Phase I trial of irinotecan and amrubicin with granulocyte colony-stimulating factor support in extensive-stage small-cell lung cancer

Purpose

We conducted a phase I trial of irinotecan (CPT-11), a topoisomerase I inhibitor, combined with amrubicin, a topoisomerase II inhibitor, with recombinant human granulocyte colony-stimulating factor (rhG-CSF) support to overcome the neutropenia associated with this particular combination. The aim was to determine the maximum tolerated dose (MTD) of amrubicin combined with a fixed dose of CPT-11 and the dose-limiting toxicities (DLTs) of this combination in extensive-stage small-cell lung cancer (ED-SCLC) patients.

Methods

Fifteen patients with ED-SCLC were treated at 3-week intervals with amrubicin on days 1–3 plus 60?mg/m² CPT-11 on days 1 and 8. In addition, prophylactic rhG-CSF (50?μg/m²) was given from day 4 to day 21, except on the day of CPT-11 administration. Amrubicin was started at 30?mg/m² and then escalated in 5?mg/m² increments until MTD was reached.

Results

The MTD of amrubicin was 35?mg/m², since 2 of 4 patients experienced DLTs during the first cycle of treatment at the 40 mg/m² dose level. Neutropenia, neutropenic fever, ileus, and diarrhea were the DLTs. There were 13 partial responses among the 13 assessable patients, yielding an overall response rate of 100?%. Median progression-free survival and overall survival were 7.4?months and 13.4?months, respectively.

Conclusion

The combination of amrubicin and CPT-11 showed high activity against ED-SCLC with acceptable toxicity. Use of rhG-CSF allowed the dose of amrubicin to be raised 40?% above that in the original regimen (60?mg/m² CPT-11 and 25?mg/m² amrubicin).     

A phase I study of combination therapy with S-1 and irinotecan in patients with previously untreated metastatic or recurrent colorectal cancer

Background

To investigate the combination of S-1 and irinotecan (CPT-11) as an alternative to infusional 5-fluorouracil/leucovorin plus CPT-11, we performed a phase I trial to determine the maximum tolerated dose, recommended dose (RD), and dose-limiting toxicities (DLTs) in patients with metastatic or recurrent colorectal cancer.

Patients and methods

S-1 and CPT-11 doses were escalated using a standard 3?+?3 design. S-1 was administered orally at 70?mg/m² (levels 1?C3) or 80?mg/m² (levels 4 and 5) for 14 consecutive days followed by 1-week rest. CPT-11 was administered intravenously on day 1, at 175?mg/m² (level 1), 200?mg/m² (level 2), 225?mg/m² (levels 3 and 4), or 250?mg/m² (level 5). Treatment was repeated every 3?weeks, unless disease progression or severe toxicities were observed.

Results

Twenty-three patients were treated. One patient at each of levels 2 and 4 developed a DLT, grade 3 ileus, and grade 3 diarrhea, respectively. At both levels, an additional three patients did not experience DLTs. At level 5, two of five patients experienced DLTs, including grade 3 enteritis and grade 4 neutropenia for more than 5?days. The RD was determined at level 4 (80?mg/m² S-1 and 225?mg/m² CPT-11). An objective response was observed in 7 of 17 patients with measurable disease: 2 of 5 at level 2; 3 of 4 at level 4; and 2 of 4 at level 5.

Conclusions

The RDs of CPT-11 and S-1 were determined as 225 and 80?mg/m², respectively, and further phase II trials are warranted.     

Phase I dose-finding and pharmacokinetic trial of irinotecan (CPT-11) administered every two weeks

Objectives:This trial was performed to determine themaximum tolerated dose (MTD), dose-limiting toxicity (DLT), andpharmacokinetic profile of irinotecan (CPT-11) when administered on aonce-every-2-week schedule. Patients and methods:CPT-11was administered to successive cohorts of patients at progressivelyincreasing starting doses ranging from 125 to 350 mg/m². TheMTD and DLTs were determined both for CPT-11 alone and for CPT-11followed by filgrastim (G-CSF). Plasma samples were obtained during thefirst 24 hours after initial dosing to determine the totalconcentrations (lactone + carboxylate forms) of CPT-11; of theactive metabolite SN-38; and of SN-38 glucuronide (SN-38G). Results:Neutropenic fever was the DLT for CPT-11 atthe 300 mg/m² dose level. When G-CSF was added, doseescalation beyond 350 mg/m² could not be achieved due tograde 2–3 toxicities that prevented on-time retreatment withCPT-11. Severe, late diarrhea was uncommon on this schedule. Peak plasmaconcentrations of SN-38 and SN-38G were approximately 2.5% and4.2% of the corresponding peak plasma concentration for CPT-11,respectively. The harmonic mean terminal half-lives for CPT-11, SN-38,and SN-38G were 7.1 hours, 13.4 hours, and 12.7 hours, respectively. Nopredictive correlation was observed between CPT-11 or SN-38 peakconcentration or AUC and first-cycle diarrhea, neutropenia, nausea, orvomiting. Across the range of doses studied, mean CPT-11 clearance was14.0 ± 4.0 l/h/m² and volume of distribution was 146± 45.9 l/m². Conclusions:Whenadministered every two weeks, the recommended phase II starting dose ofCPT-11 is 250 mg/m² when given alone and 300 mg/m²when supported by G-CSF. This every-two-week regimen offers a tolerableand active alternative to weekly or every-three-week single-agent CPT-11therapy.     

Phase I/II study of irinotecan, UFT and leucovorin with hepatic arterial infusion using 5-FU in colorectal cancer patients with unresectable liver metastases

Purpose

To evaluate the efficacy and tolerability of systemic chemotherapy with irinotecan (CPT-11), UFT and leucovorin (LV) combined with hepatic arterial infusion (HAI) consisting of 5-fluorouracil (5-FU) in colorectal cancer patients with unresectable liver metastases.

Methods

Patients were treated concurrently with escalating doses of intravenous CPT-11 (100, 120, and 140?mg/m²) on day 1 of each 14-day treatment cycle, with oral UFT (300?mg/m² per day) and LV (75?mg/body per day) on days 1?C7 of each cycle, and with HAI 5-FU (2,000?mg/week) on days 8?C14 of each cycle.

Results

Twelve patients were enrolled in the phase I study. The maximum-tolerated dose was not reached. Consequently, the recommended dose of CPT-11 for the phase II study was determined to be 140?mg/m². Twenty-two patients were evaluated in the phase II study. Five patients experienced grade 3 neutropenia, two experienced grade 3 anorexia, two experienced nausea, and two experienced vomiting. An overall response was observed in 19 out of 22 patients (86.4%). The median progression-free survival period was 11.2?months, and the 3-year survival rate was 50.6%. Fourteen patients (63.6%) were ultimately able to undergo a complete liver resection.

Conclusions

Chemotherapy with CPT-11 and UFT/LV combined with HAI yielded a high response rate and enabled a significant proportion of patients with initially unresectable liver metastases to undergo surgical resection. Further trials are warranted.     

A Phase 1 study of UCN-01 in combination with irinotecan in patients with resistant solid tumor malignancies

Purpose

UCN-01 (7-hydroxystaurosporine) is a multi-targeted protein kinase inhibitor that exhibits synergistic activity with DNA-damaging agents in preclinical studies. We conducted a Phase I study to determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetic, and pharmacodynamic effects of UCN-01 and irinotecan in patients with resistant solid tumors.

Experimental design

Patients received irinotecan (75?C125?mg/m² IV on days 1, 8, 15, 22) and UCN-01 (50?C90?mg/m² IV on day 2 and 25?C45?mg/m² on day 23 and subsequent doses) every 42?days. Blood for pharmacokinetics of UCN-01 and irinotecan, and blood, normal rectal mucosa, and tumor biopsies for pharmacodynamic studies were obtained.

Results

Twenty-five patients enrolled to 5 dose levels. The MTD was irinotecan 125?mg/m² on days 1, 8, 15, 22 and UCN-01 70?mg/m² on day 2 and 35?mg/m² on day 23. DLTs included grade 3 diarrhea/dehydration and dyspnea. UCN-01 had a prolonged half-life and a low clearance rate. There was a significant reduction in SN-38 C_max and aminopentanocarboxylic acid (APC) and SN-38 glucuronide half-lives. Phosphorylated ribosomal protein S6 was reduced in blood, normal rectal mucosa, and tumor biopsies at 24?h post-UCN-01. Two partial responses were observed in women with ER, PgR, and HER2-negative breast cancers (TBNC). Both tumors were defective for p53. Twelve patients had stable disease (mean duration 18?weeks, range 7?C30?weeks).

Conclusion

UCN-01 and irinotecan demonstrated acceptable toxicity and target inhibition. Anti-tumor activity was observed and a study of this combination in women with TNBC is underway.     

Phase I dose escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors

Purpose

This phase I study endeavored to estimate the maximum tolerated dose and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors.

Methods

Oral irinotecan was administered on days 1–5 and 8–12 with oral gefitinib (fixed dose, 150 mg/m²/day) on days 1–12 of a 21-day course. The escalation with overdose control method guided irinotecan dose escalation (7 dose levels, range 5–40 mg/m²/day).

Results

Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in ten patients. Diagnoses included osteosarcoma (N = 5), neuroblastoma (N = 3), sarcoma (N = 3), and others (N = 5). Patients received a median of two courses (range 1–20), with at least two patients treated on dose levels 2–7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N = 2 and hypophosphatemia, N = 1) at dose levels two (10 mg/m²) and four (20 mg/m²). One patient experienced grade 3 diarrhea (40 mg/m²). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib, while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35 mg/m²). Of 11 patients receiving at least two courses of therapy, three had stable disease lasting two to four courses and one patient maintained a complete response through 18 courses.

Conclusions

The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure.     

Usefulness of one-point plasma SN-38G/SN-38 concentration ratios as a substitute for UGT1A1 genetic information after irinotecan administration

Background

It was recently reported that genetic polymorphisms of UDP glucuronyltransferase-1 polypeptide A1 (UGT1A1), a glucuronidation enzyme, were associated with irinotecan (CPT-11) metabolism. The active metabolite of CPT-11, 7-ethyl-10-hydroxycamptothecin (SN-38) was glucuronidated (SN-38G) by UGT1A1. Genetic polymorphisms of UGT1A1 were associated with potentially serious adverse events, including neutropenia. Several studies have suggested that the dose of CPT-11 should be decreased in patients homozygous for UGT1A1*6 or UGT1A1*28, or double heterozygotes (*6/*28). However, the reference dose for patients with these genetic polymorphisms is unclear.

Methods

We investigated the relationship between the SN-38G/SN-38 concentration ratio and the dose of CPT-11 in 70 patients with colorectal cancer who received FOLFIRI-based regimens, by measuring the plasma concentrations of CPT-11, SN-38, and SN-38G.

Results

The SN-38G/SN-38 concentration ratio was lower in patients who were homozygous for UGT1A1*6, heterozygous for UGT1A1*6 or UGT1A1*28, or were double heterozygotes compared with patients with wild-type genes. The relative decreases in the SN-38G/SN-38 concentration ratio in patients homozygous for UGT1A1*6 and in double heterozygotes were greater than in patients heterozygous for UGT1A1*6 or UGT1A1*28. Interestingly, decreases in the SN-38G/SN-38 concentration ratio were associated with decreases in the neutrophil count and the final infusion dose of CPT-11.

Conclusion

Our results suggest that the SN-38G/SN-38 concentration ratio is an important factor for guiding dose adjustments, even in patients with wild-type genes. Therefore, the SN-38G/SN-38 concentration ratio, as an index of the patient’s metabolic capacity, is useful for assessing dose adjustments of CPT-11.     

Area under the curve calculation of nedaplatin dose used in combination chemotherapy with irinotecan in a phase I study of gynecologic malignancies

Purpose

Although the pharmacokinetic mechanism of nedaplatin (NDP) is similar to carboplatin, the dose of NDP is typically determined by body surface area and not by the area under the curve (AUC). We conducted a phase I study to determine the AUC-calculated optimal dosage of NDP used in combination chemotherapy with irinotecan (CPT-11) for gynecologic malignancies.

Methods

A total of 15 patients who were to undergo combination chemotherapy consisting of NDP and CPT-11 were enrolled in this study. The dose of CPT-11 was administered at a fixed dose of 60?mg/m² and that of NDP was gradually increased from 8 to 12???g?h/mL (AUC). The individual dose of NDP was calculated based on cratinine clearance of the patient according following formula: Dose_NDP?=?AUC?×?CL_NDP, where CL_NDP?=?0.0738?×?creatinine clearance?+?4.47 (Ishibashi??s formula).

Results

One patient had dose-limiting toxicity (DLT) at level 1, and two patients suffered DLT at level 3. The dosage of NDP at AUC 12 was determined to be the maximum tolerated dose in combination chemotherapy with CPT-11, even though only two of the six patients showed DLT at level 3.

Conclusions

The recommended dosage of NDP calculated by AUC with Ishibashi??s fomula was set to AUC 10 in combination chemotherapy with CPT-11.     

A phase I study of irinotecan and pegylated liposomal doxorubicin in recurrent ovarian cancer (Tohoku Gynecologic Cancer Unit 104 study)

Purpose

A phase I clinical study was conducted to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan hydrochloride (CPT-11) in CPT-11/pegylated liposomal doxorubicin (PLD) combination therapy, a novel treatment regimen for platinum- and taxane-resistant recurrent ovarian cancer.

Methods

Pegylated liposomal doxorubicin was administered intravenously on day 3 at a fixed dose of 30 mg/m². CPT-11 was administered intravenously on days 1 and 15, at a dose of 50 mg/m² on both days. One course of chemotherapy was 28 days, and patients were given a maximum of six courses, with the CPT-11 dose being increased in increments of 10 mg/m² (level 1, 50 mg/m²; level 2, 60 mg/m²; level 3, 70 mg/m²; level 4, 80 mg/m²) to determine MTD and RD.

Results

During the period from April 2010 to March 2013, three patients were enrolled for each level. In the first course, no dose-limiting toxicity occurred in any of the patients. Grade 4 neutropenia was observed in two of three patients at level 4. At level 4, the antitumor effect was a partial response (PR) in two of the three patients and stable disease (SD) in one. At level 3, one of the three patients showed PR and two had SD. At level 4, the start of the next course was postponed in two of three patients. In addition, one patient at level 4 experienced hemotoxicity that met the criteria for dose reduction in the next course. The above results suggested that administration of CPT-11 at dose level 5 (90 mg/m²) would result in more patients with severe neutropenia and in more patients requiring postponement of the next course or a dose reduction. Based on the above, the RD of CPT-11 was determined to be 80 mg/m².

Conclusions

The results suggest that CPT-11/PLD combination therapy for recurrent ovarian cancer is a useful treatment method with a high response rate and manageable adverse reactions. In the future phase II study, the safety and efficacy of this therapy will be assessed at 80 mg/m² of CPT-11 and 30 mg/m² of PLD.     

Pharmacokinetics of irinotecan and its metabolites in human blood,bile, and urine

Two patients were treated with CPT-11 for colorectal cancer and had a percutaneous biliary catheter for extrahepatic biliary obstruction. The first patient was treated with CPT-11 according to the 100-mg/m² weekly therapeutic schedule, and the second patient was treated every 3 weeks, with a dose of 350 mg/m² being given at the first course, after which it was decreased to 300 mg/m² for the following courses. In plasma, the active identified metabolite of CPT-11, SN-38, occurred mainly in the form of a glucuronide conjugate. CPT-11 was mainly excreted in bile and urine as CPT-11. The cumulative biliary and urinary excretion of CPT-11 and its metabolites (SN-38 and SN-38 glucuronide conjugate) over a period of up to 48 h ranged from 25% (100 mg/m² weekly) to 50% (300 mg/m² every 3 weeks). This means that CPT-11 can be excreted under other, not yet identified metabolite forms. CPT-11 is active in vivo, the intensity of its in vitro activity seems rather low. It has been suggested that its major identified metabolite, 7-ethyl-10-hydroxycamptothecin (SN-38) plays a key role in the antitumor activity of CPT-11 [4]. Some in vitro data suggest that SN-38 is 250-to 1,000-fold as potent as CPT-11 in the inhibition of topoisomerase I activity [5]. Although a glucuronide of SN-38 has been found in the bile and urine of rats [3], data have not been reported on humans. However, only Rothenberg et al. [10] have studies the bile concentrations of CPT-11 and SN-38. This report summarizes the pharmacokinetics of CPT-11 and SN-38 and their glucuronide metabolites in the blood, bile, and urine of two patients treated with CPT-11.     

Phase I trial of dose escalation of capecitabine combined with fixed docetaxel in previously treated patients with non-small cell lung cancer

Objective

Capecitabine combined with docetaxel have demonstrated antitumor synergy for non-small cell lung cancer (NSCLC). Due to absence of phase I trial in China, we conducted this study to define the maximum-tolerated dose (MTD) of capecitabine with fixed docetaxel for Chinese patients with previously treated NSCLC.

Methods

Previously treated patients with NSCLC were entered into this study. Escalating doses of capecitabine with fixed docetaxel were administered in a modified Fibonacci sequence. The initial doses were capecitabine 625 mg/m², bid, on days d5?Cd18, and docetaxel 30 mg/m² on days 1 and 8, respectively. The regimen was repeated every 21 days. If no dose-limiting toxicity (DLT) was observed, the next dose level was applied. The procedures were repeated until DLT appeared. The MTD was declared to be one dose level below the level at which DLT appeared.

Results

Eighteen patients received 67 cycles at capecitabine of level I (1250 mg/m², divided into 625 mg/m², bid) and level II (1500 mg/m², 750 mg/m², bid). The most common toxicities were neutropenia, hand and feet syndrome, fatigue and nausea. Eight DLTs occurred in 5 patients in the whole group, including 1 DLT in dose level I and 7 DLTs in dose level 2. Since 4 of 6 patients in level II experienced DLTs, we declared thus level I was MTD.

Conclusion

MTD of our phase I trial was capecitabine of 1250 mg/m²/d combined with docetaxel of 30 mg/m²/wk. This combination regimen was well tolerated for previously treated patients with NSCLC. The efficacy of this schedule is currently being further evaluated in a prospective phase II trial.     

A phase I and pharmacokinetic study of elisidepsin (PM02734) in patients with advanced solid tumors

Purpose

To determine the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), and recommended phase II dose (RD) of elisidepsin.

Methods

Eligible patients with refractory, advanced solid tumors received elisidepsin as 24-h intravenous infusion every 3?weeks. Pharmacokinetic profiles were analyzed during cycles 1 and 2.

Results

Forty-two patients received elisidepsin at doses from 0.5 to 6.8?mg/m². The MTD was 6.8?mg/m², and the RD was 5.5?mg/m². Cohort expansion at the RD was done at a fixed dose (FD) of 10?mg, considered equivalent to 5.5?mg/m². DLTs (reversible grade 3 transaminase increases) occurred at 6.8?mg/m² (n?=?2 patients), 5.5?mg/m² (n?=?1), and 10?mg FD (n?=?1). One patient with esophageal adenocarcinoma achieved complete response for >38?months, and 12 patients had disease stabilization (8 for ≥3?months). Median time-to-progression for these 12 patients was 4.8?months. Plasma elisidepsin concentrations increased with dose. No drug accumulation between cycles was found. No correlation was observed between body surface area (BSA) and plasma clearance; therefore, elisidepsin was given as flat dose (in mg) in the expansion cohort at the RD and in ongoing clinical trials.

Conclusions

Elisidepsin is well tolerated with predictable reversible transaminase increases. Encouraging preliminary evidence of antitumor activity was observed.     

Phase I study of 3-weekly combination chemotherapy using epirubicin, oxaliplatin, and S-1 (EOS) in patients with previously untreated advanced gastric cancer

Purpose

This study was performed to determine the recommended dose (RD) and dose-limiting toxicity (DLT) associated with epirubicin, oxaliplatin, and S-1 (EOS) combination therapy in patients with previously untreated advanced gastric cancer (AGC).

Materials and methods

Previously untreated patients with histologically proven metastatic AGC, with an ECOG performance status of 0?C2, were enrolled in this study. A fixed dose of epirubicin (50?mg/m²) and oxaliplatin (130?mg/m²) was intravenously administered on day 1 of treatment, followed by oral S-1 administration twice daily on days 1?C14. The S-1 dose was escalated according to the following schedule: level I, 35?mg/m²; level II, 40?mg/m²; level III, 45?mg/m²; Level IV, 50?mg/m². Each cycle was repeated every 21?days. DLTs were evaluated during the first two cycles of treatment.

Results

Nineteen patients with a median age of 53?years (range, 40?C71?years) were enrolled in this study. One case of DLT (grade 4 neutropenia lasting more than 5?days) developed from among the six dose level II patients, while 2 DLTs (grade 3 diarrhea and nausea) were observed among the 4 dose level III patients. Based on these results, dose level II was determined as the RD. Of the 13 patients with measurable lesions, eight achieved partial response, three showed stable disease, and the objective response rate was 61.5?% (95?% confidence interval (CI), 13.3?C66.6?%). The median progression-free survival and overall survival of all patients was 6.8?months (95?% CI, 1.4?C9.5?months) and 13.3?months (95?% CI, 1.9?C24.6?months), respectively.

Conclusion

The RD of the EOS regimen in patients with previously untreated AGC was 50?mg/m² of epirubicin and 130?mg/m² of oxaliplatin on day 1, with administration of 40?mg/m² of S-1 twice a day on days 1?C14 for each 21-day cycle. The EOS regimen described produced promising results.     

A phase I study of S-1 and irinotecan combination therapy in previously treated advanced non-small cell lung cancer patients

Background

This phase I study was conducted to evaluate the feasibility and to determine the recommended doses of the combination therapy of S-1 and irinotecan (CPT-11) in patients with advanced non-small cell lung cancer (NSCLC) as second-line treatment.

Methods

Patients with NSCLC who were previously treated with one chemotherapy regimen and had a performance status of 0 or 1 were eligible. CPT-11 was administered at 60 mg/m² (level 1), 80 mg/m² (level 2) on days 1 and 8, and oral S-1 was administered at 80 mg/day for body surface area (BSA) less than 1.25 m², 100 mg/day for BSA 1.25–1.5 m², and 120 mg/day for BSA more than 1.5 m² on days 1–14 every 3 weeks. The dose-limiting toxicity (DLT) was defined as grade 4 leukocytopenia or neutropenia, grade ≥3 neutropenia with fever over 38°C, grade ≥3 thrombocytopenia, or grade ≥3 major nonhematological toxicities.

Results

Nine patients were enrolled in the study. None of 3 patients enrolled in level 1 had any DLT. Of 6 patients in level 2, 2 patients had grade 3 diarrhea and one had grade 3 interstitial pneumonia. Level 1 was declared as the recommended dose.

Conclusion

The feasibility of the combination therapy of S-1 and CPT-11 was shown in the second-line setting for the treatment of advanced NSCLC. The recommended dose of CPT-11 was 60 mg/m² combined with standard dose of S-1 for phase II trials of pretreated advanced NSCLC patients.     

Down-regulation of lipids transporter ABCA1 increases the cytotoxicity of Nitidine

Purpose

This study examined the pharmacokinetics of irinotecan (CPT-11), active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38), SN-38 glucuronide (SN-38G) amrubicin (AMR), and active metabolite amrubicinol (AMR-OH) after intravenous administration of this combination therapy in rats.

Methods

Male Sprague-Dawley rats were treated with 10 mg/kg CPT-11 with 10 mg/kg AMR. AMR, AMR-OH, CPT-11, SN-38 and SN-38G were measured in plasma, bile, and tissues using high-performance liquid chromatography.

Results

Co-administration of CPT-11 resulted in a significant decrease in plasma concentrations and area under the curves (AUC) of AMR-OH compared with treatment with AMR alone. On the other hand, co-administration of AMR resulted in a slight increase in the initial plasma concentration of SN-38; however, there were no differences in AUC values in CPT-11 and SN-38. The cumulative biliary excretion curves of AMR, CPT-11, and their active metabolites were not changed. CPT-11 inhibited the conversion of AMR to AMR-OH in rat cytosolic fractions.

Conclusions

CPT-11 did not affect the pharmacokinetic of AMR but decreased the plasma concentration of AMR-OH and might affect the formation of AMR-OH from AMR in hepatocytes.     

Phase I and pharmacokinetic study of irinotecan (CPT-11) administered daily for three consecutive days every three weeks in patients with advanced solid tumors

BACKGROUND: We conducted a phase I and pharmacokinetic study to determinethe maximum tolerable dose (MTD), toxicities, pharmacokineticprofile, and antitumor activity of Irinotecan (CPT-11) in patientswith refractory solid malignancies. PATIENTS AND METHODS: Forty-six patients were entered in this phase I study. CPT-11was administered intravenously over 30 minutes for 3 consecutivedays every 3 weeks. Dose levels ranged from 33 mg/m²/day to115 mg/m²/day on days 1 through 3. The pharmacokinetics of totalCPT-11 and its active metabolite SN-38 were assayed by HPLC. RESULTS: The combination of leukopenia and diarrhea was dose-limitingtoxicity at 115 mg/m²/day dose level, since 50% of the patients(5/10) experienced either grade 3–4 leukopenia, or diarrhea,or both. Leukopenia appeared to be a cumulative toxicity, witha global increase in its incidence and severity upon repeatedadministration of CPT-11. Other toxicities included nausea,vomiting, fatigue and alopecia. CPT-11 and active metaboliteSN-38 inetics were determined in 21 patients (29 courses). BothCPT-11 and SN-38 pharmacokinetics presented a high interpatientvariability. CPT-11 mean maximum plasma concentrations reached2034 ng/ml at the MTD (115 mg/m²). The terminal-phase half-lifewas 8.3 h and the mean residence time 10.2 h. The mean volumeof distribution at steady state was 141 l/m²/h. CPT-11 reboundconcentrations were observed in many courses at about 0.5 to1 hour following the end of the i.v. infusion, which is suggestiveof enterohepatic recycling. Total body clearance did not varywith increased dosage (mean=14.3 l/h/m²), indicating linearpharmacokinetics within the dose range administered in thistrial. The total area under the plasma concentration versustime curve (AUC) increased proportionally to the CPT-11 dose.Mean metabolite SN-38 peak levels reached 41 ng/ml at the MTD.A significant correlation was observed between CPT-11 area underthe curve (AUC) and its corresponding metabolite SN-38 AUC (r=0.52,p < 0.05). S-38 rebound concentrations were observed in manycourses at about 0.5 to 1 hour following the end of the i.v.infusion, which is suggestive of enterohepatic recycling. Mean24-h urinary excretion of CPT-11 accounted for 10% of the administereddose by the third day, whereas SN-38 urinary excretion accountedfor 0.18% of the CPT-11 dose. In this phase I trial, the hemato-logicaltoxicity correlated with neither CPT-11 nor SN-38 AUC. Diarrheagrade correlated significantly with CPT-11 AUC. Two partial(breast adenocarcinoma and carcinoma of unknown primary) and2 minor (hepatocarcinoma and pancreatic adenocarcinoma) responseswere observed. CONCLUSION: The MTD for CPT-11 administered in a 3 consecutive-days-every-3weeks schedule in this patient population is 115 mg/m²/day.The recommended dose for phase II studies is 100 mg/m²/day. CPT-11, camptothecin analogue, topoisomerase I inhibitor, phase I, pharmacokinetics     

Phase I/II study of intraperitoneal docetaxel plus S-1 for the gastric cancer patients with peritoneal carcinomatosis

Purpose

We designed a phase I/II trial of intraperitoneal (IP) docetaxel plus S-1 to determine the maximum tolerated dose (MTD) and recommended dose (RD) and to evaluate its efficacy and safety in gastric cancer patients with peritoneal carcinomatosis (PC).

Methods

Patients with PC confirmed by laparoscopy or laparotomy received IP docetaxel on days 1 and 15 and S-1 (80 mg/m²) on days 1–14 every 4 weeks.

Results

In the phase I part (n = 12), each cohort received escalating doses of docetaxel (35–50 mg/m²); the MTD was determined to be 50 mg/m² and the RD was determined to be 45 mg/m². Dose-limiting toxicities included grade 3 febrile neutropenia and grade 3 diarrhea. In the phase II part (n = 27), the median number of courses was 4 (range 2–11). The 1-year overall survival (OS) rate was 70 % (95 % confidence interval 53–87 %). The overall response rate was 22 % and peritoneal cytology turned negative in 18 of 22 (81 %) patients. The most frequent grade 3/4 toxicities included anorexia (19 %), neutropenia (7 %), and leukopenia (7 %).

Conclusion

IP docetaxel plus S-1 is active and safety in gastric cancer patients with PC.     

Effects of bevacizumab on plasma concentration of irinotecan and its metabolites in advanced colorectal cancer patients receiving FOLFIRI with bevacizumab as second-line chemotherapy

Purpose

Bevacizumab (BV) prolongs the survival of colorectal cancer patients when combined with irinotecan (CPT-11)-based regimens. In the AVF2107g study, the area under the curve (AUC) ratio for bolus CPT-11/5-fluorouracil (5-FU)/leucovorin (LV) (IFL) with the BV arm to bolus IFL with placebo indicated that SN-38 concentrations may have been increased in subjects receiving BV. However, the mechanism underlying such increase remains unclear, and the difference might be caused by an imbalance between the two arms and a possible inter-subject variability of CPT-11 metabolism. Within-subject comparisons were used to evaluate the effect of BV on advanced colorectal cancer patients when administered with the FOLFIRI regimen as second-line chemotherapy.

Methods

Ten advanced colorectal cancer patients received the FOLFIRI regimen every 2 weeks. At cycle 1, BV was administered following FOLFIRI administration to allow baseline pharmacokinetic (PK) analysis of CPT-11 and its metabolites. From cycle 2, BV was administered just before FOLFIRI administration. Plasma samples were collected under the same condition (at cycle 3).

Results

There were no significant differences in the C _max and AUC_0-∞ of CPT-11, SN-38, and SN-38G between cycle 1 (without BV) and cycle 3 (with BV). PK parameters of CPT-11, SN-38, and SN-38G were not significantly affected by BV. There were no significant differences in the changes in the AUC ratio of CPT-11 to SN-38 between cycles 1 and 3, as well as in the ratio of SN-38 to SN-38G.

Conclusion

BV does not affect the plasma concentration of CPT-11 and its metabolites on FOLFIRI regimen.     

Phase I study of 3-weekly docetaxel, capecitabine and oxaliplatin combination chemotherapy in patients with previously untreated advanced gastric cancer

Purpose

Adding docetaxel to cisplatin and 5-fluorouracil (5-FU) (DCF) significantly improved clinical efficacy in advanced gastric cancer (AGC). To further improve the efficacy and tolerability, we substituted oxaliplatin for cisplatin and capecitabine for 5-FU in the DCF regimen and performed a phase I study to determine the recommended dose (RD) and dose-limiting toxicity (DLT) of docetaxel, capecitabine and oxaliplatin (DXO) combination in patients with AGC.

Materials and methods

Previously untreated patients with histologically proven metastatic AGC and ECOG performance status 0–2 were enrolled. Docetaxel and oxaliplatin were administered i.v. on day 1. Capecitabine was administered orally bid on days 1–14. Each cycle was repeated every 3 weeks. DLTs were evaluated during the first two cycles of treatment.

Results

Twenty-one patients were enrolled: 15 patients in dose-escalation phase and 6 patients in the extension at the RD. Median age was 50 years (range 21–65 years). At dose level 3 (60 mg/m² docetaxel, 1,000 mg/m² capecitabine, 100 mg/m² oxaliplatin), 1 diarrhea (DLT) was found among 6 patients while at dose level 4 (60 mg/m² docetaxel, 800 mg/m² capecitabine, 130 mg/m² oxaliplatin), 2 DLTs (febrile neutropenia and diarrhea) were observed among 3 patients. Therefore, the dose level 3 was determined as RD. DLTs include grade 3 diarrhea and febrile neutropenia. Cumulative (all cycles) grade 3/4 toxicity included neutropenia (75%), leucopenia (50%), febrile neutropenia (25%), diarrhea (17%), and neuropathy (17%). Of 14 patients with measurable lesions, 11 achieved partial response and 3 showed stable disease.

Conclusion

The RD of the DXO regimen in patients with AGC is capecitabine 1,000 mg/m² twice daily on days 1–14, in combination with decetaxel 60 mg/m² (day 1) and oxaliplatin 100 mg/m² (day 1) repeated every 3 weeks. The DXO regimen seems to have promising activity and offers an easy alternative to DCF. The toxicities appear to be still substantial, but manageable.     

A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy

Background

The aim of this study was to evaluate the efficacy of irinotecan (CPT-11) monotherapy and CPT-11 plus 5-fluorouracil (5-FU)/leucovorin (LV) combination (mFOLFIRI) as second-line treatment in patients with advanced gastric cancer (AGC).

Methods

A total of 59 patients were randomly assigned to either CPT-11 (150 mg/m² iv on day 1) or mFOLFIRI (CPT-11 150 mg/m² plus LV 20 mg/m² on day 1 followed by 5-FU 2,000 mg/m² over 48 h), every 2 weeks. The primary end point was objective response rate (ORR).

Results

Following random assignment, 29 patients received CPT-11 and 30 patients mFOLFIRI. The ORR was 17.2 % [95 % confidence interval (CI) 3.4–30.9] and 20.0 % (95 % CI 5.6–34.3) for the CPT-11 and mFOLFIRI arms, respectively (P = 0.525). There was no significant difference in median progression-free survival: 2.2 months (95 % CI 0.2–4.3) for CPT-11 versus 3.0 months (95 % CI 2.0–3.7) for mFOLFIRI (P = 0.481) or in median overall survival: 5.8 months (95 % CI 3.0–8.7), compared with 6.7 months (95 % CI 5.3–8.2) (P = 0.514). Grade 3/4 toxicity was observed in 21 and 28 events in the CPT-11 and mFOLFIRI arms, respectively.

Conclusions

Although this study had a small sample size and limited statistical power, CPT-11 monotherapy and mFOLFIRI appear to be equally active and tolerable as second-line chemotherapy for AGC. The addition of 5-FU/LV to CPT-11 did not significantly improve efficacy.