Scheduled administration of low dose irinotecan before gemcitabine in the second line therapy of non-small cell lung cancer: a phase II study.

We had previously demonstrated that low dose irinotecan (CPT-11) leads to increased accumulation of cells in S-phase and shows a therapeutic synergy with S-phase specific chemotherapy such as gemcitabine and 5-fluorouracil. In this phase II study, our objectives were to evaluate the tolerability and activity of low dose CPT-11 followed 24 h later by gemcitabine as second line therapy in patients with metastatic non-small cell lung cancer (NSCLC). CPT-11 (60 mg/m) was administered 24 h before gemcitabine (1000 mg/m) on days 1, 2, 8, and 9 every 3 weeks. Twenty-nine patients were evaluable for response. The median follow-up was 7.4 months. Partial response (PR) was seen in two (6.9, 95% confidence interval (CI): 0.009-0.228). PR and stable disease were seen in 22 patients (75.9, 95% CI: 0.564-0.897). The median survival time was 13.8 months (95% CI: 8.1-19.3). The median time to progression was 4.6 months (95% CI: 2.6-6.2). Thirty-eight patients were evaluable for toxicity. Neutropenia (grade 3 or 4) was observed in 27 patients (71%). Eight patients did not receive cycle 2 of therapy owing to prolonged neutropenia. No treatment-related deaths occurred. Scheduled administration of low dose CPT-11, 24 h before gemcitabine in the second line therapy of NSCLC yielded comparable disease control rates (PR and stable disease) when compared with other studies using the two chemotherapy drugs in the traditional sequence. However, this approach was associated with higher grade 3/4 neutropenia and is not recommended for further study in metastatic NSCLC.

A Phase I and pharmacokinetic study of selenomethionine in combination with a fixed dose of irinotecan in solid tumors.

PURPOSE: We conducted a phase I study to determine the recommended dose of selenomethionine (SLM) in combination with irinotecan that consistently results in a protective plasma selenium (Se) concentrations > 15 microM after 1 week of SLM loading. EXPERIMENTAL DESIGN: A 3-3 standard escalation design was followed. SLM was given orally twice daily (BID) for one week (loading) followed by continuous once daily (QD) dosing (maintenance). Seven dose levels of selenomethionine were investigated. Irinotecan was given intravenously at a fixed standard weekly dose, starting on the first day of maintenance SLM. RESULTS: Thirty-one patients were treated on study. Dose limiting diarrhea complicated by sepsis was noted in one of six patients at each of the dose-levels 1 and 7. Dose-levels > or = 5 (4,800 mcg/dose loading maintenance) resulted in day 8 Se concentrations >15 microM while dose-level 7 (7,200 mcg/dose loading and maintenance) resulted in day 8 Se concentrations > 20 muM. No significant variations in SN-38 or biliary index were noted between weeks 1 and 4 of treatment. Despite achieving target Se concentrations, gastrointestinal and bone marrow toxicities were common and irinotecan dose modification was prevalent. Objective responses were seen in two patients and nine patients had disease control for 6 months or longer. CONCLUSIONS: Selenomethionine can be escalated safely to 7,200 mcg BID x 1 week followed by 7,200 mcg QD in combination with a standard dose of irinotecan. No major protection against irinotecan toxicity was established; however, interesting clinical benefits were noted-supporting the investigation of this combination in future efficacy trials.

A phase I pharmacokinetic and pharmacodynamic study of s-3304, a novel matrix metalloproteinase inhibitor, in patients with advanced and refractory solid tumors.

PURPOSE: Matrix metalloproteinases (MMP) play a fundamental role in cancer development and progression. S-3304 is a potent, orally active, noncytotoxic inhibitor of MMPs, primarily MMP-2 and MMP-9, that prolongs survival in mice xenografts and is well tolerated in healthy volunteers. EXPERIMENTAL DESIGN: The aims of this phase I clinical trial were to determine the maximum tolerated dose, dose-limiting toxicities, pharmacokinetic profile, and intratumoral MMP inhibitory activity of single-agent S-3304 in advanced and refractory solid tumors. MMP activity was determined by film in situ zymography (FIZ). Patients had tumor biopsies before and after S-3304 administration and were also evaluated for response and survival. RESULTS: Four dose levels were explored [DL1-DL4 or 800, 1,600, 2,400, and 3200 mg twice daily (BID), respectively], and 32 patients were enrolled. Toxicities were mostly gastrointestinal. The maximum tolerated dose was not reached, but dose escalations beyond DL4 were impractical (number of capsules needed). S-3304 steady-state concentrations were reached by day 8, and day 1 mean C(max) and AUC(0-8) increases were less than dose proportional. After S-3304 administration, 17 of 18 patients experienced inhibition of MMP activity by FIZ. Strong mean inhibition of MMP activity was observed in DL1 to DL3. The negative mean inhibitory activity calculated for DL4 was due to one patient with a 397% MMP activity increase. CONCLUSION: S-3304 is safe, well tolerated, and achieves plasma concentrations above those required to inhibit MMP-2 and MMP-9. Its intratumoral MMP inhibitory activity has been shown using FIZ, which is useful as a biomarker with this and other MMP inhibitors.

Celecoxib and mucosal protection: translation from an animal model to a phase I clinical trial of celecoxib, irinotecan, and 5-fluorouracil.

PURPOSE: Chemotherapy-induced diarrhea occurs secondary to mucosal inflammation and may be cyclooxygenase-2 mediated. Cyclooxygenase-2 inhibitors may ameliorate chemotherapy-induced mucosal toxicity and enhance its antitumor effect. We investigated this hypothesis in the Ward colorectal cancer rat model and in a phase I clinical study. EXPERIMENTAL DESIGN: In the Ward rat model, irinotecan was given daily x 3 or weekly x 4 with or without celecoxib. In the phase I clinical study, we planned to escalate the dose of irinotecan in the FOLFIRI regimen (irinotecan, 5-fluorouracil, and leucovorin) with a fixed dose of celecoxib. Irinotecan was escalated in four dose levels: 180, 200, 220, and 260 mg/m2. Celecoxib was administered as 400 mg, twice daily starting on day 2 of cycle 1. Pharmacokinetics of irinotecan, SN-38, and SN-38G were obtained on days 1 and 14. A standard 3+3 dose escalation scheme was used. Plasma concentrations of irinotecan, SN-38, and SN-38G were measured using high-pressure liquid chromatography. RESULTS: Celecoxib ameliorated diarrhea, weight loss, and lethality and resulted in synergistic antitumor effect in the rat model. Twelve patients with advanced cancers were enrolled and evaluable for dose-limiting toxicity (DLT). Diarrhea was the cause for discontinuation in one. Grade 2 and 3 diarrhea occurred in three and two patients, respectively. One patient had DLT at dose level 2 (grade 3 diarrhea). Two had a DLT at DL3 (G3 emesis and myocardial infarct). Celecoxib had limited influence on the pharmacokinetics of irinotecan in this data set. CONCLUSIONS: Maximum tolerated dose of irinotecan in FOLFIRI schedule with celecoxib is 200 mg/m2.

A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors.

PURPOSE: In preclinical models, calcitriol and the tyrosine kinase inhibitor gefitinib are synergistic and modulate extracellular signal-regulated kinase (Erk) and Akt pathways. Therefore, we conducted a phase I study of calcitriol and gefitinib to determine the maximum tolerated dose (MTD) of this combination. EXPERIMENTAL DESIGN: Calcitriol was given i.v. over 1 h on weeks 1, 3, and weekly thereafter. Gefitinib was given at a fixed oral daily dose of 250 mg starting at week 2 (day 8). Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for calcitriol and gefitinib. Serial skin biopsies were done to investigate epidermal growth factor receptor (EGFR) pathway pharmacodynamic interactions. RESULTS: Thirty-two patients were treated. Dose-limiting hypercalcemia was noted in two of four patients receiving 96 mug/wk of calcitriol. One of seven patients developed dose-limiting hypercalcemia at the MTD 74 mug/wk calcitriol dose level. The relationship between calcitriol dose and peak serum calcitriol (C(max)) and systemic exposure (AUC) was linear. Mean (+/-SD) serum calcitriol C(max) at the MTD was 6.68 +/- 1.42 ng/mL. Gefitinib treatment inhibited EGFR, Akt, and Erk phosphorylation in the skin. Calcitriol did not have consistent effects on skin EGFR or its downstream elements. The combination of gefitinib and calcitriol did not modulate tumor EGFR pathway in patients with serial tumor biopsies. CONCLUSIONS: High doses of weekly i.v. calcitriol can be administered safely in combination with gefitinib. Calcitriol concentrations achieved at the MTD 74 mug calcitriol exceed in vivo concentrations associated with antitumor activity in preclinical models.

A phase I and pharmacokinetic study of fixed-dose selenomethionine and irinotecan in solid tumors.

PURPOSE: We conducted a phase I study to determine the maximum tolerated dose (MTD) of irinotecan with fixed, nontoxic high dose of selenomethionine. EXPERIMENTAL DESIGN: Selenomethionine was given orally as a single daily dose containing 2,200 mug of elemental selenium (Se) starting 1 week before the first dose of irinotecan. Irinotecan was given i.v. once weekly x 4 every 6 weeks (one cycle). The starting dose of irinotecan was 125 mg/m(2)/wk. Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for selenium and irinotecan and its metabolites. RESULTS: Three of four evaluable patients at dose level 2 of irinotecan (160 mg/m(2)/wk) had a dose-limiting diarrhea. None of the six evaluable patients at dose level 1 (125 mg/m(2)/wk irinotecan) had a dose-limiting toxicity. One patient with history of irinotecan-refractory colon cancer achieved a partial response. The long half-life of selenium resulted in a prolonged accumulation towards steady-state concentrations. No significant changes in the pharmacokinetics of CPT-11, SN-38, or SN-38G were identified; however, the coadministration of selenomethionine significantly reduced the irinotecan biliary index, which has been associated with gastrointestinal toxicity. CONCLUSIONS: Selenomethionine at 2,200 mug/d did not allow the safe escalation of irinotecan beyond the previously defined MTD of 125 mg/m(2). None of the patients receiving 125 mg/m(2) of irinotecan had grade >2 diarrhea. Unexpected responses and disease stabilizations were noted in a highly refractory population. Further escalation of selenomethionine is recommended in future trials to achieve defined protective serum concentrations of selenium.

Phase I and pharmacokinetic study of weekly docetaxel, cisplatin, and daily capecitabine in patients with advanced solid tumors.

PURPOSE: Docetaxel, cisplatin, and capecitabine are three active chemotherapeutic agents with different mechanisms of action. This phase I study investigated the feasibility and pharmacokinetics of this combination given on a weekly schedule. EXPERIMENTAL DESIGN: Docetaxel and cisplatin were given i.v. over 30 minutes on days 1 and 8 and capecitabine was given orally bid on days 1 to 14 (every 21 days). Escalation occurred in cohorts of three patients until the maximum tolerated dose was defined. Pharmacokinetics studies of docetaxel and total and ultrafiltrate platinum after cisplatin administration were done on cycle 1 (with capecitabine) and cycle 2 (without capecitabine). RESULTS: Twenty-five patients were enrolled. Two of six patients at dose level 5 had a dose-limiting infection and diarrhea. One of six evaluable patients at dose level 4 (27 mg/m2 docetaxel, 27 mg/m2 cisplatin, 825 mg/m2 capecitabine) had a dose-limiting hypomagnesemia. Pharmacokinetics of docetaxel were similar on cycles 1 and 2. Area under the plasma concentrations versus time curves of total platinum was significantly greater in cycle 2 compared with cycle 1 (P = 0.001). There was no difference in the disposition of docetaxel on cycles 1 and 2. CONCLUSIONS: The recommended docetaxel, cisplatin, and capecitabine dose for phase II studies is 27/27/825 mg/m2. The alteration in total and ultrafiltrate platinum disposition on cycle 2 compared with cycle 1 may be inherent to sequential cisplatin administration; however, prior treatment with capecitabine cannot be ruled out as a factor.

Matrix metalloproteinase inhibitors.

Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are associated with the tumorigenic process. MMPs degrade the extracellular matrix, promoting tumor invasion and metastasis. They also regulate host defense mechanisms and normal cell function; blocking all MMPs may not lead to a positive therapeutic outcome. Most clinical trials of MMP inhibitors (MMPIs) have yielded disappointing results, perhaps due to inappropriate study design or tumor staging, or to lack of selectivity. Positive results have been seen in gastric cancer with marimastat and in Kaposi's sarcoma with metastat. This review summarizes the current status of MMPIs.

Pharmacokinetics and pharmacodynamics of mesna-mediated plasma cysteine depletion.

Cellular glutathione (GSH) levels are related to the resistance of tumor cells to platinum and alkylating agents, and depletion of GSH may enhance the activity of these drugs. The pharmacodynamic effects of mesna on depleting plasma cysteine, a GSH precursor, were evaluated in 22 patients as part of a Phase I study. Escalating doses of ifosfamide and mesna were administered; carboplatin was administered to achieve an AUC of 4 mg x min/mL. Plasma samples were collected and assayed by reverse-phase high-performance liquid chromatography (HPLC) for total mesna and total cysteine concentrations at 0, 1, 3, 6, 24, 25, 28, and 48 hours. A one-compartment pharmacokinetic model was fit to the mesna plasma concentrations, using M.A.P. Bayesian estimation (ADAPT II). Pharmacodynamics were evaluated by fitting an inhibitory Emax model to the cysteine concentration data. Both the pharmacokinetic (median R2 = 0.95; range = 0.85-0.98) and pharmacodynamic (median R2 = 0.96; range = 0.74-1.0) models fit the data well. Mean (coefficient of variation [CV%]) mesna pharmacokinetic parameter estimates were as follows: Vss of 15.3 (29) L/m2, CL of 4.6 (29) L/h/m2, and half-life of 2.2 (37) hours. Mean (CV%) pharmacodynamic parameter estimates were as follows: Emax of 31.7 (19) microg/mL and EC50 of 10.3 (52) microg/mL. Mesna produced a rapid, concentration-dependent reduction in plasma cysteine concentrations that could be adequately characterized by an inhibitory Emax pharmacodynamic model. The depletion of plasma cysteine was facilitated by ifosfamide, suggesting a pharmacodynamic interaction between these two agents. Further increases in mesna doses beyond those administered in this study would be unlikely to provide additional benefit.

Phase I and pharmacokinetic study of anhydrovinblastine every 3 weeks in patients with refractory solid tumors.

PURPOSE: Anhydrovinblastine (AVLB) is a novel semisynthetic vinca alkaloid. We conducted a phase I trial to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and pharmacokinetics of AVLB given as a 1-h intravenous infusion once every 3 weeks in patients with advanced refractory solid tumors. PATIENTS AND METHODS: Entered into the study were 24 patients with normal bone marrow, hepatic and renal function, and of these 21 were evaluable. There were 12 males and 12 females with a median age of 60 years (range 27-75 years). Diagnoses were non-small-cell lung cancer (NSCLC) (11), colorectal cancer (5), soft tissue sarcoma (4), and miscellaneous (4). Patients had had a median of three prior chemotherapy regimens (range one to six). A total of 51 courses were administered at doses of 2.5, 5, 10, 16.5, 21, 25 and 30 mg/m(2) in one, three, one, three, six, six and one patient respectively. RESULTS: Grade 2 infusional hypertension, anemia, and dizziness were noted at 16.5 mg/m(2). At 25 mg/m(2), two of six evaluable patients had DLT. DLT was grade 4 constipation, neutropenia and grade 3 nausea/vomiting. At 21 mg/m(2) one of six evaluable patients had DLT (grade 3 nausea/vomiting). This dose was the MTD. Stable disease was noted in one patient with metastatic sarcoma to the lungs and in three patients with metastatic NSCLC. The pharmacokinetics of AVLB were linear, and well characterized by a two-compartment model, with a mean clearance of 26.4 l/h per m(2) and median terminal half-life of 18 h. CONCLUSIONS: The recommended phase II dose is 21 mg/m(2). A phase II study in NSCLC is being initiated.