over the dosing interval, suggesting sustained effective trapping of VEGF. Conclusions: AF 4 mg/kg combined with FOLFOX4 was selected for further investigations, based on activity, overall safety profile (consistent with that of other agents from the same class), and PK. Updated data will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis

Carcinoembryonic antigen in monitoring of response to cetuximab plus FOLFIRI or FOLFOX-4 in patients with metastatic colorectal cancer

First-line treatment of metastatic colorectal cancer with combinations of cetuximab and irinotecan-based or oxaliplatin-based chemotherapy has shown promising efficacy. The clinical response to such treatment is generally assessed by tumor measurement through imaging. This study was performed to evaluate the correlation between serial changes in imaging results and carcinoembryonic antigen (CEA) levels. In 64 patients with metastatic colorectal cancer receiving cetuximab plus FOLFIRI or FOLFOX-4 chemotherapy we retrospectively analyzed the relationship between changes in serum CEA and changes in imaging results throughout the treatment course. Response in terms of serum CEA change was defined as a >/=50% drop in CEA level for more than 4 weeks. The sensitivity and specificity of serum CEA changes after targeted chemotherapy in relation to imaging results were 80.5% (33/41) and 73.9% (17/23), respectively, with a diagnostic accuracy of 78.1% (50/64). The progression-free survival time of responders assessed by serum CEA change was significantly longer than that of nonresponders (p=0.0091). Our results highlight the importance of serum CEA monitoring in assessing the response to targeted chemotherapy and in predicting the prognosis of patients with metastatic colorectal cancer.

Two Doses of Oxaliplatin with Capecitabine (XELOX) in Metastatic Colorectal Cancer

Phase II/III studies have shown XELOX to be as effective as FOLFOX in patients with advanced colorectal cancer (CRC). The study was designed to evaluate the activity and tolerability of XELOX in CRC. In August 2002, we began a prospective study of XELOX as first-line therapy for patients with metastatic CRC. Twenty-two patients were enrolled between November 2002 and August 2003 (series I). An interim analysis performed in August 2003 revealed that 32% of patients required a dose reduction of oxaliplatin because of toxicity. From August 2003 to April 2005, an additional 20 patients were included (series II). This second group of patients received oxaliplatin at a lower dose. The first 22 patients (series I) included received oxaliplatin 130 mg/m(2) on day 1 plus capecitabine 2000 mg/m(2) daily on days 1-15 (3-week cycle). The second set of 20 patients (series II) received oxaliplatin 85 mg/m(2) on day 1; the dose of capecitabine and the frequency of administration were not modified. Patient characteristics were well balanced in the 2 series. Overall response (series I vs. II): 41% vs. 65%; median time to progression was similar: 10.51 vs. 10.92 (log-rank test, P = .79). Median survival was similar in the 2 series: 19.55 vs. 21.18 months (log-rank test, P = .61). Grade 3/4 toxicity (series I vs. II): peripheral neuropathy, 14% vs. 0 (P = .23). In patients with advanced CRC, in combination with capecitabine, oxaliplatin 85 mg/m(2) is as effective with lower toxicity when compared with oxaliplatin 130 mg/m(2).

Phase III trial of capecitabine + oxaliplatin (XELOX) vs. 5-fluorouracil (5-FU), leucovorin (LV), and oxaliplatin (FOLFOX4) as 2nd-line treatment for patients with metastatic colorectal cancer (MCRC)

4031 Background: Capecitabine is an oral fluoropyrimidine that has demonstrated similar efficacy to 5-FU/LV in the 1st-line treatment of MCRC. Most patients now receive multi-agent chemotherapy and FOLFOX4 has become a popular regimen in this setting. We conducted a phase III study comparing XELOX with FOLFOX4 in patients who had received prior treatment with irinotecan in combination with bolus and/or infusional 5-FU/LV for MCRC. The primary endpoint of the study was time-to-tumor progression (TTP). With 610 patients, this study had 80% power to detect non-inferiority of the XELOX vs. FOLFOX, defined by a progression hazard ratio (HR) of &lt;1.3. Methods: Patients were treated with XELOX (oxaliplatin 130mg/m2 i.v., capecitabine 1,000mg/m2 bid oral x 14 days, q3w) or FOLFOX4 (as described previously). Results: The study recruited 627 patients (the intent-to-treat - ITT - group). Baseline characteristics were well balanced. The primary objective of the study was met with a progression HR of 0.97 for the XELOX group (95% CI, 0.83–1.14). Median TTP was 4.8 months for XELOX- and 4.7 months for FOLFOX4-treated patients. Overall survival was also similar between the groups with a death HR of 1.03 for the XELOX group (95% CI, 0.87–1.23). Median survival was 11.9 months for XELOX- and 12.6 months for FOLFOX4-treated patients. Grade 3/4 toxicities occurred in 60.1% of XELOX- and 72.4% of FOLFOX4-treated patients. The most common treatment-related grade 3/4 adverse events (XELOX vs. FOLFOX4) were: diarrhea (20 vs. 5%), neutropenia (5 vs. 35%), fatigue (5 vs. 8%), paresthesia (9 vs. 8%), nausea/vomiting (6 vs. 5%). The rate of grade 3 hand-foot syndrome was 3.5% with XELOX and 0.6% with FOLFOX4. The 60-day all cause mortality was 3.9% in XELOX- and 4.2% in FOLFOX4-treated patients. Conclusions: These results demonstrate that second-line treatment with XELOX is non-inferior to FOLFOX4 in terms of PFS. Results for overall survival and response rates were also similar between the two groups. The safety profile was similar to previous studies, with no unexpected toxicities. Study supported by Hoffmann-La Roche. No significant financial relationships to disclose.

Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study

4013 Background: The OPTIMOX2 study was designed to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: OPTIMOX2 is a large phase II study performed before the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU2 until progression then reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 202 pts were included between Feb 2004 and Apr 2006. Response rates were (OPTIMOX1/OPTIMOX2): CR+PR 63%/61%. Median PFS were OPTIMOX1/OPTIMOX2) 8.3/6.7 months (p=.04). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 10.8m in the OPTIMOX1 arm and 9.0m in the OPTIMOX2 arm, p=.32. Median duration of chemotherapy-free interval (CFI) in the OPTIMOX2 arm was 4.6 months. Patients with poor prognostic factors had a shorter CFI, p=.01. Median overall survival was 24.6m in the OPTIMOX1 arm and 18.9m in the OPTIMOX2 arm, p=.05. Median survivals (OPTIMOX1/OPTIMOX2) were not reached/28.7m in patients with good prognostic and 20.9/14.5m in patients with poor prognostic. Conclusions: Maintenance LV5FU therapy prolongs PFS and OS, especially in patients with poor prognosis. CFI can be recommended only in selected patients without adverse prognostic factors. Our next study, DREAM, is evaluating maintenance therapy with targeted agents alone. No significant financial relationships to disclose.

A phase I study of vorinostat (suberoylanilide hydroxamic acid) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)

4088 Background: At 5μM, vorinostat decreases thymidilate synthase (TS) expression by ∼ 40 fold, which translates into synergistic antitumor activity when added to 5-FU. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design with a planned expansion of the maximum tolerated dose (MTD) cohort to 10 patients (pts). Vorinostat (100mg, 200mg, 300mg, 400 mg dose levels) was given twice daily for 1 week followed by 1 week break. FOLFOX was administered at a fixed standard dose every 2 weeks on the 4th day of vorinostat. Tumor biopsies were obtained from liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 19 pts were treated on study (M/F: 12/7; median age: 58; ECOG 0/1: 6/13). All pts had failed prior FOLFOX therapy. Dose-limiting toxicities (DLT) were noted in 3 pts: 2/4 pts at dose level (DL)4 (vorinostat 400mg BID) consisting of grade (G) 3 fatigue, &amp; diarrhea in 1 pt and G3 fatigue in the other; 1/8 pts at DL3 (MTD, vorinostat 300mg BID) consisting of G3 fatigue, anorexia, nausea, and dehydration. 8 pts have been treated at the MTD for a total of 38 cycles. “All Cycles” G3–4 toxicities at the MTD consisted of 2 pts with G3 neutropenia and 2 pts with G3 thrombocytopenia along with the above described DLT. Responses were evaluable in 17 pts: 0 Objective Response, 8 Stable Disease (4 confirmed). TS expression by IHC and by RT-PCR showed modest decreases in 2/6 patients after vorinostat treatment. Cmax of SAHA was &lt; 2μM at all investigated DL, which could explain the lack of adequate TS down-regulation. Conclusions: vorinostat 300mg PO BID × 1 week every 2 weeks in combination with FOLFOX is the established recommended dose. The lack of significant TS down-regulation may be due to the suboptimal serum vorinostat concentrations. Alternate shorter vorinostat schedules may allow for further daily dose escalations and hence for better likelihood of TS down-regulation. This study was partly supported by CTEP, NCI. No significant financial relationships to disclose.

Revisiting the Cancer and Leukemia Group B/Southwest Oncology Group 80405 Trial: A Phase III Trial of Chemotherapy and Biologic Agents for Patients with Untreated Advanced Colorectal Adenocarcinoma

The management of patients with metastatic colorectal cancer (CRC) has changed dramatically over the past 5 years. The availability of new cytotoxic and biologic treatment agents, namely irinotecan, oxaliplatin, capecitabine, bevacizumab, cetuximab, and panitumumab, has altered the therapeutic strategies used as successive phases of treatment. The exposure of patients to multiple lines of chemotherapy has dramatically improved the median survival for patients with advanced CRC.1 Although the optimal timing and sequencing of these agents are unknown, the potential impact of biologic agents used in combination with chemotherapy might be more dramatic than when used alone. Further increasing the complexity, there are no predictive tests that enable the individualization of “optimal” firstline therapy before treatment. This could be increasingly important because of emerging evidence that certain patients with advanced CRC (eg, those with isolated hepatic or lung metastases) might be cured when a surgical approach is used in conjunction with the “optimal” chemotherapy.2 Current data suggest that combining oxaliplatin or irinotecan with infusional 5-fluorouracil (5-FU) and leucovorin (FOLFOX or FOLFIRI, respectively) confers relatively similar survival outcomes in the first-line setting,3,4 and the decision of which regimen to use in this setting is a function of comorbidities, anticipated toxicities, and the possibility of previous exposure to oxaliplatin in the adjuvant setting.5 Although it is also clear that biologic agents have efficacy in this disease setting, their role is less certain. There is compelling evidence that bevacizumab, a monoclonal antibody targeting vascular endothelial growth factor, improves the efficacy of bolus irinotecan/5-FU/leucovorin (IFL)6 in previously untreated patients and FOLFOX in patients with disease refractory to IFL.7 However, bevacizumab, as a single agent or as thirdor further-line treatment appears to be, at best, minimally active. Bevacizumab is currently approved for use with 5-FU–containing chemotherapy in the firstand second-line management of patients with advanced CRC. Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), was first studied in secondor subsequent-line treatment in patients with tumors overexpressing EGFR by immunohistochemistry and has demonstrated single-agent efficacy and additive activity in combination with irinotecan.8 The role of cetuximab as first-line treatment remains unclear, but evidence suggests that using it solely in patients with EGFR-positive tumors by Submitted: May 11, 2007; Accepted: May 17, 2007 1Cancer and Leukemia Group B 2University of California, San Francisco 3Southwest Oncology Group 4Oregon Health Sciences University, Portland 5Duke University, Durham, NC 6University of Southern California, Los Angeles Alan P. Venook,1,2 Charles D. Blanke,3,4 Donna Niedzwiecki,1,5 Heinz-Josef Lenz,3,6 John R. Taylor,1 Donna R. Hollis,1,5 Susan Sutherland,1,5 Richard M. Goldberg1,2

OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC). A GERCOR study

3504 Background: The OPTIMOX1 study (JCO 2006) has shown that the strategy of 6 cycles of FOLFOX7 followed by maintenance therapy and FOLFOX reintroduction was as active and better tolerated than FOLFOX4 until progression. The aim of the OPTIMOX2 study was to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: Initially planned as a phase III study, OPTIMOX2 was downgraded to a large phase II study since the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU until progression and reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 187/200 planned pts were included between Feb 2004 and Nov 2005. Response rates were (OPTIMOX1 arm/OPTIMOX2 arm): CR 2%/2%, PR 54%/51%, stable 24%/33%, progression 11%/7%, non assessable 9%/7%. Median PFS were (OPTIMOX1 arm/OPTIMOX2 arm) 36/28 weeks (p=.01), PFS in responders 41/30 weeks (p=.001), PFS in stable patients 34/26 weeks (p=.23). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 41 weeks in the OPTIMOX1 arm and 36 in the OPTIMOX2 arm, p=.17. Median duration of chemotherapy-free interval in the OPTIMOX2 arm was 25 weeks (5.7 months). Conclusions: Maintenance LV5FU therapy prolongs PFS. The quality of life of almost 6 months CFI can balance a small advantage in DDC for maintenance therapy. Our next goal is to evaluate maintenance therapy with targeted agents alone. [Table: see text]

A phase I study of vorinostat (suberoylanilide hydroxamic acid, SAHA) in combination with 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in patients with advanced colorectal cancer (CRC)

3592 Background: Vorinostat is a novel histone deacetylase (HDAC) inhibitor that potentiates 5-FU and platinum antitumor activity. This potentiation is associated with ∼ 40 fold decrease in thymidilate synthase (TS) expression, the main target of 5-FU, in preclinical models. We conducted a phase I study of vorinostat plus FOLFOX in patients with CRC to determine the recommended dose of this combination. Methods: Vorinostat was escalated in a standard 3+3 design. FOLFOX was administered at a fixed dose every 2 weeks: leucovorin 400mg/m2 and oxaliplatin 85mg/m2 over 2 hours followed by 5-FU bolus 400mg/m2 and 5-FU infusion 2400mg/m2 over 46 hours. Vorinostat started 3 days prior to FOLFOX and was given twice daily for 1 week followed by 1 week break. Investigated dose levels of vorinostat (twice daily) include 100, 200, and 300 mg. Tumor biopsies were obtained from patients with accessible liver metastases before and on the 4th day of vorinostat (prior to FOLFOX) to assess TS expression. Results: 9 patients (pts) enrolled (M/F: 8/1; median age: 57, ECOG 0/1: 5/4). All pts had failed prior FOLFOX, irinotecan, and cetuximab therapy. One pt at dose level (DL) 1 was not evaluable due to rapid clinical progression. No dose-limiting toxicities were noted among the 8 evaluable pts. No grade (G) 3 toxicities were noted on the first cycle of treatment (within 2 weeks after 1st FOLFOX) and accrual continues on DL3. Cycle 1 toxicities were attributed to FOLFOX and consisted of 1 G2 neutropenia, 1 G2 mucositis, and 2 G2 nausea/vomiting. Responses were evaluable in 6 pts: 1 pt with peritoneal carcinomatosis on DL 1 has stable disease 5 months + along with a stable CEA; 3 patients at DL2 have stable disease at 2 months along with declining CEA in 2/3 pts. Two pts (DL1) with liver metastases biopsies had a major decrease in TS expression by IHC after 4 days of vorinostat. Conclusions: Vorinostat at 100–200mg PO BID × 1 week every 2 weeks in combination with FOLFOX is well tolerated. The lowest DL of 100 mg PO BID is associated with down-regulation of TS. Disease stabilization in highly refractory patients is promising. The investigation of this regimen in the first or second-line treatment of metastatic CRC is warranted. No significant financial relationships to disclose.