A pilot pharmacokinetic trial to determine the safety and efficacy of a flavored, orally administered irinotecan VAL-413 (Orotecan®) given with temozolomide for treatment of recurrent pediatric solid tumors including but not limited to neuroblastoma, rhabdomyosarcoma, Ewing sarcoma, hepatoblastoma and medulloblastoma

Start Date25 Oct 2021

Sponsor / Collaborator

Valent Technologies LLC

100 Clinical Results associated with Valent Technologies LLC

0 Patents (Medical) associated with Valent Technologies LLC

Literatures (Medical) associated with Valent Technologies LLC

01 Jun 2023·Journal of Clinical Oncology

A pilot clinical study of oral irinotecan HCl (VAL-413) in patients with recurrent pediatric solid tumors.

Author: Oesterheld, Javier E. ; Sankar, Neil ; Kanekal, Sarath ; Wagner, Lars M. ; Geller, James I. ; Bacha, Jeffrey A. ; McManus, Meghann ; Leggas, Markos ; Brown, Dennis ; Yam, Noymi ; Lopez, Lorena

TPS10073 Background: Intravenous irinotecan hydrochloride (IRN-IV) is approved for the treatment of adult colorectal cancer and 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, bi-weekly 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 IRN-IV is inconvenient for patients, so oral regimens utilizing IRN-IV have been developed and implemented with favorable tumor response (Wagner. ClinSarcRes, 2015). Unfortunately, the palatability of the IRN-IV 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. This pilot trial will examine the safety and tolerability of this novel formulation and assess pharmacokinetics compared to current oral regimen. Methods: Eligibility: Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors and adequate bone marrow, renal and liver function, for whom irinotecan therapy is a treatment option will be enrolled. Trial Design: Two different dose levels of VAL-413, 90mg/m2/day or 110mg/m2/day will be studied in combination with fixed-dose temozolomide using a standard 3 + 3 phase I design. In the event the starting dose of 90 mg/m2/day is not tolerable due to toxicity, a lower dose of 75 mg/m2/day may be implemented. Treatment: During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO). During all subsequent cycles, only VAL-413 will be given with temozolomide in 5-day courses administered every 21 days, as tolerated. Outcome Measures:Toxicity is assessed by NCI CCTCAEv5; tumor response is assessed by RECIST 1.1. A palatability survey instrument will assess palatability of VAL-413 vs. IRN-IVPO; comparative intra-patient pharmacokinetics of irinotecan and its metabolites will be assessed. This trial is ongoing (CT.gov: NCT04337177), with no DLT observed to date. Clinical trial information: NCT04337177 .

09 Nov 2020·Neuro-Oncology

CTNI-75. A PILOT CLINICAL TRIAL OF OROTECAN (VAL-413), A NOVEL ORAL DOSAGE FORMULATION OF IRINOTECAN: IMPLICATIONS FOR PEDIATRIC BRAIN TUMORS

Author: Kanekal, Sarath ; Lopez, Lorena ; Sankar, Neil ; Brown, Dennis ; Wagner, Lars ; Leggas, Markos ; Bacha, Jeffrey

AbstractTumors 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 ≤ 30 years of age with recurrent pediatric solid tumors will be enrolled. The primary objective is 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. IRN-IVPO, evaluating palatability of VAL-413, assessing the toxicity profile of VAL-413 in combination with temozolomide, and assessment of tumor response. Toxicity is evaluated based on CTCAEv5 and tumor response based on RECISTv1.1. An update on the progress of this trial will be presented.

15 Aug 2020·Cancer Research

Abstract CT154: An ascending single and multiple dose study of the safety, tolerability, pharmacokinetics and antitumor activity of once-daily oral treatment with EO1001, a novel irreversible pan-ErbB inhibitor with promising brain penetration, in patients with advanced cancer

Author: Shen, Wang ; Brown, Dennis ; Kanekal, Sarath ; Skoff, Kathy ; Bacha, Jeffrey A. ; Wang, Zhen Zhong ; Wheeler, Helen ; Nisbet, Ian ; Sankar, Neil

AbstractBackground: ErbB receptor tyrosine kinases: EGFR (ErbB1), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4) are part of a complex network activating signaling pathways involved in cell growth and survival. Mutations causing errant ErbB activation is an oncodriver in many cancers. Inhibitors targeting ErbB mutations have transformed patient outcomes; however, treatment resistance develops rapidly and crosstalk between ErbB family members is associated with acquired resistance. The development of next-generation 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 toxicity profile and promising activity against ErbB-driven cancers in patient-derived xenograft models. Methods: This study examines the safety and tolerability of EO1001 to define a recommended dose for advanced human clinical trials and to assess efficacy. Male or female adult participants with confirmed ErbB-positive cancer, including patients with CNS disease involvement, who have progressed after standard of care therapy, with adequate bone marrow, renal and liver function are eligible. An accelerated dose-escalation design is employed. One subject per dose cohort will be recruited until drug related toxicity (%gt=G2) is observed in the first dosing cycle, after which the dose escalation scheme will revert to a 3+3 design in a modified-Fibonacci dose-escalation scheme to determine the maximum tolerated dose (MTD). Dose Escalation: Cycle 1: Patients will receive a single dose EO1001 on day 1 and single dose pharmacokinetics will be performed. Beginning on day 8, EO1001 will be administered once daily for 21 days; multi-dose pharmacokinetics will be performed. Cycles 2-6: Oral EO1001 will be administered once daily in continuous 28-day cycles for up to 20 weeks. MTD Expansion: Oral EO1001 will be administered once daily at the MTD in continuous 28-day cycles for up to 6 cycles (24 weeks). Toxicity will be assessed based on NCI CCTCAEv5 and tumor response will be assessed by RECIST 1.1 or RANO for CNS disease. CNS exposure will be evaluated in patients via CSF collection with confirmed CNS disease involvement.Citation Format: Jeffrey A. Bacha, Dennis Brown, Sarath Kanekal, Ian Nisbet, Neil Sankar, Wang Shen, Helen Wheeler, Kathy Skoff, Zhen Zhong Wang. An ascending single and multiple dose study of the safety, tolerability, pharmacokinetics and antitumor activity of once-daily oral treatment with EO1001, a novel irreversible pan-ErbB inhibitor with promising brain penetration, in patients with advanced cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT154.

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