Abstract
Background: The nucleoside 3’-c-ethynylcytidine (TAS-106) was designed to inhibit RNA synthesis which occurs throughout the cell cycle except for the M phase. TAS-106 is incorporated into cells, is rapidly phosphorylated to a monophosphate form, and is preferentially distributed into malignant cells. Preclinical studies showed that TAS-106 has a wide antitumor spectrum against human cancer xenografts. This phase I study was conducted in order to determine the recommended phase II dose of TAS-106 administered once per week for three consecutive weeks, every 28 days in patients with solid tumors. Patients and Methods: Patients were enrolled in cohorts of three, starting at 0.22 mg/m2/dose. Patients received at least two doses in order to be evaluable in each dose cohort. Dose escalation was stopped if two or more patients experienced dose limiting toxicity at any dose level. Results: In 20 evaluable patients, TAS-106 was given at the following dose levels (mg/m2/dose): 0.22 (3 pts), 0.33 (3 pts), 0.66 (3 pts), 0.99 (1 pt), 1.32 (3 pts), 2.64 (3 pts) and 3.96 (1 pt). Three additional patients were evaluated at 2.64 mg/m2/dose for further characterization of toxicity and safety. A total of 16 patients completed courses 1 and 2. All 21 patients enrolled experienced at least one adverse event. The AE attributed to the study drug was grade 2 peripheral neuropathy characterized by peripheral sensory neuropathy, numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes, and feet. Conclusion: Due to neurotoxicity the MTD was the 2.64 mg/m2/dose for the study schedule. No suggested phase II dose was determined. However, at the 1.32 mg/m2/dose level, no patients experienced DLTs during course 1 or 2. This could be further studied to determine its viability as a potential phase II dosage.
- TAS-106
- 3’-C-ethynylcytidine
- phase I
- solid malignancies
- nucleoside
- neurotoxicity
- pharmacokinetics
- pharmacodynamics
Most antineoplastic agents target the S phase of the cell cycle, during which DNA synthesis occurs. As a result, most current therapies are more active against rapidly growing tumors than slowly growing tumors. Thus, there is a strong rationale to develop drugs that affect mechanisms other than DNA synthesis. Utilizing molecular design methods to identify new anticancer agents that interfere with both DNA and RNA synthesis, the cellular metabolism of pyrimidines was identified as a target protein (1). Fluorinated pyrimidines and their derivatives, which are classified as metabolic antagonists, are commonly used in chemotherapy against cancer. 5-Fluorouracil (5-FU), which acts as a false-pyrimidine base, was originally thought to disrupt only DNA synthesis. However, it has actually been shown to have greater cytotoxic activity by inhibiting RNA synthesis through incorporation of fluorouridine triphosphate (FUTP) into the RNA strand and thereby inhibiting cellular growth (2).
The nucleoside 3’-C-ethnylcytidine (TAS-106) (Figure 1) was designed to inhibit RNA synthesis, since RNA synthesis occurs throughout the cell cycle except in the M phase (3). In a unique mechanism distinct from that of 5-FU, TAS-106 inhibits RNA synthesis by competitively blocking RNA polymerases I, II, and III (4, 5). This occurs by TAS-106 being incorporated into cells and rapidly phosphorylated to a monophosphate form by uridine/cytidine kinase, which is preferentially distributed in malignant cells, compared to normal cells (4). The monophosphate is then phosphorylated to the corresponding diphosphate and then to a triphosphate. The triphosphate, ethynylcytidine triphosphate, (ECTP) is the active metabolite that blocks RNA polymerase I, II, and III (6). TAS-106 also induces caspase-dependant apoptosis in solid tumor cells, and induces mitochondria-dependent apoptosis (7). TAS-106 is a novel nucleoside that inhibits RNA synthesis and is anticipated to become a beneficial anticancer agent. Preclinical studies have shown that TAS-106 has a wide and potent antitumor spectrum against human cancer xenografts (3, 8, 9).
The active metabolite of ECTP exhibits prolonged retention even after brief exposure to TAS-106. There is little or no inactivation of TAS-106 by enzymes involving pyrimidine nucleoside and nucleotide metabolism. Unchanged TAS-106 is the major drug-related substance excreted in both plasma and urine. Ethynyluridine was observed as a minor drug related metabolite. There is a high distribution of TAS-106 in tumor and glandular tissues, thymus, bone marrow, and excretion related organs (kidney, urinary bladder) one hour after administration (10).
This phase I clinical trial was conducted to determine the dose-limiting toxicity (DLT) and the recommended phase II dose of TAS-106 administered as a bolus intravenous infusion on a schedule of once per week for three consecutive weeks, every 28 days, in patients with solid tumors who were refractory to all standard of care treatment regimens for their tumor type. Based on preclinical studies in rats, dogs, and monkeys, the starting dose of TAS-106 in a prior phase I study of TAS-106 was 0.67 mg/m2/dose, administered intravenously once every 21 days (11). The 0.67 mg/m2 was one-third the maximum tolerated dose in the dog – intermittent dose study (11). The starting dose of TAS-106 for the current study was established as 0.22 mg/m2/dose, approximately one-third of the starting dose in the every 21 days regimen. This starting dose is an equivalent total dose per course (0.66 mg/m2/course) to the total dose per course of the TAS-106 starting dose used in the first phase I study. In that study, the principal DLT was a cumulative peripheral sensory neuropathy, and the weekly administration schedule in this study was designed to attenuate this anticipated neurotoxicity.
Patients and Methods
This was a phase I, open label, non-randomized dose-finding study of TAS-106 administered intravenously once per week for three consecutive weeks every 28 days. Cohorts of three patients were enrolled into each dose level starting at 0.22 mg/m2/dose, and followed for the occurrence of DLT. At each dose level, three patients could be enrolled simultaneously. If a DLT was observed in a cohort, the first patient entered at the subsequent dose level was observed for four weeks prior to enrollment of additional patients at that level. Doses were escalated by 100% increments until toxicity other than alopecia was encountered. If no toxicity was noted at any given dose, the dosage was increased by 100%. If a grade 2 or less toxicity was encountered, with the exception of grade 2 neurotoxicity, the dose was increased by 50%. If grade 3 or greater non-neurotoxicity or grade 2 or greater neurotoxicity was encountered, the dosage was increased by 25%.
At least three patients were required to complete two courses (eight weeks) at each dose level before dose escalation could occur in subsequent cohorts. If a DLT occurred in one of the three patients at any dose level, that dose cohort was expanded and an additional three patients were to be treated at that dose level. Dose escalation was to be stopped if DLTs occurred in two or more patients at any dose level. If two or more patients in a dose cohort experienced DLTs, the dose was de-escalated to the previous dose and that cohort expanded with at least three additional patients. The recommended phase II dose was defined as the highest dose level that did not cause a drug-related DLT in two or more out of six patients. A maximum of nine patients could be treated at one dose level below the dose that produced two or more DLTs. This allowed further characterization of that dose level and ensured that this dose level met the phase II dose selection criteria, before declaring it as the suggested phase II dose.
A minimum of two courses of therapy was required for patients to meet criteria to be evaluated for tumor response. However, patients with progressive disease following a single course of therapy were also considered evaluable for response. Patients who achieved stable disease, a partial or complete tumor response could continue TAS-106 for up to 6 months. Patients with a partial remission or no change in disease could continue until documentation of disease progression. Patients who experienced a significant toxicity, not ameliorated by dose reduction, were to be discontinued from study participation.
Patients. Patients who had a histological or cytological confirmed diagnosis of a solid tumor who had advanced or metastatic disease that was refractory to standard treatment or for which no standard therapy existed were eligible for the study. Patients were to be 18 years or older, have a life expectancy of at least 12 weeks, and a performance status of ≤2 on the Zubrod scale (12). Patients must not have received chemotherapy, immunotherapy, or radiotherapy for at least four weeks prior to entry in or during the study (six weeks for nitosureas or mitomycin). Patients were not allowed to take any other investigational drugs within 28 days prior to registration, nor while participating in this study.
To be eligible, patients had to have adequate liver and renal function defined as bilirubin ≤1.5 mg/dl and transaminase within two times the upper limit of normal (ULN) (except for patients with liver metastasis where transaminases were within 5 times ULN) and creatinine ≤1.5 mg/dl. Patients had to have an absolute granulocyte count ≥1,500/μl, platelet count ≥100,000/μl, and hemoglobin ≥9.0 g/dl.
Patients were excluded from the study if they had clinical signs of brain involvement or leptomeningeal disease, were pregnant or nursing, had serious illnesses (including, but not limited to congestive heart failure, angina pectoris, previous myocardial infarction, uncontrolled hypertension, arrhythmias), had active infection, unstable diabetes mellitus, interstitial pneumonitis, psychiatric disorder that may have interfered with consent and/or compliance, peripheral neuropathy, or if they had received concomitant treatment with drugs known to interact with TAS-106.
Patients were discontinued from the study due to disease progression, concurrent illness which precluded further therapy, development of toxicity which precluded further therapy, development of a greater than grade 2 neuropathy which persisted for more than two days beyond the next scheduled dose, patient refusal, or if the Investigator concluded that it was in the patient's best interest to discontinue. All patients gave written informed consent before study enrollment in accordance with federal and institutional guidelines.
Criteria for evaluation. Efficacy was determined by radiographic tumor response, duration of response, and by time to treatment failure. All measurable disease was to be recorded in centimeters as the measurement of the longest diameter and perpendicular diameter applied to the widest portions of the tumor recorded. Evaluable disease was defined as a lesion on physical examination or imaging that could be assessed with respect to changes but could not be clearly measured in two dimensions. Thus, patients who were excluded were those with elevated tumor markers, pleural effusion, lymphedema, or ascites as the only indicator of their disease. Tumor response was to be summarized by four categories of response: Complete response, disappearance of all clinical tumor evidence for at least 4 weeks, partial response, greater than 50% decreases in diameter of measured lesions with no new lesions for at least four weeks), no change, and progressive disease. The latter two were considered treatment failures. Efficacy was also based on duration of response and time to treatment. Response duration was measured from the time of response until evidence of progressive disease. Time to treatment failure was measured in responding patients.
Safety measurements included assessment of adverse events (AEs), laboratory tests (chemistry, hematology, and urinalysis), vital signs, electrocardiograms (ECGs), chest x-rays, physical examinations, detailed neurological assessment, neurobehavioral evaluation, and toxicity evaluations. Evaluable patients were patients who received at least one dose of study drug for at least two courses, or who experienced progressive disease following a single course of therapy. Toxicity was evaluated at each clinical evaluation, for each dose level and each course of therapy using the National Cancer Institute (NCI) Common Toxicity Grading Criteria (CTC) Version 2 (13). A detailed neurological examination was performed prior to every course. An AE was any unfavorable or unintended sign, symptom or disease temporally associated with the use of TAS-106, whether it was considered related to the drug or not. A serious AE was considered if it occurred within 30 days of the last dose of study drug, was associated with the drug, was life threatening, and resulted in death, in patient hospitalization or prolonged existing hospitalization, a persistent or significant disability or incapacity, or resulted in an important medical event defined to be jeopardizing to the patient or require interventions to prevent one of the aforementioned outcomes.
A DLT was defined as ≥CTC grade 3 non-hematological toxicity (excluding nausea/vomiting); ≥grade 3 nausea/vomiting uncontrolled by aggressive antiemetic support, grade 4 granulocytopenia lasting more than three days without GM-CSF, G-CSF, or febrile event (≥38.5°C) with ≥grade 3 granulocytopenia of any duration, or grade 4 thrombocytopenia; grade 3 granulocytopenia or grade 3 thrombo-cytopenia on a treatment day; grade 2 non-hematological toxicity which required a decrease in dose, or an unresolved toxicity that resulted in a longer than two-week delay from the next scheduled dose; or ≥grade 2 neurological toxicity observed during course 1 or 2.
Pharmacokinetics of TAS-106 was evaluated in patients who consented to participate in the pharmacokinetic portion of this study. Plasma samples were collected immediately before TAS-106 administration, and at 5, 15, 30 minutes and 1, 2, 4, 6, 8, 12 and 24 hours after the first dose on the first day the drug was given. Urine samples were collected prior to TAS-106 administration, and at 0-6, 6-12 and 12-24 hours on the first day the drug was given. The biospecimens were analyzed using a validated liquid chromatography-tandem mass spectrometric (LC-MS/MS) method with electro-spray ionization (14). TAS-106 and its stable isotope-labeled internal standard were extracted from the biological samples using a polymer-based cation-exchange cartridge, and were analyzed by LC-MS/MS in multiple reactions monitoring (MRM) mode. For the plasma concentration data, concentration at 5 minutes after administration (C5min), area under the concentration (AUC) curve up to infinity (AUC0-∞), total body clearance (CLtot), terminal half life time (t1/2), and the volume of distribution at steady state (Vdss) were calculated using WinNonlin version 3.1 (Pharsight Corporation, Cary, NC, USA). For the urine concentration data, cumulative amount of excreted TAS-106 was determined, and then renal clearance (CLr) was calculated from the ratio to AUC.
In order to explore the pharmocokinetic/pharmocodynamic (PK/PD) profile of TAS-106, the pharmacokinetic parameters C5min and AUC0-inf for TAS-106 were evaluated on course 1, day 1. Pharmacodynamic variables regarding bone marrow suppression (counts of granulocytes, WBC, platelets, and hemoglobin), neuropathy (maximum toxicity grade of neuropathy AEs) and skin toxicity (maximum toxicity grade of skin toxicity AEs) were evaluated by Spearman's rank correlation between PK parameters and the percentage change from the baseline or the maximum grade of AEs.
Results
A total of 21 patients were enrolled and treated in the study, and all 21 received at least one dose of the study drug. The median age of patients was 55.0 years. The majority of the patients were male (12, 57.1%) and Caucasian (16, 76.2%). Fifteen patients had a primary diagnosis of colorectal cancer, one had breast cancer, one had lung cancer, and four had a primary diagnosis of other cancer, which included two cases of pancreatic cancers, one of leiomyosarcoma, and one of carcinoma of the gall bladder (Table I). Patients had received between one and seven prior-chemotherapy regimens.
20 patients received the planned weekly doses for three weeks of TAS-106 therapy during course 1 and were considered evaluable. A total of 16 patients received course 1 and course 2. One patient received two doses of TAS-106, but therapy was discontinued due to rapid disease progression. Three patients, each were enrolled and treated at the 0.22 mg/m2/dose, 0.33 mg/m2/dose, and 0.66 mg/m2/dose (100% dose escalations). One patient was enrolled and treated in error at the 0.99 mg/m2/dose level. Subsequently, a cohort of three patients was enrolled and treated at the 1.32 mg/m2/dose. One patient was enrolled and treated at the 2.64 mg/m2/dose level, but due to AEs as a result of rapid disease progression, the patient was discontinued from the study after two doses. One patient was enrolled and treated at the 3.96 mg/m2/dose level (50% dose escalation), and that patient experienced grade 2 neuropathy and dose escalation was ceased. An additional cohort of three patients was enrolled and treated at the 2.64 mg/m2/dose level to fully characterize the safety profile of TAS-106 at this level. Two patients at this level experienced grade 2 neurotoxicity.
All 21 patients experienced at least one AE (Table II). The most common AEs were asthenia (10 patients, 47.6%), nausea (8 patients, 38.1%), and vomiting (7 patients, 33.3%). Four patients died during the study, but none of these deaths were considered to be related to the study drug. During the study, nine patients (42.9%) experienced serious AEs. One patient had a serious AE of death. The cause of death was determined to be cancer related, and not related to TAS-106. Three patients (14.3%) experienced serious AEs that were considered by the Investigator to be related to the study drug. Four patients (19.0%) were discontinued from the study due to drug-related AEs.
During course 1, of the three patients treated at the 0.22 mg/m2/dose, one patient experienced an AE of maximum toxicity grade 1, one patient of grade 2, and one of grade 3. Asthenia was reported by three patients and vomiting by two patients. All other AEs were reported by one patient each. Of three patients treated during course 1 at 0.33 mg/m2/dose, two patients experienced an AE of maximum toxicity grade 1 and one patient experienced an AE of maximum toxicity grade 4. Two patients reported nausea, and all other AEs were reported by one patient each. One patient experienced grade 3 digestive system AEs of intestinal obstruction, nausea, and vomiting, and also a grade 3 abdominal pain in the body as a whole. At the course 1 dose of 0.66 mg/m2, two patients experienced AEs of maximum toxicity grade 1, and one patient experienced an AE of maximum toxicity grade 2. The one patient treated at a course 1 dose of 0.99 mg/m2 experienced a grade 2 maximum toxicity grade of postural hypotension and grade 2 anemia. At the dose of 1.32 mg/m2, two patients experienced a maximum toxicity grade 2 AE and one patient experienced an AE of maximum toxicity grade 3. Out of the seven patients treated during course 1 at the 2.64 mg/m2/dose, six experienced AEs. One patient experienced a maximum toxicity grade 1, two patients experienced maximum toxicity grade 2, and three patients experienced AEs of maximum toxicity grade 3. The AEs were distributed between the body as a whole (four patients), the digestive system (six patients), the home and lymphatic system (four patients), the metabolic and nutritional system (five patients), the nervous system (three patients), the respiratory system (two patients), the skin and the appendages (five patients), and the argental system (two patients). One patient was treated during course 1 at the 3.96 mg/m2/dose, and the patient experienced AEs of maximum toxicity grade 1 for body as a whole, musculoskeletal system, nervous system, and skin and appendages.
One patient experienced a protocol-defined DLT during the study. This patient, who was treated at the 2.64 mg/m2/dose, had grade 2 numbness in the hands and feet and grade 2 tremor in the hands and knees during course 2 of the trial. These events were considered probably related to TAS-106.
Review of the AEs during all courses administered (Table III), shows that two out of the three patients treated at the 0.22 mg/m2/dose experienced study-drug related AEs during all courses. Asthenia was reported by both patients, and was grade 1 or 2. No grade 3 or 4 toxicities were found to be study drug-related. One of the three patients at the 0.33 mg/m2/dose experienced drug-related AEs of constipation, diarrhea and alopecia of grade 1 during all courses. Two out of the three patients at the 0.66 mg/m2/dose experienced drug-related toxicity. One patient each reported asthenia, nausea, myalgia, and vasodilatation. All AEs reported at this level were considered to be grade 1 or grade 2. Only one patient was treated at the 0.99 mg/m2/dose and AEs of anemia and edema were present. One out of the three patients treated at the 1.32 mg/m2/dose experienced an AE of grade 1 tremor that was deemed to be related to the study drug. Six out of the seven patients treated at the 2.64 mg/m2/dose experienced study drug-related toxicities during all courses. The most frequently reported (>40%) were ex-foliative dermatitis (57.1%) and asthenia, hypochromic anemia, and peripheral neuritis (42.9% each). The majority were grade 1 or 2, with one patient experiencing grade 4 myocardial infarction that was considered to be possibly related to the TAS-106. Only one patient was treated at the 3.96 mg/m2/dose and this patient experienced grade 3 peripheral neuritis and grade 2 neuritis.
Of the 21 patients treated during the study, six patients (28.6%) experienced study drug-related neuropathy AE during all courses. The most frequently reported AE that was considered to be possibly, probably, or definitely related to study drug during all courses was peripheral neuropathy (19%).
Three patients were treated at the 2.64-mg/m2/dose level and there was no DLT during course 1. Dosing was escalated per protocol and one patient was enrolled at the 3.96 mg/m2/dose. This patient experienced grade 2 neurotoxicity, and that dose cohort was discontinued. Subsequently two patients treated at the 2.64 mg/m2/dose experienced grade 2 neurotoxicity late in course 2, which did not resolve after study drug discontinuation. Thus the investigators determined late neurotoxicity to be a DLT, and decided against further dose escalation. A total of seven patients were treated at the 2.64 mg/m2 dose, therefore, the investigators established the maximum tolerated dose to be less than the 2.64 mg/m2/dose. At the 1.32-mg/m2/dose level (three patients), no patients experienced DLTs during course 1 or course 2. Thus a clear suggested phase II dose could not be established.
Laboratory AEs reflected by laboratory parameters considered to be possibly, probably, or definitely related in any way to the study drug, were also noted. Two patients were reported to have leucopenia considered related to the study drug. For one patient, leucopenia was toxicity grade 2 during course 2. Another patient had leucopenia of toxicity grade 1 and considered to be possibly study drug-related. Three patients at the 2.64 mg/m2/dose were found to have hypochromic anemia, two of grade 2 and one of grade 1 toxicity. The one patient at the 0.99 mg/m2/dose was reported to have grade 2 anemia considered to be related to the drug.
Neurocognitive results showed that treatment with TAS-106 was associated with mild declines in memory function, and patients also developed significantly more AEs while on treatment. However, it was concluded that the neurotoxic side-effects of the regimen were no greater than those reported for other chemotherapy treatments and were substantially less than those reported for immunotherapy for cancer.
The results of this study provide an extensive safety profile for TAS-106. The most common drug-related toxicity is peripheral sensory neuropathy, a known side-effect of TAS-106. This was observed during course 1 and course 2 at the 1.32 mg/m2/dose, 2.64 mg/m2/dose, and 3.96 mg/m2/dose. These neuropathies were of grade 1 and 2, and no grade 3 or 4 neurotoxicity were observed. The most common subjective toxicities amongst the patients in this study were asthenia, constipation, diarrhea, nausea, hypoesthesia, vomiting, and paresthesia.
Efficacy. Out of the 20 evaluable patients, 17 discontinued the study due to disease progression, 2 patients discontinued due to the occurrence of unacceptable toxicity, and 2 patients discontinued due to an AE. None of the patients had a complete or partial response (Table IV). Three patients had no change in tumor size, one patient discontinued early in course 1 without tumor assessment, and 16 patients were diagnosed as having progressive disease. Overall, all 21 patients were treatment failures with a median time to treatment failure of 56 days.
Pharmacokinetics of TAS-106. Pharmacokinetics of TAS-106 was evaluated in a total of 16 patients at the dose level of 0.22 - 2.64 mg/m2, and in 2 out of 16 patients at the dose level of 2.64 mg/m2; plasma samples were further collected on day 15 after repeated administration of TAS-106. The mean concentration time profiles of TAS-106 are presented in Figure 2, and the calculated PK parameters are summarized in Table V. Plasma concentration of TAS-106 showed multiple phase elimination, with the terminal t1/2 ranging from 8.7 to 13.0 hours. The peak concentration C5min, the concentration at the first sampling point, and AUC0-inf increased with increasing dose. The relationship between these parameters and the dose of TAS-106 was dose-proportional as similar to the previous phase I study reported by Hammond-Thelin et al. (13). Consistently, CLtot and Vdss were generally constant among the dose levels, and those ranged from 57.4 to 108.4 ml/h/kg and 0.9 to 1.1 l/kg, respectively. Renal clearance (CLr) of TAS-106 ranged from 37.1 to 69.7 ml/h/kg, meaning that, approximately 60% of the TAS-106 dose was excreted into urine. Although the number of patients, the PK parameters after repeated administration of TAS-106 (day-15) were generally similar to those after the first administration (day 1) at the dose level of 2.64 mg/m2.
Pharmacokinetics/Pharmacodynamics of TAS-106. PK/PD profile of TAS-106 was evaluated for various hematological parameters as well as for neuropathy and skin toxicities. The percentage change at nadir was analyzed for hematological parameters, whereas the maximum grade in all courses was analyzed for neuropathy and skin toxicities. Spearman's rank correlation and the corresponding p-values are presented in Table VI. Hematological toxicity of TAS-106 was generally mild and no patient with toxicities of grade 3 was observed during course 1. At a starting dose of 2.64 mg/m2, grade 3 values were observed for one patient each for nadir values of hemoglobin and lymphocytes. No PK/PD relationship was observed for granulocytes and WBC, whereas a positive correlation for platelets, and a negative correlation for hemoglobin were found. Both neuropathy and skin toxicities were significantly related to the PK parameters, AUC0-inf and C5min of TAS-106.
Discussion
In general, TAS-106 was well tolerated. There were several drug-related toxicities, but the most characteristic and DLT was neurotoxicity. The characteristic neuropathy was a peripheral sensory neuropathy, which was manifested by numbness, tremor, pain, and hyperesthesia involving the fingers, hands, toes and feet. The onset of the neuropathy was delayed and occurred during or after course 2. In some patients, the neuropathy persisted or worsened, even after discontinuation of TAS-106.
In addition, mild desquamation the skin of the fingers and toes was noted in some patients in association with the peripheral sensory neuropathy. One patient experienced an apparent motor neuropathy when he developed a tremor in addition to sensory neuropathy.
Due to the neurotoxicity seen at the 2.64 mg/m2/dose, it was concluded that this would be the maximum tolerated dose for this particular schedule. No suggested phase II dose was determined, however at the 1.32 mg/m2/dose level, no patients experienced DLTs during course 1 or 2. However, given the fact that peripheral neuropathy continued or even worsened after stopping the treatment, particular care should be taken during following studies.
PK/PD discussion. Of the total 21 patients enrolled in this trial, PK of TAS-106 was evaluated in a total of 16 patients who received the treatment at the dose level of 0.22-2.64 mg/m2. Both maximum and overall exposures to TAS-106, represented as C5min and AUC0-inf, respectively, were proportional to the dose and the individual variation was generally less than 20% as CV%. The renal clearance of TAS-106 accounted for approximately 60-70% of the total body clearance, suggesting its major elimination pathway is renal excretion. The values of renal clearance were slightly lower than the glomerular filtration rate (GFR, approximately 100 ml/min). The renal function of the individual patient will likely be an intrinsic factor, influencing the clearance of TAS-106. The volume of distribution of TAS-106 at steady state ranged from 0.9 to 1.1 l/kg, suggesting moderate distribution of this drug to tissue or organs. Although the number of patients was limited, the PK parameters were generally similar after the first administration (day 1) and after the third administration (day 15) in two patients who received 2.64 mg/m2 of TAS-106 with the once weekly schedule.
The relationship between the PK parameters and the hematological parameters, neuropathy and skin toxicity was evaluated by correlation analysis. The hematological parameters were analyzed for the percentage change from baseline at nadir in the overall courses. Similarly, neuropathy and skin toxicity were analyzed for the maximum grade in the overall courses. Although the PK parameters analyzed were determined after the first administration on the first course, these can represent the individual drug exposure during the overall treatments, since the intra-individual variability of PK is expected to be so small as to be negligible. No significant relationship was seen for granulocytes and WBC. Though significant correlations were seen for platelets and hemoglobin, the toxicity was generally mild. However, two patients at the 2.64 mg/m2 dose level experienced grade 2 neuropathy and that hampered the dose escalation or continuation of the treatment. The maximum grade of neuropathy and skin toxicity was significantly correlated to both C5min and AUC0-inf of TAS-106, suggesting that the occurrence of these toxicities is related to the drug concentration rather than the duration of the exposure to drug. A continuous infusion of TAS-106 might be an alternative treatment to reduce the DLT of this drug.
- Received February 20, 2012.
- Revision received March 19, 2012.
- Accepted March 20, 2012.
- Copyright© 2012 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved