Safety, tolerability, and pharmacokinetics of IPI-493, an oral Hsp90 inhibitor, in patients with advanced cancers
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Background:
Inhibition of the Hsp90 chaperone protein is associated with clinical activity in selected patients (pts). IPI-493, an oral Hsp90 inhibitor, was assessed in advanced solid and hematologic malignancies in two phase 1 studies. Study objectives included determination of the following: maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended phase 2 dose, safety/tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), and clinical activity.
Methods:
Pts with advanced cancers received oral IPI-493 for 21-day cycles in a routine 3+3, sequential dose escalation design with three unique schedules: three times weekly for 2 weeks + 1 week rest (TIW), twice weekly for 2 weeks + 1 week rest (BIW), and once weekly continuously (QW). PK and PD samples were obtained in Cycle 1 during Weeks 1 and 3. CT scans were performed at baseline and every 2 cycles thereafter.
Results:
IPI-493 (TIW n=14, BIW n=21 and QW n=22) at doses from 50 to 250 mg was administered to 57 pts (53 with solid tumors, 4 with hematologic malignancies) with a median age of 58 years (range 21-86), ECOG score 0-1, and a median of 5 previous chemotherapy agents (range 1-16). The most common tumor types were colorectal cancer (10 pts) and gastrointestinal stromal tumor (6 pts). The median time on study was 65 days (range 15-544). Fourteen total DLTs were observed in 4 pts on the TIW (200 mg and 150 mg) schedule and 1 pt on the BIW (125 mg) schedule, which were primarily elevations in aspartate aminotransferase (AST), alanine aminotransferase, and alkaline phosphatase (ALP). No DLTs were observed on the QW schedule. DLTs of metabolic acidosis and acute renal failure were fatal in a single pt; all other DLTs were reversible. A maximum tolerated dose was not determined. The most common treatment-related adverse events were fatigue (35%), diarrhea (30%), elevated AST (28%), elevated ALP (25%), and nausea (21%). Maximal plasma concentrations occurred approximately 2-3 hours following single and repeat oral administration. Across all doses and schedules, the mean terminal elimination half life was approximately 14 hours, with no drug accumulation observed upon repeat dosing. Systemic exposure increased with dose across the 50-150 mg dose levels and demonstrated a plateau at 150 mg with no further increases in mean exposure at doses up to 250 mg.
Conclusions:
IPI-493 tolerability was schedule dependent, with increasing toxicity identified on the TIW schedule. Development of IPI-493 is no longer being pursued due to the lack of increased exposure with increasing doses.
Note INFI is pursuing their other first generation HSP90 inhibitor (IPI-504 or retaspamycin chloride) in phase 2 development and has abandoned IPI-493.
Link
Background:
Inhibition of the Hsp90 chaperone protein is associated with clinical activity in selected patients (pts). IPI-493, an oral Hsp90 inhibitor, was assessed in advanced solid and hematologic malignancies in two phase 1 studies. Study objectives included determination of the following: maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), recommended phase 2 dose, safety/tolerability, pharmacokinetics (PK)/pharmacodynamics (PD), and clinical activity.
Methods:
Pts with advanced cancers received oral IPI-493 for 21-day cycles in a routine 3+3, sequential dose escalation design with three unique schedules: three times weekly for 2 weeks + 1 week rest (TIW), twice weekly for 2 weeks + 1 week rest (BIW), and once weekly continuously (QW). PK and PD samples were obtained in Cycle 1 during Weeks 1 and 3. CT scans were performed at baseline and every 2 cycles thereafter.
Results:
IPI-493 (TIW n=14, BIW n=21 and QW n=22) at doses from 50 to 250 mg was administered to 57 pts (53 with solid tumors, 4 with hematologic malignancies) with a median age of 58 years (range 21-86), ECOG score 0-1, and a median of 5 previous chemotherapy agents (range 1-16). The most common tumor types were colorectal cancer (10 pts) and gastrointestinal stromal tumor (6 pts). The median time on study was 65 days (range 15-544). Fourteen total DLTs were observed in 4 pts on the TIW (200 mg and 150 mg) schedule and 1 pt on the BIW (125 mg) schedule, which were primarily elevations in aspartate aminotransferase (AST), alanine aminotransferase, and alkaline phosphatase (ALP). No DLTs were observed on the QW schedule. DLTs of metabolic acidosis and acute renal failure were fatal in a single pt; all other DLTs were reversible. A maximum tolerated dose was not determined. The most common treatment-related adverse events were fatigue (35%), diarrhea (30%), elevated AST (28%), elevated ALP (25%), and nausea (21%). Maximal plasma concentrations occurred approximately 2-3 hours following single and repeat oral administration. Across all doses and schedules, the mean terminal elimination half life was approximately 14 hours, with no drug accumulation observed upon repeat dosing. Systemic exposure increased with dose across the 50-150 mg dose levels and demonstrated a plateau at 150 mg with no further increases in mean exposure at doses up to 250 mg.
Conclusions:
IPI-493 tolerability was schedule dependent, with increasing toxicity identified on the TIW schedule. Development of IPI-493 is no longer being pursued due to the lack of increased exposure with increasing doses.
Note INFI is pursuing their other first generation HSP90 inhibitor (IPI-504 or retaspamycin chloride) in phase 2 development and has abandoned IPI-493.
The novel Hedgehog pathway inhibitor, IPI-926, delays metastatic spread and provides a survival benefit in an experimental model of pancreatic liver metastasis
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Metastasis, or the spread of disseminated tumor cells to and colonization of distal sites, is a major cause of cancer mortality. The Hedgehog (Hh) signaling pathway is normally involved in embryogenesis; however recent evidence suggests a role for this pathway in cancer and metastasis. Thus, inhibitors of Hh signaling may have potential utility as novel targeted anti-tumor therapies. IPI-926 is a novel, selective, small molecule that antagonizes the Hh pathway by binding to the Smoothened receptor, the major upstream facilitator of Hh signal transduction, and is currently in phase 2 clinical trials for pancreatic cancer, chondrosarcoma and primary myelofibrosis. Administration of IPI-926 in combination with gemcitabine inhibits incidence of metastases in a KRAS/p53 transgenic model of pancreatic cancer (Olive et al., 2009), supporting an integral role for the Hh pathway in this process.
To further explore the activity of IPI-926 in the setting of metastasis, we developed an experimental model of pancreatic cancer liver metastasis where luciferase-tagged tumor cells were implanted in the liver via an intra-splenic injection, followed by splenectomy, resulting in liver metastases. Tumor burden, as assessed by bioluminescence and survival were employed to evaluate IPI-926 activity utilizing different dosing regimens. While treatment of tumor-bearing animals with established disease provided no survival benefit, IPI-926 administered on the day of cell implant provided modest but reproducible increase in survival. However, prophylactic administration of IPI-926 beginning 14 days (d) prior to cell implant resulted in a significant decrease in disease burden and enhanced survival. The activity was dependent on the schedule of IPI-926 administration. Treatment initiated 14d prior to cell implant was more effective than 7d before cell implant, and treatment started only 2d prior to cell implantation showed no difference compared to treatment initiated on the day of cell implant. Histological analysis of pre-treated vs control livers confirmed decreased metastatic nodule formation. In addition, analysis of serum harvested from IPI-926 14d pre-treated vs control animals showed down-regulation of components of the VEGF, PDGF and MMP pathways, suggesting that IPI-926 modulation of these pathways may be involved in the observed effects on metastatic spread. The activity of IPI-926 was also evaluated in the setting of sunitinib enhancement of metastases (Ebos et al., 2010) in the above model. As has been shown previously, short, high-dose sunitinib administration resulted in striking increases in disease burden and shortening of survival compared to control animals. However, when IPI-926 was administered 14d prior to cell implant and sunitinib treatment, disease burden and survival were returned to the levels observed in the control group.In summary, IPI-926 administration delays metastasis in an experimental model of pancreatic liver metastasis and in response to high-dose anti-angiogenic therapy.
These results provide rationale for the evaluation of IPI-926 as adjuvant/neoadjuvant therapy to help control metastatic spread post surgical resection in pancreatic cancer.
Link
Metastasis, or the spread of disseminated tumor cells to and colonization of distal sites, is a major cause of cancer mortality. The Hedgehog (Hh) signaling pathway is normally involved in embryogenesis; however recent evidence suggests a role for this pathway in cancer and metastasis. Thus, inhibitors of Hh signaling may have potential utility as novel targeted anti-tumor therapies. IPI-926 is a novel, selective, small molecule that antagonizes the Hh pathway by binding to the Smoothened receptor, the major upstream facilitator of Hh signal transduction, and is currently in phase 2 clinical trials for pancreatic cancer, chondrosarcoma and primary myelofibrosis. Administration of IPI-926 in combination with gemcitabine inhibits incidence of metastases in a KRAS/p53 transgenic model of pancreatic cancer (Olive et al., 2009), supporting an integral role for the Hh pathway in this process.
To further explore the activity of IPI-926 in the setting of metastasis, we developed an experimental model of pancreatic cancer liver metastasis where luciferase-tagged tumor cells were implanted in the liver via an intra-splenic injection, followed by splenectomy, resulting in liver metastases. Tumor burden, as assessed by bioluminescence and survival were employed to evaluate IPI-926 activity utilizing different dosing regimens. While treatment of tumor-bearing animals with established disease provided no survival benefit, IPI-926 administered on the day of cell implant provided modest but reproducible increase in survival. However, prophylactic administration of IPI-926 beginning 14 days (d) prior to cell implant resulted in a significant decrease in disease burden and enhanced survival. The activity was dependent on the schedule of IPI-926 administration. Treatment initiated 14d prior to cell implant was more effective than 7d before cell implant, and treatment started only 2d prior to cell implantation showed no difference compared to treatment initiated on the day of cell implant. Histological analysis of pre-treated vs control livers confirmed decreased metastatic nodule formation. In addition, analysis of serum harvested from IPI-926 14d pre-treated vs control animals showed down-regulation of components of the VEGF, PDGF and MMP pathways, suggesting that IPI-926 modulation of these pathways may be involved in the observed effects on metastatic spread. The activity of IPI-926 was also evaluated in the setting of sunitinib enhancement of metastases (Ebos et al., 2010) in the above model. As has been shown previously, short, high-dose sunitinib administration resulted in striking increases in disease burden and shortening of survival compared to control animals. However, when IPI-926 was administered 14d prior to cell implant and sunitinib treatment, disease burden and survival were returned to the levels observed in the control group.In summary, IPI-926 administration delays metastasis in an experimental model of pancreatic liver metastasis and in response to high-dose anti-angiogenic therapy.
These results provide rationale for the evaluation of IPI-926 as adjuvant/neoadjuvant therapy to help control metastatic spread post surgical resection in pancreatic cancer.
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