Synta Pharma $SNTA will present the following abstracts on their HSP90 inhibitor ganetespib at ASCO June 4-7, 2011.
Abstract 7500 presents the openlabel phase 2 trial of ganetespib in advanced NSCLC. Unfortunately the data contained in the abstract are less current than what was presented in February 2011 (see summary on SNTA research page). Hopefully the data will be updated at the meeting.
Abstract e13591 summarizes preliminary phase 1 combo data of docetaxel plus gantespib that is the basis for the p2b/3 program initiating this quarter. 4 of the first 7 evaluable pts had stable disease (SD) after 2 cycles. Hopefully the data will be updated at the meeting.
Abstract 10011 summaries an open-label phase 2 trial of ganetespib in advanced GIST pts. 12/23 pts had SD, far exceeding the efficacy hurdle to expand the study. However there was concern that the dosing schedule might not be optimal for reducing tumor levels of mutant KIT protein.
Abstract 3051 updates the ongoing phase 1 trial of twice-weekly ganetespib in advanced solid tumors. 49 pts are reported, currently expanding 144 mg/m2 dose cohort due to DLT of liver enzyme elevation. Half-life 10-14 hrs. Durable PR (melanoma) and 2 durable SD (NSCLC) seen so far.
Abstract 7500 presents the openlabel phase 2 trial of ganetespib in advanced NSCLC. Unfortunately the data contained in the abstract are less current than what was presented in February 2011 (see summary on SNTA research page). Hopefully the data will be updated at the meeting.
Abstract e13591 summarizes preliminary phase 1 combo data of docetaxel plus gantespib that is the basis for the p2b/3 program initiating this quarter. 4 of the first 7 evaluable pts had stable disease (SD) after 2 cycles. Hopefully the data will be updated at the meeting.
Abstract 10011 summaries an open-label phase 2 trial of ganetespib in advanced GIST pts. 12/23 pts had SD, far exceeding the efficacy hurdle to expand the study. However there was concern that the dosing schedule might not be optimal for reducing tumor levels of mutant KIT protein.
Abstract 3051 updates the ongoing phase 1 trial of twice-weekly ganetespib in advanced solid tumors. 49 pts are reported, currently expanding 144 mg/m2 dose cohort due to DLT of liver enzyme elevation. Half-life 10-14 hrs. Durable PR (melanoma) and 2 durable SD (NSCLC) seen so far.
Saturday June 4th: Oral Presentation 8:00 AM - 8:15 AM Abstract #7500
"An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC)."
Kwok-Kin Wong, MD
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. Ganetespib has been well tolerated and has shown promising antitumor activity in early trials in multiple cancers.
Methods: Patients (pts) with advanced NSCLC who failed prior treatments received 200 mg/m2 ganetespib as a 1-hr infusion once weekly for 3 of a 4-wk cycle in a Simon two-stage study design assessing primary endpoint of PFS rate at 16 wks. Initial cohorts were defined by mutation status: A) EGFR B) KRAS C) EGFR and KRAS wild type (WT). If ≥2/14 pts in A, B or C were progression-free at 16 wks, enrollment increased to 23 pts for that cohort. Tumor response was assessed every 8 wks. Cohort D was added to include 35 additional EGFR and KRAS WT pts with adenocarcinoma histology. Additional mutational analysis of BRAF, PIK3CA, ERBB2 and MET, as well as FISH analysis for ALK translocation, were performed for Cohorts C and D.
Results: 73 pts (31 M, 42 F; median age 62 yrs, range 28-82; ECOG 0-1; prior therapies range 1-10) received a median of 2 cycles (range 1-12) of ganetespib in cohorts A (14), B (17), and C+D (42). AEs reported in ≥20% of pts included diarrhea, fatigue, nausea, anorexia, constipation, and dyspnea and were generally grade 1-2. Expansion criteria were achieved for cohort C, including a durable partial response (PR) and seven pts with prolonged stable disease (≥16 wks). Cohort D continues recruitment. Mutational analyses of Cohort C and D samples will be presented.
Conclusions: Ganetespib administered as a single-agent is well-tolerated in pts with NSCLC at 200 mg/m2 once weekly without severe liver, ocular, cardiovascular or renal toxicity. Clinical activity has been observed in pts with advanced NSCLC tumors harboring wild-type EGFR and KRAS.
Abstract # e13591 (Publication-only abstract)
A Phase 1 and Pharmacokinetic Study of Ganetespib (STA-9090), a Heat Shock Protein 90 Inhibitor, in Combination with Docetaxel in Subjects with Advanced Solid Tumor Malignancies.
R. Donald Harvey et al
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally
unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown
superior activity to these agents in preclinical studies. Ganetespib has been well tolerated
and has shown promising antitumor activity in early trials in multiple cancers. Based on
preclinical synergy between ganetespib (G) and docetaxel (D), a phase I pharmacokinetic
(PK) and feasibility study was initiated with the combination.
Methods: Patients with advanced solid tumor malignancies, ECOG performance status
(PS) 0-2 and adequate liver, renal and bone marrow function were eligible. Sequential
cohorts of patients are treated with increasing doses of D (day 1) and G (IV weekly, days
1, 8). PK sampling was performed on days 1 and 8 of cycle 1. Treatment cycles were
repeated every 3 weeks. A standard 3+3 dose escalation scheme was utilized. The
primary endpoint was determination of optimal doses of the two agents for combination
therapy.
Results: Twelve patients have been enrolled. Median age-63 (44-72); 1-M, 11-F; ECOG
PS 0-1; # of prior regimens: 1 (2 pts), 2-3 (5 pts), >3 (5 pts). At dose levels 1 (D-60
mg/m2, G-150 mg/m2) and 2 (D-75 mg/m2, G-150 mg/m2), none of 6 patients initially
treated had a DLT. Two of 4 patients at dose level 3 (D-75 mg/m2, G-200 mg/m2) had
DLTs (g4 febrile neutropenia and one g4 neutropenia of > 7 days), requiring expansion of
dose level 2. Common adverse events included neutropenia (n=9), diarrhea (n=4),
fatigue, vomiting, and nausea (n=3 each). Grade 3/4 toxicities included neutropenia (n=9)
asthenia, febrile neutropenia and pulmonary embolus (n=1 each). The median number of
cycles is 2 (1-6), with 6 patients still on study. Among 7 patients evaluable for response,
4 had disease stabilization following cycle 2, with one > 12 weeks. PK data will also be
presented.
Conclusions: The combination of docetaxel and ganetespib is well tolerated at the
recommended doses of 75 mg/m2 and 150 mg/m2, respectively. Promising anti-cancer
activity was noted, and a randomized phase II study of the combination will soon be
initiated in advanced NSCLC.
"An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC)."
Kwok-Kin Wong, MD
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. Ganetespib has been well tolerated and has shown promising antitumor activity in early trials in multiple cancers.
Methods: Patients (pts) with advanced NSCLC who failed prior treatments received 200 mg/m2 ganetespib as a 1-hr infusion once weekly for 3 of a 4-wk cycle in a Simon two-stage study design assessing primary endpoint of PFS rate at 16 wks. Initial cohorts were defined by mutation status: A) EGFR B) KRAS C) EGFR and KRAS wild type (WT). If ≥2/14 pts in A, B or C were progression-free at 16 wks, enrollment increased to 23 pts for that cohort. Tumor response was assessed every 8 wks. Cohort D was added to include 35 additional EGFR and KRAS WT pts with adenocarcinoma histology. Additional mutational analysis of BRAF, PIK3CA, ERBB2 and MET, as well as FISH analysis for ALK translocation, were performed for Cohorts C and D.
Results: 73 pts (31 M, 42 F; median age 62 yrs, range 28-82; ECOG 0-1; prior therapies range 1-10) received a median of 2 cycles (range 1-12) of ganetespib in cohorts A (14), B (17), and C+D (42). AEs reported in ≥20% of pts included diarrhea, fatigue, nausea, anorexia, constipation, and dyspnea and were generally grade 1-2. Expansion criteria were achieved for cohort C, including a durable partial response (PR) and seven pts with prolonged stable disease (≥16 wks). Cohort D continues recruitment. Mutational analyses of Cohort C and D samples will be presented.
Conclusions: Ganetespib administered as a single-agent is well-tolerated in pts with NSCLC at 200 mg/m2 once weekly without severe liver, ocular, cardiovascular or renal toxicity. Clinical activity has been observed in pts with advanced NSCLC tumors harboring wild-type EGFR and KRAS.
Abstract # e13591 (Publication-only abstract)
A Phase 1 and Pharmacokinetic Study of Ganetespib (STA-9090), a Heat Shock Protein 90 Inhibitor, in Combination with Docetaxel in Subjects with Advanced Solid Tumor Malignancies.
R. Donald Harvey et al
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally
unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown
superior activity to these agents in preclinical studies. Ganetespib has been well tolerated
and has shown promising antitumor activity in early trials in multiple cancers. Based on
preclinical synergy between ganetespib (G) and docetaxel (D), a phase I pharmacokinetic
(PK) and feasibility study was initiated with the combination.
Methods: Patients with advanced solid tumor malignancies, ECOG performance status
(PS) 0-2 and adequate liver, renal and bone marrow function were eligible. Sequential
cohorts of patients are treated with increasing doses of D (day 1) and G (IV weekly, days
1, 8). PK sampling was performed on days 1 and 8 of cycle 1. Treatment cycles were
repeated every 3 weeks. A standard 3+3 dose escalation scheme was utilized. The
primary endpoint was determination of optimal doses of the two agents for combination
therapy.
Results: Twelve patients have been enrolled. Median age-63 (44-72); 1-M, 11-F; ECOG
PS 0-1; # of prior regimens: 1 (2 pts), 2-3 (5 pts), >3 (5 pts). At dose levels 1 (D-60
mg/m2, G-150 mg/m2) and 2 (D-75 mg/m2, G-150 mg/m2), none of 6 patients initially
treated had a DLT. Two of 4 patients at dose level 3 (D-75 mg/m2, G-200 mg/m2) had
DLTs (g4 febrile neutropenia and one g4 neutropenia of > 7 days), requiring expansion of
dose level 2. Common adverse events included neutropenia (n=9), diarrhea (n=4),
fatigue, vomiting, and nausea (n=3 each). Grade 3/4 toxicities included neutropenia (n=9)
asthenia, febrile neutropenia and pulmonary embolus (n=1 each). The median number of
cycles is 2 (1-6), with 6 patients still on study. Among 7 patients evaluable for response,
4 had disease stabilization following cycle 2, with one > 12 weeks. PK data will also be
presented.
Conclusions: The combination of docetaxel and ganetespib is well tolerated at the
recommended doses of 75 mg/m2 and 150 mg/m2, respectively. Promising anti-cancer
activity was noted, and a randomized phase II study of the combination will soon be
initiated in advanced NSCLC.
Saturday June 4th: Poster Presentation Abstract #10011
"An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in patients (pts) with metastatic and/or unresectable GIST."
George D. Demetri, MD
Background: Ganetespib, a potent, synthetic small-molecule inhibitor of Hsp90, has shown an improved safety profile relative to 1st-generation agents as well as promising signals of antitumor activity in early clinical studies, including one pt with PDGFRAD842V mutant GIST. Preclinical studies have shown that human GIST cells with primary or secondary TKI-resistance mutations are highly sensitive to ganetespib, justifying this phase 2 trial in GIST.
Methods: Pts with advanced GIST following failure of prior therapy (tx) received ganetespib (200 mg/m2) as a 1 hour IV infusion qw for 3 wks of a 28 day cycle. GIST status was assessed q8 wks per RECIST, until progression. In this Simon’s 2 stage study design, if ≥4/23 pts in Stage 1 had clinical benefit (CR+PR+SD ≥ 16 wks) enrolment would continue with Stage 2. Hsp90 client protein levels were analyzed in biopsies pre-tx and 24-48 h post-ganetespib in a subset of pts.
Results: 26 pts (15 M, 11 F; median age 53 yrs, range 33-67; ECOG status 0-1; median 5 prior tx regimens, range 3-12, wild-type PDGFRA) received a median of 2 cycles of ganetespib (range 1-8). AEs reported in >20% of pts were generally NCI CTC grade 1-2 and included diarrhea, fatigue, nausea, vomiting, increased alkaline phosphatase, headache, insomnia, and abdominal pain. 12/23 evaluable pts had SD (4 SD ≥16 wks, 8 SD ≥8 wks), meeting formal criteria to enroll Stage 2. However, analysis of client proteins in paired tumor biopsies from 4 pts did not show prolonged inhibition of activated KIT or its downstream pathways. These data suggest the once-weekly tx schedule is likely not optimal for inhibition of KIT. At this time, accrual has been limited to pts with PDGFRA mutations to allow further preclinical development of alternative schedules and combinations.
Conclusions: Ganetespib given by once-weekly dosing was well tolerated in pts with heavily pre-treated advanced GIST, with no evidence of severe liver, ocular, cardiac or renal toxicity. Disease stabilization was seen in a subset of pts. Advanced preclinical modeling is ongoing to optimize the impact of ganetespib on mutant KIT in GIST.
Monday June 6th: Poster Presentation Abstract #3051
"A phase I dose-escalation study of the Hsp90 inhibitor ganetespib (STA-9090) administered twice weekly in patients with solid tumors: Updated report."
Daniel C. Cho, MD
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. It has been well tolerated and shown promising antitumor activity in early trials in multiple cancers. Preclinical data indicate that different client proteins show disparate expression kinetics upon Hsp90 inhibition. Therefore, twice-weekly dosing may be needed in some tumor types.
Methods: Patients (pts) with solid tumors who have exhausted standard treatment options received ganetespib as a 1 hr infusion twice weekly for 3 weeks (wks) of a 28 day cycle until disease progression. Serial PK and pharmacodynamic samples were obtained during cycle 1. Safety assessments included frequency and grade of AEs, laboratory parameters and ECG changes.
Results: Data are presented for 49 pts (22 M, 27 F; median age 55 yrs, range 32-81; ECOG status range 0-2) treated at doses from 2-144 mg/m2. Pts received a median of 2 (range 1-12) cycles of ganetespib. AEs reported in ≥20% of pts treated at doses from 2-120 mg/m2 are fatigue, diarrhea, nausea, anemia, abdominal pain, constipation, anorexia, vomiting, and headache; the majority of events were mild to moderate in severity with absence of severe liver, ocular, cardiac and renal toxicity. Two DLTs (elevated transaminases) have been reported in the 10 and 144 mg/m2 cohorts; expansion of the latter cohort is ongoing. Ganetespib shows linear PK, rapid distribution, a mean terminal half-life of 10-14 hours, a volume of distribution greater than total body water and no accumulation in plasma. HSP70 plasma protein levels will be presented. A confirmed durable PR by RECIST has been seen in a pt with metastatic melanoma. Additionally, 2 NSCLC pts who received 6 months of treatment had durable SD, with tumor shrinkage.
Conclusions: Ganetespib has been well tolerated at dose levels up to 120 mg/m2 administered twice weekly. Preliminary safety profile, activity signals and differences in client protein kinetics warrant continued evaluation of ganetespib using a twice-weekly dosing regimen. Dose escalation continues
"An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) in patients (pts) with metastatic and/or unresectable GIST."
George D. Demetri, MD
Background: Ganetespib, a potent, synthetic small-molecule inhibitor of Hsp90, has shown an improved safety profile relative to 1st-generation agents as well as promising signals of antitumor activity in early clinical studies, including one pt with PDGFRAD842V mutant GIST. Preclinical studies have shown that human GIST cells with primary or secondary TKI-resistance mutations are highly sensitive to ganetespib, justifying this phase 2 trial in GIST.
Methods: Pts with advanced GIST following failure of prior therapy (tx) received ganetespib (200 mg/m2) as a 1 hour IV infusion qw for 3 wks of a 28 day cycle. GIST status was assessed q8 wks per RECIST, until progression. In this Simon’s 2 stage study design, if ≥4/23 pts in Stage 1 had clinical benefit (CR+PR+SD ≥ 16 wks) enrolment would continue with Stage 2. Hsp90 client protein levels were analyzed in biopsies pre-tx and 24-48 h post-ganetespib in a subset of pts.
Results: 26 pts (15 M, 11 F; median age 53 yrs, range 33-67; ECOG status 0-1; median 5 prior tx regimens, range 3-12, wild-type PDGFRA) received a median of 2 cycles of ganetespib (range 1-8). AEs reported in >20% of pts were generally NCI CTC grade 1-2 and included diarrhea, fatigue, nausea, vomiting, increased alkaline phosphatase, headache, insomnia, and abdominal pain. 12/23 evaluable pts had SD (4 SD ≥16 wks, 8 SD ≥8 wks), meeting formal criteria to enroll Stage 2. However, analysis of client proteins in paired tumor biopsies from 4 pts did not show prolonged inhibition of activated KIT or its downstream pathways. These data suggest the once-weekly tx schedule is likely not optimal for inhibition of KIT. At this time, accrual has been limited to pts with PDGFRA mutations to allow further preclinical development of alternative schedules and combinations.
Conclusions: Ganetespib given by once-weekly dosing was well tolerated in pts with heavily pre-treated advanced GIST, with no evidence of severe liver, ocular, cardiac or renal toxicity. Disease stabilization was seen in a subset of pts. Advanced preclinical modeling is ongoing to optimize the impact of ganetespib on mutant KIT in GIST.
Monday June 6th: Poster Presentation Abstract #3051
"A phase I dose-escalation study of the Hsp90 inhibitor ganetespib (STA-9090) administered twice weekly in patients with solid tumors: Updated report."
Daniel C. Cho, MD
Background: Ganetespib is a potent, next-generation Hsp90 inhibitor that is structurally unrelated to the first-generation ansamycin class of Hsp90 inhibitors and has shown superior activity to these agents in preclinical studies. It has been well tolerated and shown promising antitumor activity in early trials in multiple cancers. Preclinical data indicate that different client proteins show disparate expression kinetics upon Hsp90 inhibition. Therefore, twice-weekly dosing may be needed in some tumor types.
Methods: Patients (pts) with solid tumors who have exhausted standard treatment options received ganetespib as a 1 hr infusion twice weekly for 3 weeks (wks) of a 28 day cycle until disease progression. Serial PK and pharmacodynamic samples were obtained during cycle 1. Safety assessments included frequency and grade of AEs, laboratory parameters and ECG changes.
Results: Data are presented for 49 pts (22 M, 27 F; median age 55 yrs, range 32-81; ECOG status range 0-2) treated at doses from 2-144 mg/m2. Pts received a median of 2 (range 1-12) cycles of ganetespib. AEs reported in ≥20% of pts treated at doses from 2-120 mg/m2 are fatigue, diarrhea, nausea, anemia, abdominal pain, constipation, anorexia, vomiting, and headache; the majority of events were mild to moderate in severity with absence of severe liver, ocular, cardiac and renal toxicity. Two DLTs (elevated transaminases) have been reported in the 10 and 144 mg/m2 cohorts; expansion of the latter cohort is ongoing. Ganetespib shows linear PK, rapid distribution, a mean terminal half-life of 10-14 hours, a volume of distribution greater than total body water and no accumulation in plasma. HSP70 plasma protein levels will be presented. A confirmed durable PR by RECIST has been seen in a pt with metastatic melanoma. Additionally, 2 NSCLC pts who received 6 months of treatment had durable SD, with tumor shrinkage.
Conclusions: Ganetespib has been well tolerated at dose levels up to 120 mg/m2 administered twice weekly. Preliminary safety profile, activity signals and differences in client protein kinetics warrant continued evaluation of ganetespib using a twice-weekly dosing regimen. Dose escalation continues
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