- Email: [email protected]
P-358 Dose escalation study of pivanex (a histone deacetylase inhibitor) in combination with docetaxel for advanced non-small cell lung cancer
S182
Poster Session 2/Navel Therapies
and on progression SRL172 was continued if further treatment of any kind was considered. All patients were followed for survival. Results: 76 patients were randomised, 38 to each arm. 72 patients received carboplatin and etoposide chemotherapy. There was no difference in response rates between the two arms, 73% without vaccine and 68% with vaccine. Median duration of response and median survival was 9 months for both groups. The standard arm (chemotherapy only) response was better than the pilot study of 57% as was the median survival; 9 compared to 8.6 months. Conclusion: Despite initial encouraging results from phase II data, this study suggests no advantage to response or survival in adding SRL172 to standard treatment in SCLC. Improved results in the standard arm of this phase Ill study compared to the anthracycline/low dose platinum regimen used in the phase II study may account for the lack of difference. The majority of patients received etoposide and carboplatin as compared to MVP (mitomycin, vinblastine and cisplatin) and ACE (adriamycin, cyclophosphamide and etoposide) in the original pilot. Putting together this result with SRL172 in SCLC and the results of SRL172 in NSCLC, the strategy of combining SRL172 with chemotherapy will not be pursued.
I P 357
Cyclooxygenase-2 (COX-2) inhibition in advanced non-small cell lung cancer (NSCLC): preliminary results of a phase II trial (THO-0054)
lldiko Csiki, Adriana Gonzalez, David P. Carbone, Shiva Gautam, Alan Sandler, Norma Campbell, Ben Garcia, Jason Morrow, David H. Johnson. Vanderbilt-lngram Cancer Center, Nashville, USA COX-2 is upregulated in many malignancies including NSCLC & may play an integral role in the growth & development of cancer. Prostaglandin E2 (PGE2), a downstream product of COX-2, can promote tumor growth & invasion via stimulation of vascular endothelial growth factor (VEGF), inhibition of immune surveillance & upregulation of Bcl-2 and various MMPs. To assess the role of COX-2 inhibition in recurrent NSCLC, we initiated a phase II trial combining celecoxib (a selective inhibitor of COX-2) 400 mg P.0 bid & docetaxel 75 mg/m2 I.V. q3wk. Eligibility requirements include histologically confirmed NSCLC, 21 prior chemotherapy regimens, ECOG PS=O-I, ALT/AST/AP &I.5 ULN, Hb>8 g/dl, WBC ?1500/~1 & plt>lOOk, no current NSAID use or sulfa allergy. Blood & urine samples are obtained pre- & post-celecoxib for angiogenic markers & PGE-M (major urinary metabolite of PGE2) assays respectively. To date, 31 patients are eligible for response assessment with the following outcomes: PR = 4, SD = 6, baseline = 3, PD = 18. MTDP = 53 days & median survival = 240 days. COX-2 expression by immunohistochemistry was elevated in 9/12 (75%) analyzed tumors. Average serum VEGF levels (n=38) pre- & post-celecoxib were 749.7 pg/ml & 536.8 pg/ml respectively (31% decrease, p=O.O03). Postcelecoxib serum endostatin levels (n=38) increased from 87.2 rig/ml to 161.2 rig/ml (p=O.2) and serum VEGF to endostatin ratio (n=38) decreased from 11.9 to 7.2 (41% decrease, p=O.Oi) following celecoxib administration. Post- vs precelecoxib intra-tumoral tissue PGE2 levels, obtained from a laboratory correlative study (THO 0055), demonstrated a marked decline (47.5 rig/g vs. 237.9 rig/g respectively). These preliminary data indicate that celecoxib inhibits intratumoral COX-2 leading to a decrease in intratumoral PGEP levels that in turn may modulate downstream angiogenic effects. Enrollment will continue to a planned accrual of 54 pts. Grant support: NIH grants CA90949 (Lung SPORE) & CA68485 &from Aventis Pharmaceuticals. Celecoxib generously provided by Pharmacia.
I P 358
Dose Escalation Study of Pivanex (a Histone Deacetylase Inhibitor) in Combination with Docetaxel for Advanced Non-Small Cell Lung Cancer
Tony Reid’, Thomas M. Cosgriff2, Kristen Yet-?, Piotr Scislowski3, Frank H. Valone“, Anish Bhatnagar3, Frank A. Scappaticci3. r VA Hospital, Palo Alto, CA, Pa/o Alfo, USA; 2 Hematology and Oncology Specialist, LLC, Metairie, USA; 3 Titan Pharmaceuticals, Inc., South San Francisco, USA; 4 Titan Pharmaceuticals, Inc., South San Francisco, CA Pivanex is a histone deacetylase inhibitor that induces tumor cell differentiation and/or apoptosis. It has been well tolerated in clinical trials and has shown preliminary evidence for efficacy as a single agent in patients with advanced non-small cell lung cancer (NSCLC) who have previously received chemotherapy. In a previous Phase I study of Pivanex alone, the drug was well tolerated in the dose range 0.047-3.3 g/m2/d administered on Days l-3 of a 21 day cycle. The most common toxicities were fatigue, dysgeusia, and nausea. In a Phase II trial of advanced NSCLC with single agent Pivanex, 3 patients out of 29 (10%) who had received less than 3 prior chemotherapy regimens showed partial responses with one patient currently receiving drug after 29 cycles of therapy. Patients who received less than 3 prior chemotherapy regimens also had a median survival of 11 months and their one year survival was 47%. In recent preclinical studies, Pivanex has shown synergy with docetaxel for growth inhi-
bition of NSCLC cell lines in vifro and for improved survival in animal models. Because the drug has shown: (1) an excellent safety profile, (2) promising activity in clinical trials of NSCLC, (3) no overlapping toxicities with docetaxel, and (4) synergy with docetaxel, we undertook a dose escalation study to assess the safety of Pivanex combined with docetaxel. Pivanex is administered intravenously over 6 hours/day on Days 1-3. Docetaxel is administered on Day 4 (75 mg/m’). The regimen is repeated every 3 weeks. To date, accrual into the first cohort has been completed at a Pivanex dose of 1.5 g/m’ in combination with 75 mg/m” of docetaxel. No dose-limiting toxicity was observed. The plan is to escalate the Pivanex dose over multiple cohorts until the maximally tolerated or planned dose is reached. This dose will be used in a subsequent Phase Ilb trial that will randomize 225 patients with advanced, refractory NSCLC to Pivanex + docetaxel versus docetaxel alone.
P 359 El
Results from a Phase I study of the oral VEGF receptor . . . . . tyrosme kmase mhlbitor ZD6474, in patients with solid tumors
Catherine Wheeler’, Hironobu Minami’, Hiromichi Ebi’, Makoto Tahara”, Yasutsuna Sasaki2, Noboru Yamamoto3, Yasuhide Yamada3, Tomohide Tamura3, Nagahiro Saijo3. ’ AstraZeneca, Waltham, USA; 2 National Cancer Center Hospital East, Chiba, Japan; 3 National Cancer Center Hospital, Tokyo, Japan ZD6474 is a novel, orally available, VEGFRP tyrosine kinase inhibitor that also has activity against epidermal growth factor receptor tyrosine kinase. Chronic once-daily administration of ZD6474 has been shown to result in significant tumor growth inhibition in a range of histologically diverse human xenograft models. ZD6474 has been assessed in an open label study conducted in 2 centers in Japan. To date, results from 18 patients (aged 31-72) with solid malignant tumors refractory to standard therapy are available. Most patients had NSCLC or CRC (N = 9 and 4 respectively). Patients were required to have a life expectancy of p 3 months; those with significant cardiac, hematopoietic, hepatic or renal function were excluded, as were those who had received other anticancer therapy during the previous 4 weeks. Patients received a single oral dose of ZD6474 (100, 200, 300 or 400 mg, N = 3, 6, 6 and 3 respectively; Cycle 0) followed by a 7-day observation period. Subjects then received daily therapy, at the same dose, for a total of 28 days (Cycle 1). Further 28-day treatment cy cles were administered until evidence of tumor progression or a DLT emerged. ZD6474 therapy was well tolerated at doses of ( 300 mg/day. Common adverse events in all groups were rash (N = 14), asymptomatic QTc prolongation (N = 1 I), diarrhea (N = IO), proteinuria (N = IO) and hypertension (N = 7). Two of the 3 patients in the ZD6474 400 mg/day group developed a DLT (G3 ALT elevation and G3 hypertension); the maximum tolerated dose was therefore considered to have been exceeded at this level. ZD6474 exposure in terms of Cmax and AUC increased linearly with dose. The terminal half-life was long (median 96 hours) with no apparent change with increasing dose. The accumulation of ZD6474 was large following multiple oral daily dosing for 28 days (AUC O-24 approximately 6-14 times that following single oral doses). Preliminary observations of tumor regression (determined by RECIST) were observed in 4 patients with NSCLC receiving ZD6474 200 or 300 mg/day. Clinical evaluation of ZD6474 continues in a series of Phase II studies.
P 360 El
hTERT-specific CTL lysed lung cancer cell lines in an HLA-A24 restricted fasion
Kouhei Taiima’, Kiyotaka Kuzushima’, Hideki Endo’, Hiroyuki Kuwano3, Tetsuya Mitsudomi”. ’ Division of Immunology Aichi Cancer Center, Nagoya, Japan; p Division of Thoracic Surgery, Aichi Cancer Center, Nagoya, Japan; 3 Dept. of First Surgery, Gunma University Faculty of Medicine, Maebashi, Japan There are accumulating evidences that peptides derived from the catalytic subunit of human telomerase reverse transcriptase (hTERT) are specifically recognized by CD8+ cytotoxic T lymphocytes (CTL) which lyse cancer-derived cultured cells. Because hTERT is expressed in more than 80% of lung cancers, we investigated the cytotoxicity of human leucocyte antigen (HLA)-A*2402restricted hTERT-derived peptide 461-469 (hTERT461)-specific CTL against a panel of lung cancers. The telomerase activity, which highly correlates with hTERT expression, was detected in all lung cancer cell lines examined. An hTERT461 -specific CTL clone, designated K3-1, was established from a healthy donor by repetitive peptide stimulation with the guidpnce of HLAA24/hTERT461-tetramer. K3-1 exhibited cytotoxicity against 4 out of 6 HLAA24-positive cell lines, but not 4 HLA-A24-negative ones. These findings indicate that the CTL epitope for K3-1 is naturally processed in HLA-A2Cpositive lung cancer cells. In addition, K3-1 also lysed HLA-A2Cpositive lymphoblastoid cell lines (LCL) whose telomerase activity was positive. Our data outline usefulness of peptide hTERT461 in immunotherapy for lung cancer as well as other malignancies reported to date. The findings of this study confirm and ex-
Poster Session 2/Navel Therapies
and on progression SRL172 was continued if further treatment of any kind was considered. All patients were followed for survival. Results: 76 patients were randomised, 38 to each arm. 72 patients received carboplatin and etoposide chemotherapy. There was no difference in response rates between the two arms, 73% without vaccine and 68% with vaccine. Median duration of response and median survival was 9 months for both groups. The standard arm (chemotherapy only) response was better than the pilot study of 57% as was the median survival; 9 compared to 8.6 months. Conclusion: Despite initial encouraging results from phase II data, this study suggests no advantage to response or survival in adding SRL172 to standard treatment in SCLC. Improved results in the standard arm of this phase Ill study compared to the anthracycline/low dose platinum regimen used in the phase II study may account for the lack of difference. The majority of patients received etoposide and carboplatin as compared to MVP (mitomycin, vinblastine and cisplatin) and ACE (adriamycin, cyclophosphamide and etoposide) in the original pilot. Putting together this result with SRL172 in SCLC and the results of SRL172 in NSCLC, the strategy of combining SRL172 with chemotherapy will not be pursued.
I P 357
Cyclooxygenase-2 (COX-2) inhibition in advanced non-small cell lung cancer (NSCLC): preliminary results of a phase II trial (THO-0054)
lldiko Csiki, Adriana Gonzalez, David P. Carbone, Shiva Gautam, Alan Sandler, Norma Campbell, Ben Garcia, Jason Morrow, David H. Johnson. Vanderbilt-lngram Cancer Center, Nashville, USA COX-2 is upregulated in many malignancies including NSCLC & may play an integral role in the growth & development of cancer. Prostaglandin E2 (PGE2), a downstream product of COX-2, can promote tumor growth & invasion via stimulation of vascular endothelial growth factor (VEGF), inhibition of immune surveillance & upregulation of Bcl-2 and various MMPs. To assess the role of COX-2 inhibition in recurrent NSCLC, we initiated a phase II trial combining celecoxib (a selective inhibitor of COX-2) 400 mg P.0 bid & docetaxel 75 mg/m2 I.V. q3wk. Eligibility requirements include histologically confirmed NSCLC, 21 prior chemotherapy regimens, ECOG PS=O-I, ALT/AST/AP &I.5 ULN, Hb>8 g/dl, WBC ?1500/~1 & plt>lOOk, no current NSAID use or sulfa allergy. Blood & urine samples are obtained pre- & post-celecoxib for angiogenic markers & PGE-M (major urinary metabolite of PGE2) assays respectively. To date, 31 patients are eligible for response assessment with the following outcomes: PR = 4, SD = 6, baseline = 3, PD = 18. MTDP = 53 days & median survival = 240 days. COX-2 expression by immunohistochemistry was elevated in 9/12 (75%) analyzed tumors. Average serum VEGF levels (n=38) pre- & post-celecoxib were 749.7 pg/ml & 536.8 pg/ml respectively (31% decrease, p=O.O03). Postcelecoxib serum endostatin levels (n=38) increased from 87.2 rig/ml to 161.2 rig/ml (p=O.2) and serum VEGF to endostatin ratio (n=38) decreased from 11.9 to 7.2 (41% decrease, p=O.Oi) following celecoxib administration. Post- vs precelecoxib intra-tumoral tissue PGE2 levels, obtained from a laboratory correlative study (THO 0055), demonstrated a marked decline (47.5 rig/g vs. 237.9 rig/g respectively). These preliminary data indicate that celecoxib inhibits intratumoral COX-2 leading to a decrease in intratumoral PGEP levels that in turn may modulate downstream angiogenic effects. Enrollment will continue to a planned accrual of 54 pts. Grant support: NIH grants CA90949 (Lung SPORE) & CA68485 &from Aventis Pharmaceuticals. Celecoxib generously provided by Pharmacia.
I P 358
Dose Escalation Study of Pivanex (a Histone Deacetylase Inhibitor) in Combination with Docetaxel for Advanced Non-Small Cell Lung Cancer
Tony Reid’, Thomas M. Cosgriff2, Kristen Yet-?, Piotr Scislowski3, Frank H. Valone“, Anish Bhatnagar3, Frank A. Scappaticci3. r VA Hospital, Palo Alto, CA, Pa/o Alfo, USA; 2 Hematology and Oncology Specialist, LLC, Metairie, USA; 3 Titan Pharmaceuticals, Inc., South San Francisco, USA; 4 Titan Pharmaceuticals, Inc., South San Francisco, CA Pivanex is a histone deacetylase inhibitor that induces tumor cell differentiation and/or apoptosis. It has been well tolerated in clinical trials and has shown preliminary evidence for efficacy as a single agent in patients with advanced non-small cell lung cancer (NSCLC) who have previously received chemotherapy. In a previous Phase I study of Pivanex alone, the drug was well tolerated in the dose range 0.047-3.3 g/m2/d administered on Days l-3 of a 21 day cycle. The most common toxicities were fatigue, dysgeusia, and nausea. In a Phase II trial of advanced NSCLC with single agent Pivanex, 3 patients out of 29 (10%) who had received less than 3 prior chemotherapy regimens showed partial responses with one patient currently receiving drug after 29 cycles of therapy. Patients who received less than 3 prior chemotherapy regimens also had a median survival of 11 months and their one year survival was 47%. In recent preclinical studies, Pivanex has shown synergy with docetaxel for growth inhi-
bition of NSCLC cell lines in vifro and for improved survival in animal models. Because the drug has shown: (1) an excellent safety profile, (2) promising activity in clinical trials of NSCLC, (3) no overlapping toxicities with docetaxel, and (4) synergy with docetaxel, we undertook a dose escalation study to assess the safety of Pivanex combined with docetaxel. Pivanex is administered intravenously over 6 hours/day on Days 1-3. Docetaxel is administered on Day 4 (75 mg/m’). The regimen is repeated every 3 weeks. To date, accrual into the first cohort has been completed at a Pivanex dose of 1.5 g/m’ in combination with 75 mg/m” of docetaxel. No dose-limiting toxicity was observed. The plan is to escalate the Pivanex dose over multiple cohorts until the maximally tolerated or planned dose is reached. This dose will be used in a subsequent Phase Ilb trial that will randomize 225 patients with advanced, refractory NSCLC to Pivanex + docetaxel versus docetaxel alone.
P 359 El
Results from a Phase I study of the oral VEGF receptor . . . . . tyrosme kmase mhlbitor ZD6474, in patients with solid tumors
Catherine Wheeler’, Hironobu Minami’, Hiromichi Ebi’, Makoto Tahara”, Yasutsuna Sasaki2, Noboru Yamamoto3, Yasuhide Yamada3, Tomohide Tamura3, Nagahiro Saijo3. ’ AstraZeneca, Waltham, USA; 2 National Cancer Center Hospital East, Chiba, Japan; 3 National Cancer Center Hospital, Tokyo, Japan ZD6474 is a novel, orally available, VEGFRP tyrosine kinase inhibitor that also has activity against epidermal growth factor receptor tyrosine kinase. Chronic once-daily administration of ZD6474 has been shown to result in significant tumor growth inhibition in a range of histologically diverse human xenograft models. ZD6474 has been assessed in an open label study conducted in 2 centers in Japan. To date, results from 18 patients (aged 31-72) with solid malignant tumors refractory to standard therapy are available. Most patients had NSCLC or CRC (N = 9 and 4 respectively). Patients were required to have a life expectancy of p 3 months; those with significant cardiac, hematopoietic, hepatic or renal function were excluded, as were those who had received other anticancer therapy during the previous 4 weeks. Patients received a single oral dose of ZD6474 (100, 200, 300 or 400 mg, N = 3, 6, 6 and 3 respectively; Cycle 0) followed by a 7-day observation period. Subjects then received daily therapy, at the same dose, for a total of 28 days (Cycle 1). Further 28-day treatment cy cles were administered until evidence of tumor progression or a DLT emerged. ZD6474 therapy was well tolerated at doses of ( 300 mg/day. Common adverse events in all groups were rash (N = 14), asymptomatic QTc prolongation (N = 1 I), diarrhea (N = IO), proteinuria (N = IO) and hypertension (N = 7). Two of the 3 patients in the ZD6474 400 mg/day group developed a DLT (G3 ALT elevation and G3 hypertension); the maximum tolerated dose was therefore considered to have been exceeded at this level. ZD6474 exposure in terms of Cmax and AUC increased linearly with dose. The terminal half-life was long (median 96 hours) with no apparent change with increasing dose. The accumulation of ZD6474 was large following multiple oral daily dosing for 28 days (AUC O-24 approximately 6-14 times that following single oral doses). Preliminary observations of tumor regression (determined by RECIST) were observed in 4 patients with NSCLC receiving ZD6474 200 or 300 mg/day. Clinical evaluation of ZD6474 continues in a series of Phase II studies.
P 360 El
hTERT-specific CTL lysed lung cancer cell lines in an HLA-A24 restricted fasion
Kouhei Taiima’, Kiyotaka Kuzushima’, Hideki Endo’, Hiroyuki Kuwano3, Tetsuya Mitsudomi”. ’ Division of Immunology Aichi Cancer Center, Nagoya, Japan; p Division of Thoracic Surgery, Aichi Cancer Center, Nagoya, Japan; 3 Dept. of First Surgery, Gunma University Faculty of Medicine, Maebashi, Japan There are accumulating evidences that peptides derived from the catalytic subunit of human telomerase reverse transcriptase (hTERT) are specifically recognized by CD8+ cytotoxic T lymphocytes (CTL) which lyse cancer-derived cultured cells. Because hTERT is expressed in more than 80% of lung cancers, we investigated the cytotoxicity of human leucocyte antigen (HLA)-A*2402restricted hTERT-derived peptide 461-469 (hTERT461)-specific CTL against a panel of lung cancers. The telomerase activity, which highly correlates with hTERT expression, was detected in all lung cancer cell lines examined. An hTERT461 -specific CTL clone, designated K3-1, was established from a healthy donor by repetitive peptide stimulation with the guidpnce of HLAA24/hTERT461-tetramer. K3-1 exhibited cytotoxicity against 4 out of 6 HLAA24-positive cell lines, but not 4 HLA-A24-negative ones. These findings indicate that the CTL epitope for K3-1 is naturally processed in HLA-A2Cpositive lung cancer cells. In addition, K3-1 also lysed HLA-A2Cpositive lymphoblastoid cell lines (LCL) whose telomerase activity was positive. Our data outline usefulness of peptide hTERT461 in immunotherapy for lung cancer as well as other malignancies reported to date. The findings of this study confirm and ex-