Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult ... more Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important...
Introduction: Poly-adenosine diphosphate-ribose polymerase (PARP) inhibition is an effective, FDA... more Introduction: Poly-adenosine diphosphate-ribose polymerase (PARP) inhibition is an effective, FDA-approved treatment against cancers with DNA damage repair (DDR) deficiencies, such as BRCA1 or BRCA2 mutations. PARP is a core component of single-strand break repair, so in tumors with DDR deficiencies, double-strand breaks (DSBs) and single-strand breaks (SSBs) accumulate and lead to cell death. Combining PARP inhibition with other DNA-damaging therapies, such as DNA alkylating agents, has proven to be more effective than PARP inhibition alone, as DNA alkylators can lead to the formation of DSBs. However, combination therapies often require sequential administration due to pharmacokinetic considerations and overlapping toxicities, severely limiting their clinical utility. Here, we evaluate a novel class of PARP inhibitors combined with DNA alkylating functionality, in formulation as a single molecule. Methods: PARP1 activity was determined using the Trevigen Universal Colorimetric PAR...
Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal c... more Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to improve convenience, reduce in-clinic time and overall cost of treatment. Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. We will report on an ongoing Phase 1-2 first-in-human clinical trial of VAL-413, designed to test the hypothesis that V...
TPS10063 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment ... more TPS10063 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days, every 21 days has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001 ). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015 ). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet clinical need...
CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted t... more CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive cross-talk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1–2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, wi...
CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted t... more CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive crosstalk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1-2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, wit...
CNS metastasis has become a prominent driver of morbidity and mortality in recent years as new ta... more CNS metastasis has become a prominent driver of morbidity and mortality in recent years as new targeted therapies have improved systemic outcomes. Mutations in the ErbB family of kinases are known oncodrivers in many of these cancers. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor with superior CNS penetration targeting ErbB1, ErbB2 and ErbB4. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver func...
Tumors of the brain and of the central nervous system (CNS) are the most common solid tumors in c... more Tumors of the brain and of the central nervous system (CNS) are the most common solid tumors in children. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label in a wide range of treatment regimens for recurrent adult and pediatric tumors including glioblastoma, pediatric glioma and medulloblastoma. Recently, commercially available IRN-IV has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the poor palatability of this preparation leads to poor compliance, especially in pediatric patients. VAL-413 is novel formulation developed to improve tolerability of oral irinotecan. The current study (NCT04337177) evaluates the safety and pharmacokinetics of VAL-413 administered with temozolomide for treatment of recurrent pediatric solid tumors. METHODS: Up to 20 patients ≥ 1 to ...
Mutations causing errant ErbB activation are implicated in many cancers, including tumors correla... more Mutations causing errant ErbB activation are implicated in many cancers, including tumors correlated with high incidence of CNS metastasis. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs, particularly in advanced disease. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. EO1001 is being advanced into first-in-man studies under the Australia Clinical Trials Notification (CTN) scheme (ANZCTR Reg.#ACTRN12320000589343p). METHODS: Adult patients with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal...
Background: Ewing9s sarcoma (EWS) is the second most common malignant bone tumor affecting childr... more Background: Ewing9s sarcoma (EWS) is the second most common malignant bone tumor affecting children, adolescents and young adults. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label as salvage therapy for patients with recurrent EWS, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, and medulloblastoma. Prior adult and pediatric trials demonstrate that the combination of intravenous irinotecan and temozolomide has significant antitumor activity in advanced EWS. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the taste of the iv preparation can be limiting, leading to poor compliance especially in pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. Methods: VAL-413 is novel formulation developed to improve tolerability of oral irinotecan for the treatment of cancer. This study (USIND#135675) aims to establish the recommended phase II dose of VAL-413 when given in combination with temozolomide. Secondary objectives include characterization of the pharmacokinetics of VAL-413 vs. conventional irinotecan given orally (IRN-IVPO), evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Up to 20 patients g 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT137.
Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult ... more Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label to treat a range of adult and pediatric tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days in combination with other agents such as temozolomide has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important...
Introduction: Poly-adenosine diphosphate-ribose polymerase (PARP) inhibition is an effective, FDA... more Introduction: Poly-adenosine diphosphate-ribose polymerase (PARP) inhibition is an effective, FDA-approved treatment against cancers with DNA damage repair (DDR) deficiencies, such as BRCA1 or BRCA2 mutations. PARP is a core component of single-strand break repair, so in tumors with DDR deficiencies, double-strand breaks (DSBs) and single-strand breaks (SSBs) accumulate and lead to cell death. Combining PARP inhibition with other DNA-damaging therapies, such as DNA alkylating agents, has proven to be more effective than PARP inhibition alone, as DNA alkylators can lead to the formation of DSBs. However, combination therapies often require sequential administration due to pharmacokinetic considerations and overlapping toxicities, severely limiting their clinical utility. Here, we evaluate a novel class of PARP inhibitors combined with DNA alkylating functionality, in formulation as a single molecule. Methods: PARP1 activity was determined using the Trevigen Universal Colorimetric PAR...
Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal c... more Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to improve convenience, reduce in-clinic time and overall cost of treatment. Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. VAL-413 is a novel formulation developed to improve palatability of oral irinotecan. We will report on an ongoing Phase 1-2 first-in-human clinical trial of VAL-413, designed to test the hypothesis that V...
TPS10063 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment ... more TPS10063 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label for a range of adult and pediatric solid tumors including recurrent Ewing sarcoma, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, Wilms tumor, gynecologic cancers, lung cancer and medulloblastoma. Previously, a regimen of IRN-IV administered as a 60-min i.v. infusion daily for 5 days, every 21 days has been recommended use in treating children with solid tumors (Blaney. ClinCanRes, 2001 ). Protracted administration schedule of intravenous irinotecan is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed (Wagner. ClinSarcRes, 2015 ). Unfortunately, the palatability of the intravenous preparation is poor, leading to reduced compliance especially in younger pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet clinical need...
CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted t... more CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive cross-talk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1–2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, wi...
CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted t... more CNS metastases are a prominent driver of cancer morbidity and mortality, especially as targeted therapies have improved systemic outcomes. Mutations in the ErbB/HER kinase family are known oncodrivers in many cancers. Extensive crosstalk among ErbB/HER receptors suggests that inhibition of multiple family members may benefit treatment and limit drug resistance. There is a desperate need for new agents that are more tolerable and effective in treating CNS metastases. EO1001 (APL-122) is a first-in-class, oral, irreversible pan-ErbB inhibitor targeting ErbB1, ErbB2 and ErbB4 with promising CNS penetration in preclinical models. Preclinical data suggests a favorable pharmacokinetic and safety profile and activity against ErbB-driven cancers in patient-derived xenograft models. We report on a first-in-human Phase 1-2 clinical trial in progress. Adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard-of-care, wit...
CNS metastasis has become a prominent driver of morbidity and mortality in recent years as new ta... more CNS metastasis has become a prominent driver of morbidity and mortality in recent years as new targeted therapies have improved systemic outcomes. Mutations in the ErbB family of kinases are known oncodrivers in many of these cancers. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor with superior CNS penetration targeting ErbB1, ErbB2 and ErbB4. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver func...
Tumors of the brain and of the central nervous system (CNS) are the most common solid tumors in c... more Tumors of the brain and of the central nervous system (CNS) are the most common solid tumors in children. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also used off-label in a wide range of treatment regimens for recurrent adult and pediatric tumors including glioblastoma, pediatric glioma and medulloblastoma. Recently, commercially available IRN-IV has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the poor palatability of this preparation leads to poor compliance, especially in pediatric patients. VAL-413 is novel formulation developed to improve tolerability of oral irinotecan. The current study (NCT04337177) evaluates the safety and pharmacokinetics of VAL-413 administered with temozolomide for treatment of recurrent pediatric solid tumors. METHODS: Up to 20 patients ≥ 1 to ...
Mutations causing errant ErbB activation are implicated in many cancers, including tumors correla... more Mutations causing errant ErbB activation are implicated in many cancers, including tumors correlated with high incidence of CNS metastasis. ErbB family member “crosstalk” is associated with rapid development acquired resistance to ErbB TKIs, particularly in advanced disease. The development of agents targeting multiple ErbB receptors has shown promise but has been limited by toxicity and poor brain penetration. EO1001 is a first-in-class, oral, brain penetrating, irreversible pan-ErbB inhibitor. Preclinical data suggests a favorable pharmacokinetic and safety profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. EO1001 is being advanced into first-in-man studies under the Australia Clinical Trials Notification (CTN) scheme (ANZCTR Reg.#ACTRN12320000589343p). METHODS: Adult patients with confirmed ErbB-positive cancer, including patients with CNS involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal...
Background: Ewing9s sarcoma (EWS) is the second most common malignant bone tumor affecting childr... more Background: Ewing9s sarcoma (EWS) is the second most common malignant bone tumor affecting children, adolescents and young adults. Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer. IRN-IV is also widely used off-label as salvage therapy for patients with recurrent EWS, rhabdomyosarcoma, neuroblastoma, hepatoblastoma, and medulloblastoma. Prior adult and pediatric trials demonstrate that the combination of intravenous irinotecan and temozolomide has significant antitumor activity in advanced EWS. Recently, commercially available intravenous irinotecan has been administered orally (IRN-IVPO) in pediatric patients to reduce intravenous administration-related side effects, improve convenience and reduce clinic time and costs. Unfortunately, the taste of the iv preparation can be limiting, leading to poor compliance especially in pediatric patients. Development of an advanced formulation to improve tolerability and patient compliance is an important unmet need. Methods: VAL-413 is novel formulation developed to improve tolerability of oral irinotecan for the treatment of cancer. This study (USIND#135675) aims to establish the recommended phase II dose of VAL-413 when given in combination with temozolomide. Secondary objectives include characterization of the pharmacokinetics of VAL-413 vs. conventional irinotecan given orally (IRN-IVPO), evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Up to 20 patients g 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT137.
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Papers by Neil Sankar M.D