A phase I study of tasisulam sodium (LY573636 sodium), a novel anticancer compound in patients with refractory solid tumors

This study was conducted at the H. Lee Moffitt Cancer Center, Tampa, FL and the Memorial Sloan-Kettering Cancer Center, New York, NY, in collaboration with Eli Lilly and Company. From August 2003 to February 2007, 62 patients were entered into the study and 53 received at least one dose of tasisulam (seven patients did not meet enrollment criteria and two withdrew consent). Patient demographics are summarized in Table 1.

On the basis of preclinical toxicity and efficacy testing (Lilly data on file), tasisulam was administered as a flat dose, ranging from 100 to 2,400 mg, to 34 patients enrolled in cohorts 1 through 9 (Table 2). DLTs were not observed in patients enrolled in cohorts 1 through 6 (100–1,400 mg). One of the three patients treated in cohort 7 (1,800 mg) was discontinued from the study in cycle 1 because of tumor-related spinal cord compression and was replaced; this patient had a grade 3 DLT (diarrhea). Three additional patients were then enrolled in this cohort (for a total of seven patients), and no additional DLTs were observed. In cohort 8 (2,400 mg), all three enrolled patients experienced DLT. One patient with metastatic NSCLC and a history of inflammatory colitis developed grade 3 stomatitis, grade 3 thrombocytopenia, and gastrointestinal bleeding, and later developed grade 4 febrile neutropenia and fatal acute respiratory distress syndrome (ARDS) in the setting of bilateral pulmonary nodules and pleural effusions. Another patient developed a prolonged prothrombin time (16-day duration without significant bleeding) that was later attributed to an interaction between tasisulam and the concomitantly administered medication, warfarin. The third patient developed hemoptysis from a tracheostomy site and grade 3 bilateral pneumonia 3 days after administration of tasisulam; the patient’s white blood cell count was 12.4 k/μL and platelet count was 159 k/μL. Bronchoscopy was negative for active bleeding, and no further hemoptysis was noted, but secretions were considered consistent with alveolar hemorrhage (grade 3 pulmonary hemorrhage). Because the MTD had been surpassed at the 2,400-mg flat-dose cohort, three patients were enrolled at an intermediate flat dose of 2,000 mg (cohort 9), and three additional patients were enrolled at the 1,800-mg flat dose (cohort 7). No additional DLTs were observed.

One patient each in cohorts 7 and 9 had grade 4 hematologic toxicity (thrombocytopenia/pancytopenia, respectively) in cycle 2 that lasted at least 8 days in one patient, suggesting the possibility of cumulative toxicity from the accumulation of bound drug with repeated flat dosing.

Of the 34 patients administered flat doses of 100–2,400 mg (cohorts 1–9), 33 had full pharmacokinetic profiles from cycle 1. The analysis of pharmacokinetic data showed high interpatient variability (Table 3), a low total plasma clearance (approximately 0.03 L/h), a volume of distribution that was likely limited to the distribution volume of albumin (approximately 9 L) [8], and a terminal elimination half-life that corresponded to the turnover rate of albumin (approximately 11 days) [9]. Values of C _max increased less than proportionately with dose, with coefficients of variation of 22% after adjusting for dose (Fig. 1a). On the basis of preclinical animal studies, in which the degree of C _max variability appeared to be associated with the risk of toxicity (Lilly data on file), it was thought that controlling C _max variability in patients should reduce their risk of toxicity. Therefore, the relationship between body size-related parameters and C _max was explored. LBW, which was calculated using an algorithm incorporating the patient’s height, weight, and gender [10, 11], was identified as an important cofactor that demonstrated a clear inverse relationship between LBW and C _max (Fig. 1b) and reduced the interpatient variability of C _max (from 22 to 13%) (Fig. 1c). Thus, pharmacokinetic analysis revealed that the C _max for tasisulam (defined as its concentration at the end of the 2-h infusion) negatively correlated with the LBW of the patient. This led to a change from the flat-dose paradigm to a LBW-based dosing paradigm targeting an individualized C _max.

Although the dose-escalation findings suggested an MTD for tasisulam of approximately 2,000 mg, the significant interpatient and intrapatient variability of C _max in the flat-dose cohorts and the high degree of albumin binding of tasisulam (99.7–99.9%) suggested that the flat-dosing schema was unlikely to provide consistent drug exposure. These findings led to a change from flat-dosing to a LBW-based dosing paradigm targeting specific C _max values in cohorts 10 and 11.

Because of the hematologic toxicity observed in later cycles in cohorts 7 and 9, a loading dose was implemented in cycle 1 followed by a lower chronic dose in subsequent cycles in cohorts 10 and 11 to decrease the risk of drug accumulation due to the relatively long terminal half-life of tasisulam. The loading dose in cycle 1 for the LBW-based cohorts targeted a C _max of 400 μg/mL (cohort 10) or 420 μg/mL (cohort 11). The chronic doses were 70 and 65% of the loading doses for cohorts 10 and 11, respectively. The initial LBW-based C _max dose of 400 μg/mL was considered equivalent to the flat doses that were considered tolerable and showed antitumor activity (disease stabilization).

None of the three patients enrolled in cohort 10 had DLT (Table 2). In cohort 11, one of the six enrolled patients had DLT (transient grade 3 hepatic transaminase elevation); however, two of the six patients developed grade 3 or 4 hematologic toxicity in cycle 2, suggesting that escalation to a higher targeted C _max was unlikely to identify a dose suitable for administration in phase II. Therefore, cohort 11 was expanded for further study. Of the 16 patients treated in cohort 11, one patient had DLT, and three patients developed grade 3/4 thrombocytopenia/neutropenia in later cycles (cycle 2 or more); thus, dose escalation was stopped.

The median number of treatment cycles in cohort 11 was 3 (range 1–14 cycles) (Table 2). Of the 16 patients in cohort 11, 14 completed at least two cycles, and eight completed at least four cycles. Therefore, considering the heavily pretreated patient population and the tolerability of the 420 μg/mL C _max targeted dose, this dose was recommended for phase II study.

All of the 19 patients enrolled in cohorts 10 and 11 had full pharmacokinetic profiles in cycle 1. The pharmacokinetic parameters (CL and V_ss) were similar in these cohorts compared with those of the flat-dose cohorts 1–9; however, comparison of the 1,800-mg flat-dose group and the 420-μg/mL dose group revealed that the LBW-dosing schema decreased the variability of AUC_(0-∞) and CL by approximately 50%, and the variability of C _max from 28 to 19% (Table 3). Comparisons of concentration versus time profiles for six pairs of patients, who were similar in their LBW difference, indicated smaller differences between C _max values in patients dosed to a targeted C _max of 420 μg/mL (Fig. 2a) compared with those given a flat dose (Fig. 2b).

The median number of cycles administered was 2 (range 1–18 cycles). The most common grade 3/4 toxicities considered possibly related to study drug were hematologic (thrombocytopenia, anemia, and neutropenia; Table 4). Fifteen patients received one or more transfusions (six red blood cells; seven red blood cells and platelets; one red blood cells, platelets, and plasma; and one plasma).

Of the six patients who died during the study, one patient in cohort 8 died because of complications related to bone marrow suppression (febrile neutropenia and ARDS during cycle 1), and one patient in cohort 11 died because of an outpatient cardiopulmonary arrest after receiving one cycle of study drug (for which drug relatedness could not be ruled out). An additional patient in cohort 11 died in cycle 2 from NSCLC in the setting of post-obstructive pneumonia; the patient had concurrent grade 2 neutropenia that was considered possibly related to study drug. All other patients died because of causes related to their malignancy.

Six patients (cohort 7 or above) were discontinued from the study because of adverse events considered possibly related to study drug and/or complications: coagulopathy with prolonged prothrombin time (patient had been receiving warfarin) associated with rectal bleeding; vaginal bleeding; hypokalemia; thrombocytopenia; febrile neutropenia; and pneumonia and diffuse pulmonary hemorrhage.

Eight patients were discontinued from the study or died before cycle-2 response assessment because of ARDS and cardiopulmonary arrest (one patient, each); pneumonia and pulmonary hemorrhage (one patient); lost to follow-up (one patient); withdrawal of consent (one patient); and disease progression (three patients, two of whom were objectively confirmed to have disease progression in follow-up visits). Of the 45 patients assessed for response, there were no objective responses; 25 had progressive disease, 15 had stable disease, and five had an unknown response because of incomplete evaluation. However, five patients who received extensive prior therapy (median 6, range 5–12 prior cancer treatments) for NSCLC (two patients), ovarian cancer (two patients), or thymoma (one patient) received at least 10 cycles of tasisulam (minimum of 7 months) before disease progression.