Intermittent Oxaliplatin Research Articles

VOICE trial: Final results from multicenter phaseII study of assessment of clinical efficiency and safety in capecitabine plus intermittent oxaliplatin together with bevacizumab as first-line therapy for patients with advanced colorectal cancer.

740 Background: The FOLFOX with bevacizumab (B-mab) has been established as a standard first-line therapy for metastatic colorectal cancer (mCRC), and OPTIMOX1 study suggested that stop and go strategy for oxaliplatin reduced peripheral sensory neuropathy. The CapeOx is one of the standard treatments for mCRC that has been proven to be as effective as the FOLFOX regimen. Thus we accessed the efficacy and safety of the combination of intermittent CapeOx + B-mab as a first-line therapy in patients with mCRC in this trial. Methods: Eligibility criteria included ECOG PS: 0–1, No Peripheral neuropathy ( < Grade 1). Patients received CapeOX (oxaliplatin 130mg/m2, capecitabine 2000mg/m2 + B-mab 7.5mg/kg) q3 weeks for 5 cycles, maintenance without oxaliplatin for 5 cycles, and reintroduction CapeOX + B-mab for 5 cycles until progression. Primary endpoint was Progression Free Survival (PFS). Results: Between March 2011 and August 2013, 55 pts were enrolled. Baseline characteristics were median age of 67 years (range, 20–83); PS 0/1 (49/6 pts); male/female (33/22 pts), colon/rectum (28/27pts) and metastatic lesion liver/lung/lymph nodes (32/18/21 pts). A total of 47 pts were evaluated as Par Protocol Set population. 38 pts moved from initial CapeOX to maintenance Capecitabine. 20 pts moved to CapeOx reintroduction. Median PFS was 14.7months (95%CI, 8.6–19.5) and Median TTF was 12.3 months (95%CI, 10.3–14.3). Best overall response rate was 48.0%. Oxaliplatin reintroduction rate was 57.4%. Main grade 3/4 toxicity were: neutropenia (1 pt), anemia (1 pt), peripheral neuropathy (1 pt), allergic reaction of oxaliplatin (1 pt), deep vein thrombosis (1 pt), nausea (1 pt), hand-foot syndrome (1 pt), and hypertension (1 pt). Conclusions: This study met its primary endpoint PFS. CapeOx intermittent oxaliplatin indicated to reduce incidence of severe neutropenia and peripheral sensory neuropathy. The results suggested that our treatment strategy was well tolerate and effective for first line therapy in mCRC, and maintenance duration for 5 cycles, was reasonable. Clinical trial information: UMIN000005732.

P-271 Feasibility of neoadjuvant chemotherapy with modified FOLFOX6 (combination chemotherapy of infusional 5-FU/l-Leucovorin and intermittent oxaliplatin) with bevacizumab in patients with locally advanced lower rectal cancer

P-271 Feasibility of neoadjuvant chemotherapy with modified FOLFOX6 (combination chemotherapy of infusional 5-FU/l-Leucovorin and intermittent oxaliplatin) with bevacizumab in patients with locally advanced lower rectal cancer

2071 Evaluation of neoadjuvant chemotherapy with modified FOLFOX6 (combination chemotherapy of infusional 5-FU/l-Leucovorin and intermittent oxaliplatin) with bevacizumab in patients with advanced lower rectal cancer

2071 Evaluation of neoadjuvant chemotherapy with modified FOLFOX6 (combination chemotherapy of infusional 5-FU/l-Leucovorin and intermittent oxaliplatin) with bevacizumab in patients with advanced lower rectal cancer

524P - Voice Trial-Results from a Multicenter Phase Ii Study of Assessment of Clinical Efficacy and Safety in Capecitabine Plus Intermittent Oxaliplatin Together with Bevacizumab As the First-Line Therapy for the Patients with Advanced Colorectal Cancer

ABSTRACT Aim: The FOLFOX with bevacizumab regimen has been established as a standard first-line therapy for metastatic colorectal cancer (mCRC), and the OPTIMOX1 study suggested that a stop and go strategy for oxaliplatin reduced peripheral sensory neuropathy. We had already evaluated the efficacy of OPTIMOX1 plus bevacizumab in patients (pts) with mCRC (CRAFT study, Tezuka et al, Invest New Drugs 2013). CapeOx is one of the standard treatments for mCRC that has been proven to be as effective as the FOLFOX regimen. Thus we assessed the efficacy and safety of the combination of intermittent CapeOx + Bevacizumab as a first-line therapy in patients with mCRC in this trial. Methods: Eligibility criteria included ECOG PS: 0–1, no peripheral neuropathy ( Results: Between March 2011 and August 2013, 55 pts were enrolled. Baseline characteristics were median age of 67 years (range, 20–83); PS 0/1 (49/6 pts); male/female(33/22 pts), colon/rectum (28/27pts) and metastatic lesion liver/lung/lymph nodes (32/18/21 pts). A total of 47 pts were evaluated as Par Protocol Set population. 38 pts moved from initial CapeOX to maintenance capecitabine. 20 pts moved to CapeOx reintroduction. Median PFS was 12.4 months (95%CI, 7.7–17.1) and Median TTF was 8.3 months (95%CI, 4.5–12.1). Best overall response rate was 50.9%. Median capecitabine courses were 5 cycles (range 1–5). Oxaliplatin reintroduction rate was 52%. The causes of reintroduction failure were disease progression (3 pts), successful liver resection (2 pts), peripheral sensory neuropathy grade 2 (1 pt). Main grade 3/4 toxicities: neutropenia, anemia, peripheral neuropathy, hand-foot syndrome, and hypertension in 1 patient. Conclusions: This study met its primary endpoint PFS. It was longer than the CRAFT study. CapeOx with intermittent oxaliplatin is indicated to reduce incidence of severe neutropenia and peripheral sensory neuropathy. The results suggested that our treatment strategy was well tolerated and effective for first-line therapy in mCRC, and maintenance of duration for 5 cycles was reasonable. Disclosure: All authors have declared no conflicts of interest.

Improved time to treatment failure with an intermittent oxaliplatin strategy: results of CONcePT

Oxaliplatin is an integral component of colorectal cancer treatment, but its use is limited by neurotoxicity. The Combined Oxaliplatin Neurotoxicity Prevention Trial (CONcePT) tested intermittent oxaliplatin (IO) administration and the use of concurrent calcium and magnesium salts (Ca/Mg), two modifications intended to reduce neurotoxicity and extend the duration of treatment. In this trial involving double randomization, 140 patients were randomized to receive modified FOLFOX7 plus bevacizumab with IO (eight-cycle blocks of oxaliplatin treatment) versus continuous oxaliplatin (CO); and Ca/Mg versus placebo (pre- and postoxaliplatin infusion). The primary end point was time-to-treatment failure (TTF). One hundred thirty-nine patients were entered and treated up to the point of early study termination due to concerns by the data-monitoring committee (DMC) that Ca/Mg adversely affected tumor response. Tumor response was not a study end point. Given DMC concerns, an additional independent, blinded radiology review of all images showed no adverse effect of treatment schedule or Ca/Mg on response by Response Evaluation Criteria In Solid Tumors. The IO schedule was superior to CO [hazard ratio (HR) = 0.581, P = 0.0026] for both TTF and time-to-tumor progression (TTP) (HR = 0.533, P = 0.047). An IO dosing schedule had a significant benefit on both TTF and TTP versus CO dosing in this trial despite the very attenuated sample. There was no effect of Ca/Mg on response.

Multicenter Analysis of mFOLFOX6 with Oxaliplatin Stop-and-Go Strategy Using Oral Uracil-Tegafur with Leucovorin for Unresectable Colorectal Cancer in Elderly Patients

Background: This study evaluated the tolerability and efficacy of intermittent oxaliplatin treatment based on mFOLFOX6 using oral uracil-tegafur(UFT) and leucovorin(LV) maintenance therapy in the treatment of elderly patients with advanced colorectal cancer. Methods: Ten non-elderly patients (70 years) with advanced/recurrent colorectal cancer were enrolled in this prospective, multicenter cooperative group clinical trial. The mFOLFOX6 regimen was administered for eight cycles with maintenance therapy with oral UFT/LV treatment until progression. In cases with disease progression, mFOLFOX6 was reintroduced. Results: Grade 2 peripheral neuropathy was noted in 30.0% and 25.0% of the elderly and non-elderly patients, respectively. The observed time to treatment failure (TTF) was 6.3 months in the elderly patients and 6.4 months in the non-elderly patients. The disease control rate was 83.3% in each group. Conclusion: Our new stop-and-go strategy using oral UFT/LV is well-tolerated and effective even in elderly patients.

Tumor shrinkage and overall survival (OS) from multicenter phase II study of modified FOLFOX7 (combination chemotherapy of infusional 5-FU/l-leucovorin and intermittent oxaliplatin) with bevacizumab in the first-line therapy of colorectal cancer: CRAFT trial.

616 Background: Additional bevacizumab (BV) to FOLFOX has been established as a standard 1st-line therapy for mCRC. The intermittent administration of L-OHP can reduce the peripheral sensory neurotoxicity as reported in OPTIMOX and CONcePT study. CRAFT trial was conducted to confirm the effectiveness of stop and go strategy of mFOLFOX7+BV. We previously reported the feasibility and good progression free survival (PSF) in that study (K. Ishibashi et al. ECCO2011). This time, the overall survival (OS) and possibilities for conversion surgery were reported. Methods: We administered 8cycles of mFOLFOX7/BV followedby 8 cycles of FULV/BV as a maintenance, and reintroduction of 8 cycles of mFOLFOX7/BV until disease progression. Patients who had progressive disease during maintenance phase are allowed to receive oxaliplatin ahead of schedule. The primary endpoint is the duration from the study enrollment to disease progression (PFS I). The secondary endpoints are survival time from the study enrollment to disease progression or death plus from 1st PD in the maintenance phase to 2nd PD (PFS II), tme to treatment failure (TTF) ,OS, and safety. Results: Between March 2009 and June 2010, 52pts were enrolled. Median PFS I was 13.2 (95%CI,10.3-15.0) months. PFS II was 13.5(95%CI,12.5-15.1) months. Median, TTF was 10.3 (95%CI, 5.6-12.1) months, OS was 27.4 (95%CI, 21.0-32.8) months. There was no uncontrollable toxicity. The range of tumor shrinkage wasup to - 91.0% and 3 patients received conversion surgery. Conclusions: This study met its primary endpoint PFS I (K.Ishibashi et al. ECCO 2011.). The current data indicated that stop and go strategy is effective to prolong the duration of 1st line treatment and to improve survival in mCRC. Tumor shrinkage data also suggested mFOLFOX7+BV has possibilities to make a conversion surgery. Water fall plot for all patients will be presented at the meeting.

6098 POSTER CRAFT Trial-Result From Multicenter Phase II Study of Modified FOLFOX7 (Combination Chemotherapy of Infusional 5-FU/l-Leucovorin and Intermittent Oxaliplatin) With Bevacizumab in the First-line Therapy of Colorectal Cancer

6098 POSTER CRAFT Trial-Result From Multicenter Phase II Study of Modified FOLFOX7 (Combination Chemotherapy of Infusional 5-FU/l-Leucovorin and Intermittent Oxaliplatin) With Bevacizumab in the First-line Therapy of Colorectal Cancer

MFOLFOX6 with oxaliplatin stop-and-go strategy and oral S-1 maintenance therapy in advanced colorectal cancer: CCOG-0704 study.

569 Background: In metastatic colorectal cancer (mCRC), a combination of leucovorin and fluorouracil with oxaliplatin (FOLFOX) is one of the standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. The aim of this study was to evaluate modified FOLFOX6 (mFOLFOX6) with the intermittent oxaliplatin treatment and maintenance therapy with S-1, oral fluoropyrimidine derivative, in the first-line treatment of mCRC. Methods: Thirty patients with untreated mCRC were treated with six cycles of mFOLFOX6 (oxaliplatin 85 mg/m2, leucovorin 200 mg/m2, 5-fluorouracil bolus 400 mg/m2 and 5-fluorouracil continuous 2400 mg/m2, every 2 weeks) followed by maintenance therapy with oral S-1 (S-1 80- 120mg/body days 1-28, every 6 weeks). Reintroduction of mFOLFOX6 was scheduled after four cycles of S-1 or tumor progression. The primary study end point was duration of disease control (DDC). Results: Twenty of the 30 patients (66.7%) who achieved responses or stabilizations received S-1 maintenance therapy. mFOLFOX6 was reintroduced in thirteen patients (43.0%). Median DDC was 9.3 months. Median progression-free survival (PFS) was 7.9 months. Overall response rates and disease control rates were 40.0% and 86.6% for the initial mFOLFOX6, 25.0% and 55.0% for S-1 maintenance therapy and 23.1% and 76.9% for mFOLFOX6 reintroduction. Twenty-eight patients (93.3%) had peripheral neuropathy during treatment, but grade 3 neurotoxicity was observed in only 1 patient (3.3%). Conclusions: The planned oxaliplatin stop-and-go strategy with oral S-1 maintenance therapy was feasible first-line treatment for Japanese mCRC patients. Further prospective randamized control study is warranted. No significant financial relationships to disclose.

Interim analysis of a single-arm, phase II study of bevacizumab (BV) with modified OPTIMOX1 as first-line treatment of patients with metastatic colorectal cancer (mCRC): TCOG-GI0802.

578 Background: BV is widely used for treatment of metastatic colorectal cancer (mCRC) patients. Although BV was often administrated to mCRC patients in combination with oxaliplatin, optimal schedule remains unclear. Many mCRC patients cannot continue to use oxalipatin because of cumulative neurotoxity, which decreases patient's QOL and motivation.We postulated that modification of oxaliplatin schedule would improve TTF in intermittent oxaliplatin usage. Therefore, we planned to use BV with original OPTIMOX1 adiministration schedule; modified oxaliplatin dose (85 mg/m3). Methods: Patients were enrolled with the criteria excluding neuropathy, PS ≥ 1, or no previous usage of oxaliplatin and BV, and then were received modified FOLFOX6 regimen (L-OHP 85 mg/m2, l-LV 200 mg/m2, 5-FU 400 mg/m2 bolus, 5-FU 2,400 mg/m2 46h continuous infusion) plus BV (5 mg/kg) q2wks x 6 cycles, followed sLV5FU2 (omit L-OHP) plus BV x 12 cycles regimen. After that, oxaliplatin reintroduction was done and mFOLFOX6 plus BV regimen was continued until PD. The evaluation of antitumor effect was done according to RECIST Criteria. Results: 40 patients accrued this trial. Median age was 65 years old. PS0: 89.5%, male: 75%, female: 25%, colon: 65.8%, rectal: 31.6%,colon + rectal: 2.6%. During initial 6 cycles of chemotherapy, 90% patients could continue chemotherapy. Response rate was 50%, and clinical benefit (including SD) was 92.1%. During Intial 6 cycles, G3 neuropathy occurred 2.6%, and G2 were 5%. Most frequent toxicity (≥G3) was neutropenia (30.8%) and anorexia (5.3%). One patient could complete the scheduled regimen. This patient continued mFOLFOX6+BV for 12 cycles after reintroduction keeping with PS 0, and was received FOLFIRI+BV regimen as second-line chemotherapy. Further information are under examination. Conclusions: This administration schedule was well tolerated and could continue chemotherapy longer than usual method. sLV5FU2+BV regimen was not affected reintroduction rate and progression free survival. BV with mOPTIMOX1 regimen can be expected to become a good treatment options for mCRC patients. No significant financial relationships to disclose.

A randomized phase II study of modified OPTIMOX1 or FOLFOX in advanced colorectal cancer.

519 Background: A combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) is a standard first-line regimen for advanced or unresectable colorectal cancer. Sensory neurotoxicity is its dose-limiting toxicity, but the OPTIMOX1 (stop and go) approach offers a reasonable strategy. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX4 or modified FOLFOX6 (+/− bevacizumab), a simplified leucovorin and fluorouracil regimen with normal-dose oxaliplatin. Methods: Previously untreated patients were randomly assigned to either FOLFOX administered every 2 weeks until progression (arm FOL) or FOLFOX for six cycles, maintenance without oxaliplatin for six cycles, and continued every six cycles until progression (arm OPT). Results: Sixty patients (arm FOL [n=35], arm OPT [n=33]) were enrolled. The median number of treatment cycles was 10 (range, 3-28) in arm FOL and 12.5 (range, 1-32) in arm OPT. Cumulative dose of oxaliplatin was 850 mg/m2 in arm FOL and 552.5 mg/m2 in arm OPT. Median progression-free survival was 8.5 months in patients allocated to arm FOL compared with 15 months in patients allocated to arm OPT. Response rates evaluated by RECIST criteria were 50% with arm FOL and 64% with arm OPT. National Cancer Institute Common Toxicity Criteria grade 3 toxicity was observed in 37.1% of the patients in arm FOL and 24.0% of patients in arm OPT. Grade 3 sensory neuropathy was observed in 22.8% of the patients in arm FOL and 6% of patients in arm OPT. Conclusions: Our modified OPTIMOX1 regimen may be effective and safe treatment to prevent oxaliplatin-induced neuropathy in advanced or unresectable colorectal cancer patients. No significant financial relationships to disclose.

Intermittent oxaliplatin (oxali) administration and time-to-treatment-failure (TTF) in metastatic colorectal cancer (mCRC): Final results of the phase III CONcePT trial

4010 Background: About 60% of mCRC patients (pts) discontinue oxali prior to disease progression (PD), largely driven by cumulative neurotoxicity (NT). CONcePT (Combined Oxaliplatin Neurotoxicity Prevention Trial) was initiated to test if an intermittent oxali (IO) schedule of FOLFOX/bevacizumab (BV) allows pts to remain on therapy longer compared to a conventional oxali (CO) “treat-to- failure” approach. To explore the impact of IV calcium/magnesium (CaMg: Ca-gluconate 1g, Mg-sulfate 1g, pre/post oxali) on NT, pts were randomized in a 2x2 factorial design (IO vs. CO) x (CaMg vs. placebo [PL] - double-blinded). Methods: Eligibility criteria included measurable disease, PS 0–1, no neuropathy. In CO arms, pts received mFOLFOX7 (oxali 85mg/m2, LV 200mg/m2, 5FU 2,400mg/m2 x 46h) plus BV (5mg/kg) q2wks. In the IO arms, pts alternated every 8 cycles with and without oxali. After 140 pts, a protocol amendment eliminated the CaMg vs. PL randomization and 40 subsequent pts all received CaMg. TTF (primary endpoint) was calculated as time from randomization to treatment discontinuation for any reason, including PD, death, toxicity, investigator or patient preference. Results: The study was terminated 6/07 by the IDMC based on unadjudicated tumor response data suggesting lower RR for CaMg compared with PL. In the 2x2 phase of the trial (n=139 treated pts), median age was 64y (30–88), 53% PS 0, 55% male, 80% colon, 22% prior adjuvant chemo, 12% prior radiation. Aes were the main cause of treatment failure (35% of pts, IO 28% vs. CO 43%); 22% of failures were due to PD (IO 23% vs CO 21%). Only 1 pt in the IO arm required early reintroduction of oxali. A 2-factor Cox regression model of TTF revealed a statistically significant effect for IO vs CO (median TTF 25 vs 18 wks, p=0.0025, HR=0.58, 95% CI 0.41- 0.83), but not for CaMg vs PL (p=0.1179, HR=1.32, 95% CI 0.93–1.86). Conclusions: Despite early termination, CONcePT met its primary endpoint, demonstrating that IO results in increased time on therapy compared to CO. This strategy is particularly useful in extending time on first-line therapy for oxali/BV combinations. Final results on RR, PFS, and safety (including NT) will be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration sanofi-aventis Genentech, Roche, sanofi-aventis Genentech, sanofi-aventis

Phase II study of the A-ICOX regimen [bevacizumab (Bev), weekly intermittent capecitabine (Cap) and oxaliplatin (Ox)] for untreated advanced colorectal cancer (CRC)

4092 Background: FOLFOX in combination with Bev is a standard regimen for treating advanced CRC. Cap on a d 1–14 schedule every 3 weeks is now being substituted for 5-flurouracil (CapOx); however optimal doses and schedules of Cap in combination with Ox and Bev needs continued evaluation. Intermittent weekly Cap (3,500 mg/m2, d 1–7) with Ox (85 mg/m2) every 2 weeks compared to the standard CapOx regimen in untreated advanced CRC has shown superior response and time-to-progression in Europe (Scheithauer W et al. J Clin Oncol. 21,1307; 2003). Methods: This phase II trial is designed to evaluate the A-ICOX regimen in US patients with CRC. The primary endpoint is to detect a 50% improvement in median progression free survival (PFS) from 8 to 12 months. With a sample of 40 patients, a 1-sided level 0.1 log-rank test has 81% power to detect this difference. Patients with advanced untreated CRC are eligible for study. Cap is administered at the dose of 2,500 mg/m2 in two divided doses on d 1–7 (n=11) and has been increased to 3000 mg/m2 dose (n=26), based on tolerability of the lower dose. The dose of Ox is 85 mg/m2 and Bev is 5 mg/kg. Cycles are repeated every 2 weeks. Results: Thirty-seven of 40 pts have been enrolled, with 30 evaluable for toxicity and response. Patient characteristics: Male (n=19); ECOG performance status 0 (n=18), 1 (n=12); median age 63 (range 38–80 years). Median cycles administered 4 (range 1–17). Partial responses were seen in 10 pts (33%), and metastasectomy was performed in 8 pts (27%). The PFS analysis is premature at this point. Gr 3/4 hematological toxicity occurred in only 2 pts (7 %). Other gr 3/4 adverse events have included: diarrhea (10 %), hand-foot syndrome (7 %), peripheral neuropathy (7%), nausea (7%) and vomiting (7 %). Conclusions: The first US experience of the A-ICOX regimen shows it to be very well tolerated, and Cap (3,000 mg/m2, d 1–7) in combination with Ox and Bev therapy can be safely administered. The incidence of subsequent metastasectomy, a marker of activity, is encouraging. A phase III trial of the A-ICOX regimen is now being conducted against standard Q-3 weekly CapOx/Bev. (Study supported by Genentech and Roche Pharmaceuticals) [Table: see text]

OPTIMOX1: A Randomized Study of FOLFOX4 or FOLFOX7 With Oxaliplatin in a Stop-and-Go Fashion in Advanced Colorectal Cancer—A GERCOR Study

In metastatic colorectal cancer, a combination of leucovorin (LV) and fluorouracil (FU) with oxaliplatin (FOLFOX) 4 is a standard first-line regimen. The cumulative neurotoxicity of oxaliplatin often requires therapy to be stopped in patients who are still responding. This study evaluates a new strategy of intermittent oxaliplatin treatment that is based on FOLFOX7, a simplified leucovorin and fluorouracil regimen with high-dose oxaliplatin. Previously untreated patients were randomly assigned to either FOLFOX4 administered every 2 weeks until progression (arm A) or FOLFOX7 for six cycles, maintenance without oxaliplatin for 12 cycles, and reintroduction of FOLFOX7 (arm B). Six hundred twenty patients were enrolled, including an exploratory cohort of 95 elderly or poor prognosis patients. Median progression-free survival and survival times were 9.0 and 19.3 months, respectively, in patients allocated to arm A compared with 8.7 and 21.2 months, respectively, in patients allocated to arm B (P = not significant). Response rates were 58.5% with arm A and 59.2% with arm B. National Cancer Institute Common Toxicity Criteria grade 3 or 4 toxicity was observed in 54.4% of the patients in arm A v 48.7% of patients in arm B. From cycle 7, fewer patients experienced grade 3 or 4 toxicity in arm B. Grade 3 sensory neuropathy was observed in 17.9% of the patients in arm A v 13.3% of patients in arm B (P = .12). In arm B, oxaliplatin was reintroduced in only 40.1% of the patients but achieved responses or stabilizations in 69.4% of these patients. Oxaliplatin can be safely stopped after six cycles in a FOLFOX regimen. Further study is needed to fully evaluate oxaliplatin reintroduction.