C. C. Cunningham

Phase I and Pharmacokinetic Study of the Dolastatin-15 Analogue Tasidotin (ILX651) Administered Intravenously on Days 1, 3, and 5 Every 3 Weeks in Patients with Advanced Solid Tumors

Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and pharmacokinetics of tasidotin (ILX651), a dolastatin-15 analogue, when administered on days 1, 3, and 5 every 3 weeks in patients with advanced solid tumors. Patients and Methods: Thirty-two patients were treated with 92 courses of tasidotin through seven dose levels determined by a modified Fibonacci scheme ranging from 3.9 to 45.7 mg/m2. Pharmacokinetic samples were collected during the first course. Results: Neutropenia was the principal DLT at the 45.7 mg/m2/d dose level. In addition, one patient also experienced grade 3 neutropenia complicated with grade 3 esophageal candidiasis and grade 3 dehydration. Only 1 of 11 patients treated at the MTD, 34.4 mg/m2, experienced dose-limiting neutropenia. Other common, drug-related toxicities included mild to moderate fatigue, anemia, nausea, anorexia, emesis, alopecia, and diarrhea. The best observed antitumor response consisted of stable disease and was noted in 10 patients (31%); the median duration on study for those patients with stable disease was 99.5 days compared with 37.5 days for those patients with progressive disease. Tasidotin plasma concentrations declined biphasically with an effective half-life of ≤55 minutes, and ∼11% was excreted unchanged in the urine. Conclusion: The recommended dose for phase II studies and the MTD when tasidotin is administered on days 1, 3, and 5 every 3 weeks is 34.4 mg/m2. The favorable toxicity profile of tasidotin compared with other antitubulin agents, including other dolastatin analogues, and its novel mechanism of action support further disease-directed evaluation of this agent.

Population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with cancer

Clofarabine for injection is a second-generation nucleoside analog approved in the United States (Clolar®) and Europe (Evoltra®) for the treatment of pediatric relapsed or refractory acute lymphoblastic leukemia. This report describes the population pharmacokinetics of clofarabine and its metabolite 6-ketoclofarabine in adult and pediatric patients with hematologic malignancies or solid tumors. Clofarabine pharmacokinetics were best described by a 2-compartment model with linear elimination and first-order absorption after oral administration. Clofarabine was rapidly absorbed following oral administration with a mean absorption time of less than 2xa0h and bioavailability of 57.5%. The important covariates affecting clofarabine pharmacokinetics were age, weight, and estimated creatinine clearance (eCrCL). No difference in pharmacokinetics was observed between sexes, races, or disease type. The elimination half-life was dependent on all the covariates but was generally less than 7xa0h in all cases. A difference in clofarabine pharmacokinetics was observed between adults and children. For a pediatric patient 3xa0years old weighing 16xa0kg with an eCrCL of 138xa0mL/min/1.73xa0m2, the population estimates for total systemic clearance and volume of distribution at steady-state were 18.3xa0L/h (1.14xa0L/h/kg) and 92.9xa0L (5.81xa0L/kg), respectively. α- and β-half-life were 0.9 and 4.4xa0h, respectively. For an elderly patient 82xa0years old weighing 96xa0kg with an eCrCL of 46xa0mL/min/1.73xa0m2, the population estimates for CL and Vdss were 21.5xa0L/h (0.22xa0L/h/kg) and 257.4xa0L (268xa0L/kg), respectively. α- and β-half-life were 0.5 and 10.6xa0h, respectively. Because of the difference in pharmacokinetics, adults have higher exposure than children given a similar dose standardized to body surface area. The exact mechanism of this difference is not understood. As eCrCL decreased, exposure increased due to reduced total systemic clearance. In the case of moderate (eCrCL 30 to 60xa0mL/min/1.73xa0m2) and severe (eCrCL <30xa0mL/min/1.73xa0m2) renal impairment, dose reduction may be needed to maintain similar exposure in an equivalent patient of the same age, weight, and normal renal function after both oral and intravenous administration. 6-Ketoclofarabine was a minor metabolite with peak plasma concentrations occurring about 1xa0h after the start of the infusion and having a metabolite ratio averaging less than 5% and not more than 8% for any particular individual. 6-Ketoclofarabine was rapidly cleared from plasma with an average apparent half-life of 4.9xa0h (range 3.9 to 6.2xa0h). No accumulation of 6-ketoclofarabine was observed with predose samples all below the limit of quantification on Days 8 and 15. Further monitoring of 6-ketoclofarabine is not required in future studies.

Phase I Trial of PT-100 (PT-100), A Cytokine-Inducing Small Molecule, Following Chemotherapy for Solid Tumor Malignancy

PT-100 upregulates cytokine expression competitively inhibiting the dipeptidyl peptidase activity of fibroblast activation protein (FAP) and dipeptidyl peptidase IV (DPP-IV). This dose-escalation study was conducted to evaluate the safety of PT-100 in patients receiving myelosuppressive chemotherapy and to assess its effects on neutrophil recovery. PT-100 was administered orally for 7 days as a 200 μg, 400 μg, 800 μg, or 1,200 μg total daily dose (divided twice daily) to 6, 6, 17, and 5 patients, respectively. Patients received 2 cycles of chemotherapy: The first cycle served as each individual patients control. Patients had to develop Grade 3+ neutropenia in Cycle 1 in order to receive PT-100 in Cycle 2. Most patients received PT-100 on Days 2–8 of chemotherapy in Cycle 2, except at 800 μg where an additional cohort (n = 8) was treated on a Days 5–11 schedule. Five of 7 patients receiving 800 μg on Days 2–8 experienced a ≥1-day improvement in Grade 3+ neutropenia in Cycle 2 versus Cycle 1. Overall, PT-100 was well tolerated. A reduction in chemotherapy-related nausea, vomiting, fatigue, alopecia, and diarrhea was noted in patients receiving PT-100. Edema/peripheral swelling, hypotension, hypovolemia, and dizziness were the most common nonhematologic adverse events considered related to PT-100. Two Grade 3 adverse events were considered related to PT-100: syncope (1,200 μg) and orthostatic hypotension (800 μg). A maximum tolerated dose was not reached. Given the accelerated neutrophil recovery, preclinical evidence of antitumor activity, and tolerable toxicities of PT-100, additional studies to optimize the PT-100 dosing schedule in patients receiving myelosuppressive chemotherapy are needed.

Phase II study of synthadotin (SYN-D; ILX651) administered daily for 5 consecutive days once every 3 weeks (qdx5q3w) in patients (Pts) with inoperable locally advanced or metastatic melanoma

7530 Background: SYN-D is a pentapeptide with a unique mechanism of action that potentially differs from microtubule stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids and other dolastatins) as it is postulated to inhibit microtubule nucleation. SYN-D has been chemically modified to improve pharmacological properties and is orally bioavailable with a therapeutic window potentially enhanced over previous generations of dolastatins. The substantial cardiovascular toxicity observed with previous dolastatins was not observed in the SYN-D phase I studies. Due to activity in melanoma observed both in xenograft models and in the phase I setting (Ebbinghaus, ASCO 2003), SYN-D is being evaluated in pts with locally advanced or metastatic melanoma.nnnMETHODSnIn this multi-institutional phase II study, SYN-D was administered at 28 mg/m2 IV for 30 mins qdx5q3w with response rate as the primary endpoint. The study was designed: to assess the feasibility of increasing SYN-D dose if <3/10 DLTs were observed during cycle 1 in the first 10 pts; with an early stopping rule after accrual of 25 pts in the event of no response. Pharmacokinetic blood draws were performed in cycle 1. Eligibility criteria: ECOG PS 0-1; no prior systemic chemotherapy; no active ocular melanoma; adequate organ function.nnnRESULTSnTo date 20 pts have been treated; data on the first 15 as follows: M/F=10/5; age 30-75 (median 56); ECOG 0/1=11/4; treatment naïve/prior biologics=10/5; number of courses 24 (median 2). In the first 10 pts grade 3 or 4 non-dose-limiting, predictable (day 15), and self-limited neutropenia was seen in 2 (20%) and 3 (30%) pts, respectively. Other toxicities were grade1-2: alopecia (n=4); fatigue (n=3); and nausea/vomiting (n=3). To date, no sensory neuropathy, thrombocytopenia, anemia or cardiovascular toxicity has been observed. Due to lack of DLT in the first 10 pts, the dose of SYN-D was escalated to 34 mg/m2 in subsequent pts. Assessment of response is in progress.nnnCONCLUSIONnSYN-D is a safe, well-tolerated treatment in locally advanced and metastatic melanoma pts. [Table: see text].

Clofarabine administered weekly to adult patients with advanced solid tumors in a phase I dose-finding study

3115 Background: Clofarabine, a next-generation nucleoside analogue that inhibits DNA synthesis, has demonstrated activity in acute leukemia in Phase I and II trials. The agent has also shown potent cytotoxic activity in a wide range of solid tumor cell lines and therapeutic activity in murine tumor models.nnnMETHODSnA Phase I dose-finding study is ongoing to determine the maximum tolerated dose (MTD) of clofarabine in patients with advanced solid tumors. To avoid the dose limiting toxicity of myelosuppression observed with the daily × 5 administration used for hematologic malignancies, clofarabine is administered IV on days 1, 8, and 15 of a 28-day cycle. Cohorts of patients are treated with escalating doses beginning with clofarabine 4 mg/m2 until MTD is determined.nnnRESULTSnThirty patients have been treated in 8 cohorts; 3 each at 4, 6, 10, 14, 18, and 27.5 mg/m2, and 6 each at 22 and 34 mg/m2. MTD has not been reached and enrollment is continuing. Preliminary data are available for 21 patients who have completed at least 1 cycle of treatment in the first 6 cohorts (up to 22 mg/m2), 12 males and 9 females with a median age of 65 years (range 48 to 78). Tumor types include colorectal (5); non-small cell lung (3); squamous cell larynx, transitional cell bladder, and prostate (2 each); and adenosquamous gallbladder, bronchioalveolar, hepatocellular/cholangiocarcinoma, leiomysarcoma, melanoma, pancreas, and squamous cell esophagus (1 each). Six patients completed ≥3 cycles of treatment with 4 patients completing 4 cycles. Data on 20 of the 21 patients show that 7 had stable disease (SD) as their best response; 1 prostate cancer patient had a drop in PSA level from 7975 ng/mL at baseline to 934 ng/mL at end of study. Major toxicities include myelosuppression, nausea, vomiting, and fatigue.nnnCONCLUSIONSnClofarabine has been administered weekly for 3 weeks (days 1, 8, and 15) every 28 days to adult patients with solid tumors; no dose limiting toxicity has been observed, and the MTD has not been reached. Enrollment is ongoing in the 42.5 mg/m2 cohort. [Table: see text].

Pharmacokinetics of synthadotin (ILX651), a novel tubulin polymerization inhibitor, in patients with solid tumors

2082 Background: Synthadotin (ILX651) is a pentapeptide with a unique mechanism of action that potentially differs from that of microtubule stabilizers (taxanes and epothilones) and tubulin inhibitors (vinca alkaloids and dolastatins) and is postulated to inhibit microtubule nucleation. The drug has been chemically modified to provide improved pharmacological properties and has a therapeutic window potentially enhanced over previous generations of dolastatins.nnnMETHODSnSynthadotin was administered once-daily to 36 patients daily x5 for 3 weeks every 4 weeks (Study 101) and to 31 patients every other day for 5 days every 3 weeks (Study 102). Doses ranged from 2.3 to 36.3 mg/m2 in Study 101 and 3.9 to 45.7 mg/m2 in Study 102. Blood and urine samples were collected for bioanalysis on Day 1 and 5 of Cycle 1. Synthadotin pharmacokinetics were characterized using noncompartmental methods. Linear mixed effects models were used to relate pharmacokinetic parameters to the following patient covariates: race, sex, age, BSA, dose, and baseline bilirubin, SGOT, SGPT, and creatinine (Cr).nnnRESULTSnAUC(0-∞) was not dose proportional but was time invariant. A 2-fold increase in dose resulted in a 2.3-fold increase in AUC(0-∞). Cmax was dose proportional and time invariant. CL was modeled as: CL (L/h) = 29.1*(BSA in m2)0.56*(Dose in mg/m2)-0.015*(Cr in mg/dL)-0.38. Vss was 22 L and independent of dose. Synthadotin half-life was dose-dependent but was less than 1 hour across all doses. Between-subject (BSV)/inter-occasion variability (IOV) on CL and Vss were 33%/4% and 41%/4%, respectively. Renal elimination was minimal with <15% of the dose excreted in urine. No accumulation was observed with once daily dosing.nnnCONCLUSIONSnSynthadotin exhibited dose nonlinearity and was rapidly cleared from plasma with minor renal clearance. BSV was moderate, while IOV variability was smaller. Dosing should continue to be based on BSA because of the positive effect between BSA and CL. [Table: see text].