Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors

Pilot Pharmacokinetic Study of VAL-413 (Orotecan®) in Patients With Recurrent Pediatric Solid Tumors

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

Study Overview

• Status: Active, not recruiting
• Conditions: Ewing Sarcoma; Medulloblastoma; Neuroblastoma; Solid Tumors; Rhabdomyosarcoma; Hepatoblastoma
• Intervention / Treatment: Drug: VAL-413; Drug: Temozolomide

Detailed Description

Up to 20 patients ≥ 1 year of age or ≤ 30 years of age with recurrent pediatric solid tumors will be enrolled. During the first cycle of treatment, each patient will receive 4 daily doses of VAL-413 (Orotecan®) and one daily dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO), together with 5 days of concurrent temozolomide. During all subsequent cycles, only Orotecan® will be given with temozolomide in 5 day courses administered every 21 days as tolerated.

The dosing regimen in this study will be Temozolomide at 100 mg/m2/day with Orotecan® at either 90 or 110mg/m2/day, administered orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of IRN-IVPO will be substituted at the same dosage as Orotecan® during Cycle 1. Up to 17 cycles of treatment may be administered on this study.

Data collected from this study will allow for an assessment of Orotecan® safety and efficacy. Interval medical histories, targeted physical exams, complete blood counts, and other laboratory and safety assessments will be performed at Day 1 of each treatment cycle for all study subjects. At baseline and during study, disease status will be assessed by appropriate clinical and imaging evaluation (CT, MRI, or PET) and using Response Evaluation Criteria in Solid Tumors (RECIST), International Neuroblastoma Response Criteria (INRC) for patients with neuroblastoma, or the Children's Oncology Group Response Criteria for CNS tumors. In addition, a single-response taste survey will be conducted on Day 1 and Day 4 of the first cycle, which will allow patients to evaluate the taste of Orotecan®. Serum samples will be collected at various time points on Days 1 and 4 during Cycle 1 to characterize and compare the pharmacokinetic profiles of Orotecan® and conventional irinotecan given orally.

Assessment of first-cycle toxicity will be used to identify the recommended phase II dose for Orotecan®. Toxicity will be evaluated and documented using NCI CTCAE guidelines. The recommended Phase II dose will be identified as the highest dose at which no more than 1 of 6 patients experiences a first cycle dose limiting toxicity (DLT). Additional study subjects may be enrolled at the recommended Phase II dose to ensure balanced safety and pharmacokinetic data is obtained for at least 3 patients < 12 years old and at least 3 patients > 12 years old.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Arizona
    • Phoenix, Arizona, United States, 85016
      • Phoenix Children's Hospital
  • California
    • San Francisco, California, United States, 94143
      • UCSF, Mission Bay - Benioff Children's Hospital
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20010
      • Children's National Research Institute - Children's National Hospital
  • Georgia
    • Atlanta, Georgia, United States, 30329
      • Children's Healthcare of Atlanta - Arthur M. Blank Hospital
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Indiana University School of Medicine, Riley Hospital for Children
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University - St. Louis
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27514
      • University of North Carolina at Chapel Hill - North Carolina Cancer Hospital
    • Charlotte, North Carolina, United States, 28204
      • Atrium Health Levine Children's Hospital - Carolinas Medical Center
    • Durham, North Carolina, United States, 27710
      • Duke University Children's Hospital and Health Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Cincinnati Children's Hospital Medical Center
  • Tennessee
    • Nashville, Tennessee, United States, 37203
      • Sarah Cannon Research Institute, Pediatric Hematology & Oncology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 30 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Patients must be 1 year of age to ≤ 30 years of age at the time of study entry.
2. Patients must have had histologic verification of a solid tumor or CNS tumor at either original diagnosis or relapse.
3. Measurable or evaluable disease is not required for enrollment on this safety/feasibility study.
4. Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life or for which irinotecan and/or temozolomide are acceptable therapeutic options based on existing standard of care available.
5. Karnofsky Performance Status ≥ 50% for patients > 16 years of age and Lansky Performance Status ≥ 50 for patients ≤ 16 years of age. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score.
6. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraception method during and for 30 days after study treatment. (Abstinence is considered an acceptable method of effective contraception.)
7. Prior treatment with temozolomide, vincristine or irinotecan is allowed, although patients must not have had disease progression while receiving either irinotecan, vincristine or temozolomide.

8. Patients must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study, as described below:

   1. Myelosuppressive chemotherapy: patients must not have received myelosuppressive chemotherapy within 21 days of first study treatment, but nitrosourea within 8 weeks (42 days) of first study treatment
   2. Anti-cancer agents not known to be myelosuppressive (e.g., not associated with drops in platelet or neutrophil count): must not have received these therapies within 7 days of first study treatment, or at least 5 half-lives of the agent (whichever is longer)
   3. Antibody therapy: At least 4 weeks must have elapsed since last antibody dose prior to first study treatment
   4. Radiation therapy: At least two weeks must have elapsed since last local palliative radiation (small port) prior to first study treatment. At least 6 weeks must have elapsed if more substantial radiation was administered (e.g., >50% pelvis, craniospinal, whole body), or therapeutic radiolabeled 131I MIBG or other radiopharmaceutical therapy.
   5. High-Dose Chemotherapy with Autologous Stem Cell Transplant/Rescue: At least two months must have elapsed since receiving autologous hematopoietic stem cells prior to first study treatment. Patients who have had allogeneic transplants are ineligible.
   6. Hematopoietic growth factors: must not have been received in the 14 days prior to first study treatment for a long-acting growth factor (e.g., pegfilgrastim), or 7 days prior to first study treatment for short-acting growth factor.
9. Peripheral absolute neutrophil count (ANC) ≥ 1,000/µL
10. Platelet count ≥100,000/µL (transfusion independent, defined as not receiving platelet transfusions within a 7-day period prior to first study treatment)
11. Hemoglobin ≥ 8.0 gm/dL (may receive RBC transfusions) NOTE: Patients with metastatic tumor in the bone marrow ARE eligible provided the above hematologic criteria are met.

12. Creatinine clearance or radioisotope GFR ≥ 70mL/min/1.73 m2 or Serum creatinine based on age/gender as follows:

    Age Maximum Serum Creatinine (mg/dL) Male Female 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

    ≥ 16 years 1.7 1.4

    The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.

13. Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
14. SGPT (ALT) ≤ 5 x upper limit of normal (ULN) for age
15. Serum albumin ≥ 2 g/dL

Exclusion Criteria:

1. Patients with a history of severe allergic reaction (e.g., more than simple rash) to dacarbazine or third-generation cephalosporins are ineligible.
2. Pregnant or breast-feeding women will not be entered on this study due to potential risks of fetal and teratogenic adverse events. A pregnancy test must be obtained prior to starting chemotherapy in post-menarchal female patients.
3. Patients who are currently receiving investigational drugs, or who have received an investigational drug within the last 7 days prior to first study treatment, are ineligible.
4. Patients who are currently receiving other anti-cancer agents are ineligible.
5. Patients taking strong inducers of CYP3A4, including but not limited to phenobarbital, phenytoin, carbamazepine, oxcarbazepine (Trileptal), rifampin, voriconazole, itraconazole, ketoconazole or other systemically-administered azole antifungal drugs, aprepitant (Emend) or St. John's Wort, in the 2 weeks prior to first study treatment are ineligible.
6. Patients taking strong inhibitors of CYP3A4 or UGT1A1 in the 1 week prior to first study treatment are ineligible.
7. Patients must not be receiving medications known to inhibit platelet function or known to selectively inhibit cyclooxygenase activity. Medicines in this class are excluded, with the exception of acetaminophen.
8. Patients who have uncontrolled infections, require IV antibiotics at time of enrollment, or who are currently receiving treatment for Clostridium difficile infection are excluded.
9. Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 90 mg/m2/day VAL-413 (Orotecan®); Orotecan® at 90 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.	Drug: VAL-413; a flavored preparation of orally administered irinotecan; Other Names: Orotecan®; Drug: Temozolomide; alkylating oral chemotherapy agent used to treatment brain cancers; Other Names: Temodar; Temodal; Temcad; TMZ
Experimental: 110 mg/m2/day VAL-413 (Orotecan®); Orotecan® at 110 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.	Drug: VAL-413; a flavored preparation of orally administered irinotecan; Other Names: Orotecan®; Drug: Temozolomide; alkylating oral chemotherapy agent used to treatment brain cancers; Other Names: Temodar; Temodal; Temcad; TMZ
Experimental: 75 mg/m2/day VAL-413 (Orotecan®); In the event the 90 mg/m2/day starting dose is not tolerable due to toxicity, a lower starting dose of 75 mg/m2/day may be implemented. Orotecan® at 75 mg/m2/day administered with Temozolomide at 100 mg/m2/day orally for 5 consecutive days at the beginning of every 21-day cycle. A single dose of the intravenous preparation of irinotecan taken orally (IRN-IVPO) will be substituted at the same dosage as Orotecan® for during Cycle 1.	Drug: VAL-413; a flavored preparation of orally administered irinotecan; Other Names: Orotecan®; Drug: Temozolomide; alkylating oral chemotherapy agent used to treatment brain cancers; Other Names: Temodar; Temodal; Temcad; TMZ

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recommended Phase II Dose (RP2D)	To establish the recommended Phase II dose of a flavored preparation of orally administered irinotecan VAL-413 (Orotecan®) when given in combination with temozolomide for 5 consecutive days	17 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cmax	Maximum observed concentration of VAL-413 (Orotecan®) on Day 1	1 day
Tmax	Time of observed VAL-413 (Orotecan®) Cmax on Day 1	1 day
AUClast	Area under the concentration-time curve from pre-dose (time 0) to the time of the last quantifiable VAL-413 (Orotecan®) concentration on Day 1	1 day
AUCinf	Area under the concentration-time curve for VAL-413 (Orotecan®) extrapolated to infinity on Day 1	1 day
CL/F	Total oral body clearance at steady state calculated as VAL-413 (Orotecan®) dose/AUC on Day 1	1 day
MRT	Mean Residence Time for VAL-413 (Orotecan®) calculated as AUMC/AUC where AUMC is Area under the Moment Curve	1 day
Vz	The apparent volume of distribution for VAL-413 (Orotecan®) during the terminal phase	1 day
Lambda z	The terminal elimination rate constant determined by selection of at least three decreasing data points on the terminal phase of the concentration time curve for VAL-413 (Orotecan®) on Day 1	1 day
T1/2	Terminal elimination half-life of VAL-413 (Orotecan®) on Day 1 determined from 0.693/Lambda z	1 day
Palatability	To evaluate the palatability of VAL-413 (Orotecan®) using a proprietary Valent Taste Survey which allows pediatric patients or their parents to rate how agreeable they find the flavor of VAL-413 (Orotecan®), on scale from 7, Like Very Much down to 1, Dislike Very Much	1 month
Adverse Events	To assess the toxicity profile of this combination therapy using NCI CTCAE guidelines	17 months
Treatment Response	To assess treatment response using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline, or for patients with neuroblastoma, the International Neuroblastoma Response Criteria (INRC) guideline	17 months

Collaborators and Investigators

• Sponsor: Valent Technologies, LLC
• Investigators: Principal Investigator: Mia Weiss, M.D., Washington University School of Medicine; Principal Investigator: Javier Oesterheld, M.D., Atrium Health Levine Children's Hospital - Carolinas Medical Center; Principal Investigator: Patrick Thompson, M.D., UNC Chapel Hill - North Carolina Cancer Hospital; Principal Investigator: Aerang Kim, M.D., Children's National Hospital - Washington, DC; Principal Investigator: Meghann McManus, D.O., Sarah Cannon Research Institute, Pediatric Hematology & Oncology; Principal Investigator: Kieuhoa Vo, M.D., UCSF - Mission Bay, Benioff Children's Hospital; Principal Investigator: Kyle Jackson, M.D., Indiana University School of Medicine, Riley Hospital for Children; Principal Investigator: Lars Wagner, M.D., Children's Hospital Medical Center, Cincinnati; Principal Investigator: Michael Deel, M.D., Children's Hospital Medical Center, Cincinnati; Principal Investigator: William Thomas Cash, M.D., Children's Healthcare of Atlanta - Arthur M. Blank Hospital; Principal Investigator: Alok Kothari, M.D., Phoenix Children's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2021
• Primary Completion (Estimated): June 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: March 30, 2020
• First Submitted That Met QC Criteria: April 2, 2020
• First Posted (Actual): April 7, 2020

Study Record Updates

• Last Update Posted (Actual): May 11, 2026
• Last Update Submitted That Met QC Criteria: May 7, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: pediatric; Ewing sarcoma; solid tumor; irinotecan; neuroblastoma; medulloblastoma; rhabdomyosarcoma; recurrent; hepatoblastoma
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease Attributes; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Sarcoma; Neoplasms, Connective and Soft Tissue; Neuroectodermal Tumors, Primitive, Peripheral; Neuroectodermal Tumors, Primitive; Osteosarcoma; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Muscle Tissue; Neoplasms, Complex and Mixed; Myosarcoma; Pathological Conditions, Signs and Symptoms; Recurrence; Neuroblastoma; Sarcoma, Ewing; Rhabdomyosarcoma; Medulloblastoma; Hepatoblastoma; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Dacarbazine; Triazenes; Imidazoles; Temozolomide
• Other Study ID Numbers: VAL-10-001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No