100: Phase 2 Study of TLK286 (GST P1-1 Activated Glutathione Analog) in patients with platinum and paclitaxel refractory/resistant advanced epithelial ovarian cancer
Citation: European Journal of Cancer Vol 38, Suppl. 7, November 2002, page 34
J.J. Kavanagh1, A. Kudelka1, D.R. Spriggs2, M.A. Bookman3, L. Lewis1, C. Maack4, J. Dombroski4, J. Macpherson4, W.D. Henner4, G.L. Brown4
1MD Anderson Cancer Center, Houston, USA; 2Memorial Sloan Kettering Cancer Center, New York, USA; 3Fox Chase Cancer Center, Philadelphia, USA; 4Telik, Inc., South San Francisco, USA
Objectives: To determine the objective tumor response rate (ORR), disease stabilization rate, safety and survival of patients with platinum and paclitaxel refractory or resistant ovarian cancer treated with TLK286.
Methods: TLK286 is a glutathione analog activated in cancer cells by glutathione S-transferase P1-1, resulting in apoptosis through the stress kinase pathway. Patients with ovarian cancer resistant or refractory to paclitaxel and platinum-based chemotherapy were to be enrolled in this multicenter, Fleming two-stage design study. TLK286 was given intravenously at 1,000 mg/m2 once every 3 weeks until tumor progression or unacceptable toxicities. ORR was assessed by RECIST. Toxicity was graded by NCI-CTC. Survival was estimated by Kaplan-Meier Analysis.
Results: Thirty-six patients, ECOG 0-1, prior chemotherapy regimens, median 3 (range 1-7), were enrolled between June 2001 and March 2002. A total of 117+ cycles (median 2, mean 3.2, range 1-14+) were administered at 99% of the specified dose intensity. All patients had failed prior therapy with paclitaxel and platinum. 20/36 (55%) had failed one to three additional salvage therapies, including 12/36 (33%) Doxil, 10/36 (28%) topotecan, 4/36 (11%) gemcitabine, and 1/36 (3%) docetaxel therapy. The most common possibly drug-related toxicities (< Grade 2) were: fatigue, nausea, and anemia. There were no Grade 4 toxicities, no Grade 3 myelosuppression or thrombocytopenia and no cumulative toxicities. At interim analysis, ORR was seen in 4/31 patients (13%), 1 CR (3%), 3 PRs (10%), 12 SDs (39%) and 15 PDs (48%). The ORR was 15% in 2nd-line patients. The disease stabilization rate (CR+PR+SD) was 52% (16/31). The longest duration of therapy is in the CR patient, progression-free for 14+ cycles (12+ months). Tumor responses have been accompanied by declines in CA125 and symptom improvement. Three patients have died due to disease progression. Median survival exceeds 10 months.
Conclusions: TLK286 has significant single-agent antitumor activity in platinum and paclitaxel refractory or resistant ovarian cancer and is well tolerated. Median survival has not yet been reached but exceeds 10 months. Patient follow-up for response and survival is ongoing. Objective tumor responses including a durable complete response in bulky disease and improved survival in this heavily pretreated population are encouraging and warrant future studies of TLK286 in ovarian cancer.
Abstract 101: Phase II Study of TLK286 (Glutathione Analog Activated by GST P1-1) in refractory colorectal cancer
Citation: European Journal of Cancer Vol 38, Suppl. 7, November 2002, page 35
L.S. Rosen1, T. Dragovich2, H.J. Lenz3, E. Lin4, L. Wiggins1, G.L. Brown5, C. Maack5, J. Macpherson5, J. Dombroski5, W.D. Henner5
1UCLA Jonsson Cancer Center, Department of Medicine, Los Angeles, USA; 2Arizona Cancer Center, Tucson, USA; 3USC/Norris Comprehensive Cancer Center, Los Angeles, USA; 4MD Anderson Cancer Center, Houston, USA; 5Telik, Inc, South San Francisco, USA
Introduction: TLK286 is a novel glutathione analog, activated by the enzyme glutathione-S transferase P1-1 (GST P1-1). GST P1-1 is overexpressed in many types of human malignancies and is implicated in resistance to several classes of anticancer therapies. Following activation of TLK286 by GST P1-1, apoptosis is induced through the stress response pathway.
Methods: Up to 75 evaluable patients with colorectal cancer who had failed prior 5-fluorouracil, leucovorin and irinotecan chemotherapy and any amount of cytostatic agents were to be enrolled in this multicenter, open label, single arm study. TLK286 was administered at 1000 mg/m2 every 3 weeks until tumor progression or unacceptable toxicities. Objective response rate (ORR) was determined by RECIST criteria. Time to progression (TTP) and survival were estimated by Kaplan-Meier analysis. Adverse events (AEs) were graded by the NCI-CTC.
Results: 73 patients (35 M/22F) median age 66 (range 29-81), ECOG median 1 (range 0-1), median number of prior chemotherapy regimens 2 (range 1-5) were treated with a total of 196+ TLK286 treatments (median 2, mean 2.7, range 1-8+). The target dose of TLK286 was maintained in 94% of cycles. Most frequent AEs were (Grade 1-2): fatigue (24%), nausea (15%), vomiting (7%), hematuria (9%), urinary frequency (9%) and anemia (9%). There was one Grade 4 AE reported at day 21 (ANC 476/mm3) in a patient with progressive disease and underlying bone marrow disorder. Grade 3 AEs were infrequent (7% of patients). As of interim analysis, 36 of 73 patients were evaluable for tumor response. Five patients (14%) had stable disease (SD) as best response. Median duration of SD was 167 days (range 120-219+ days). In patients with SD there were declines in the CEA tumor marker (median decrease 42%, range 6-70%) These CEA declines have not translated into objective responses. There have been 19 deaths reported due to progressive disease. At interim analysis, estimated median survival (Kaplan-Meier) was 172 days (range 30-219+ days).
Conclusions: TLK286 was well tolerated in heavily pre-treated patients with refractory colorectal cancer. There were no objective tumor responses in advanced colorectal cancer when TLK286 was administered as a single agent once every 3 weeks. Analysis of subpopulations suggests that investigation of a more intensive dose schedule or use of TLK286 in combination therapy in colorectal cancer is warranted.
106A: Phase 2 study of TLK286 (GST P1-1 activated glutathione analog) in patients with non-small cell lung cancer who failed prior platinum-based regimens
Citation: European Journal of Cancer Vol 38, Suppl. 7, November 2002, page 36
V. Papadimitrakopoulou1, R. Figlin2, L. Garland3, D. Von Hoff3, M. Kris4, M. Purdom1, G.L. Brown5, C. Maack5, J. Macpherson5, W.D. Henner5
1MD Anderson Cancer Center, Houston, USA; 2UCLA Jonsson Cancer Center, Los Angeles, USA; 3Arizona Cancer Center, Tucson, USA; 4Memorial Sloan Kettering Cancer Center, New York, USA; 5Telik, Inc., South San Francisco, USA
Introduction: TLK286 is a novel glutathione analog that is activated by the enzyme glutathione-S transferase P1-1 (GST P1-1). GST P1-1 is constitutively expressed in many cancers including non-small cell lung cancer (NSCLC) and is overexpressed following treatment with platinum-based regimens. Following activation of TLK286 by GST P1-1, apoptosis is induced through the stress response pathway.
Methods: Up to 55 Stage IIIB or IV NSCLC patients who had failed prior platinum-based therapy (up to two cytotoxic regimens) and may have had prior adjuvant therapy and cytostatic agents such as EGFR tyrosine kinase inhibitors were to be enrolled in this multicenter single-arm study. Patients received TLK286 at 1000 mg/m2 once every 3 weeks until tumor progression or unacceptable toxicities. Adverse events were graded by NCI-CTC, objective tumor response was measured by RECIST, and survival was estimated by Kaplan-Meier.
Results: 52 patients (31 M, 21 F) median age 60 (range 40-77), median ECOG performance status 1 (range 0-1), prior chemotherapy regimens median 2 (range 1-4) have received 152+ treatments (mean 2.9 cycles, range 1-16+), with dose reductions required in 3% of doses. All patients were resistant to platinum and taxanes, 24% resistant to second line docetaxel, and 55% having failed additional 3rd line salvage therapy including gemcitabine (27%), and EGFR inhibitors (20%). No Grade 4 events were reported. Grade 3 events were infrequent. No myelosuppression, thrombocytopenia or cumulative toxicity was seen. Possibly drug-related toxicities were mild (Grade 1-2) fatigue (38%), nausea (38%), and vomiting (22%). At the interim analysis, 41/52 patients were evaluable for efficacy. Disease stabilization was seen in 21/41 (51%). The median duration of stable disease exceeds 39 weeks. Median survival for both 2nd and 3rd and 4th line patients exceeds 10 months, and requires further patient follow-up to reach median survival. The longest duration of TLK286 therapy was one year. Survival at one year requires further patient follow-up.
Conclusions: TLK286 is well tolerated in this heavily pretreated advanced NSCLC population. Efficacy in this heavily treated population that includes 55% 3rd and 4th line patients is encouraging. Median survival exceeds 10 months and has not yet been reached. Future studies of TLK286 in advanced NSCLC are warranted. |
