ASCO . . .
>>438
a Phase I Pharmacokinetic Study of T138067 Administered as a Weekly 3-Hour Infusion.
Ross C. Donehower, Garry H. Schwartz, Antonio C. Wolff, Nycole Olivo, Kathleen L. Burks, Matthew Wright, Jackie Walling, Eric K. Rowinsky, The Johns Hopkins Oncology Center, Baltimore, MD; Brooke Army Medical Center, San Antonio, TX; Cancer Therapy and Research Center, San Antonio, TX; Tularik, Inc., South San Francisco, CA.
T138067 induces depolymerization by binding to cysteine 239 on [beta]-tubulin. T138067 is not a substrate for Pgp, is hepatically cleared, and myelosuppression and CNS toxicity were dose limiting in animals. This clinical study investigates a weekly 3-hour infusion schedule: 28 patients (pts) were treated at 110, 220, 330, 385 and 440 mg/m2; 18 male, 10 female - median age 61 (range 20 - 83). One hepatocellular carcinoma (HCC) pt at 110 mg/m2 who had progressed through 3 prior therapies had a durable (13+ months) PR to T138067 with symptomatic improvement. At 440 mg/m2, 2 pts had DLTs: CTC Grade (G) 3 reversible ataxia; neutrophil count that failed to return to 1000/mm3 on planned dose day, resulting in a dose omission. No acute CNS toxicity has been observed below 440 mg/m2. The recommended Phase II dose is being defined in HCC and non-HCC pts. Treatment in HCC pts was limited by mild reversible thrombocytopenia. The current dose under evaluation is 220 mg/m2. In the non-HCC group at 330 mg/m2, 1 pt experienced a G3 leucopenia and G2 neutropenia (neutrophil counts failed to return to 1000/mm3, resulting in dose omission), another pt experienced a G3 febrile neutropenia. Other toxicities include infusion pain (1 G2), diarrhea (1 G2), nausea/vomiting (1 G2), and neurotoxicity (1 G3). Linear pharmacokinetics have been observed up to 385 mg/m2. Total body clearance approximates hepatic blood flow (Cl 52.92 ± 21.97 L/h/m2, mean ± sd, n = 26) and volume of distribution is slightly smaller than total body water (Vdss 19.15 ± 10.70, n = 26). The apparent elimination half-life is short 0.49 ± 0.19 h (mean ± sd, n = 26). At 440 mg/m2 two patients had significantly lower total body clearance than expected. Given the pharmacokinetic observations in other T138067 Phase I studies the lower clearance in these patients is likely due to individual patient characteristics rather than a global non-linear disposition. The recommended Phase II dose for non-HCC pts is 330 mg/m2. This schedule has been well-tolerated, has shown evidence of activity; and is recommended for evaluation in Phase II.
443
a Phase I Pharmacokinetic Study of T138067, a Synthetic Microtubule Depolymerizing Agent, Administered as a 3-Hour Infusion Daily X 5 Every 3 Weeks.
Glenn Preston, G Schwartz, M Garrison, N Olivo, M Wright, J Walling, M Gallagher, J Stevenson, E K Rowinsky, P O'Dwyer, Brooke Army Medical Center, Fort Sam Houston, TX; Institute for Drug Development, San Antonio, TX; Tularik Inc., South San Francisco, CA; University of Pennsylvania, Philadelphia, PA.
T138067 binds irreversibly and specifically to several isotypes of [beta]-tubulin, a key component of microtubules. The compound is hepatically cleared, and is not a substrate for common cellular mechanisms of drug resistance such as P-glycoprotein drug pump overexpression. Myelosuppression and CNS toxicity were dose-limiting in animals, and toxicity appears to be related to peak plasma levels. Because the half life of T138067 bound to tubulin is 10 to 24 hours and because of the short plasma half life of the drug, a daily x 5 schedule was chosen for clinical assessment. Twelve patients (pts) have been treated at 4 dose levels (44 mg/m2, 88 mg/m2, 175 mg/m2, and 250 mg/m2). Demographic data: 7 males and 5 females, median age 61 years (range 44 to 73), 6 colorectal pts, 2 hepatocellular pts, 1 renal pt, 1 gastric pt, 1 NSCLC pt, and 1 breast pt. Treatment has been well-tolerated at doses below 250 mg/m2 (1 pt with CTC Grade [G] 1 leucopenia, 1 pt with G2 anemia and 1 pt with G1 thrombocytopenia). However, 2 DLTs occurred at the 250 mg/m2 dose level: 1 pt experienced a G4 transient and uncomplicated neutropenia and another pt had reversible G4 encephalopathy with reversible hearing loss. Day-5 pharmacokinetic data are available for 10 pts treated at the 4 dose levels (SD): clearance = 42.1 (16.1) L/h/m2, Vdss = 15.5 (5.3) L/m2, apparent terminal half life = 0.58 (0.2) h. No accumulation of T138067 has been observed and exposure remained consistent over the 5 days of treatment. Although the pt with encephalopathy had the highest Cmax among pts treated at 250 mg/m2, the levels were consistent with those that would be predicted for linear pharmacokinetics. Previous data suggest neurotoxicity is related to Cmax. Protein binding in this pt is being characterized. In summary, T138067 was well tolerated at dose levels of 175mg/m2 and below on a d x 5 schedule, but severe neurotoxicity was seen at 250mg/m2.
442
Phase I Study of T900607-Sodium, a Novel Microtubule Inhibitor, in Patients with Advanced Solid Tumors.
Robert David Schumaker, Sridhar Mani, Matthew Wright, Kelli Petersen, Kenneth R Hande, Wendy VerMeulen, Odessa Lankford, Jackie Walling, Mace L Rothenberg, Vanderbilt-Ingram Cancer Center, Nashville, TN; Montefiore Medical Center, Bronx, NY; Tularik, Inc., South San Francisco, CA; Tularik, Inc, South San Francisco, CA.
T900607 is a novel irreversible microtubule depolymerizer binding specifically to cysteine 239 on [beta]-tubulin. Unlike taxanes or vinca alkaloids, T900607 is not a substrate for p-glycoprotein. Preclinical activity has been observed in a broad spectrum of tumors, including tumor xenografts resistant to vinorelbine, doxorubicin, and paclitaxel. This phase I study evaluated a 30-minute infusion administered daily for 5 days every 3 weeks. Fourteen patients (pts) have been treated at the following dose levels: 7.5 mg[slash]m2 (1[slash]10th mouse LD10) (n=3); 15 mg[slash]m2 (n=3); 30 mg[slash]m2 (n=3); 45 mg[slash]m2 (n=3); 60 mg[slash]m2 (n=2). Demographics: 8 males/6 females; median (range) age 53 (26-75); PS 0-1 (n=12) PS 2 (n=2); median (range) # prior cytotoxic therapies 2 (1-6); breast (2); colorectal (1); lung (3); lymphoma (3); sarcoma (3); other (2). CTC Grade (G) 3 toxicities: fatigue (1pt), anemia (1pt) and low back pain (1pt). Other toxicities ([less than or equal to] G 2): anemia, fatigue, pain at infusion site, vomiting, dizziness, headache, and paresthesia. One pt with K1-anaplastic lymphoma who failed CHOP had a partial response (5+ months). The MTD has not been reached and patient accrual continues. Linear pharmacokinetics (day 1 and 5) have been observed up to and including 60 mg[slash]m2 with no accumulation by day 5. In these patients clearance was 19.1 ± 1.3 L[slash]h[slash]m2, volume of distribution (Vdss) 4.8 ± 2.5 L/m2 and apparent elimination half-life 0.4 ± 0.13 h (Mean ± sd, n = 13). Western blots of peripheral blood mononuclear cell lysates using a monoclonal antibody directed against the drug-tubulin complex from prepared after drug exposure detected drug-tubulin complexes formed at the 7.5 mg[slash] m2 dose. Tumor cells are being obtained across dose levels to determine drug-tubulin complex formation. These cells will also be assessed for mutations in b-tubulin and expression of the ABC-transporter cassette.<<
snip
Cheers, Tuck |
