A pilot pharmacokinetic trial to determine the safety and efficacy of a flavored, orally
administered irinotecan (VAL-413) given with temozolomide for treatment of recurrent
pediatric solid tumors including but not limited to neuroblastoma, rhabdomyosarcoma, Ewing
sarcoma, hepatoblastoma and medulloblastoma
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 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 VAL-413 will be given with temozolomide in 5 day courses administered every 21 days as
The dosing regimen in this study will be Temozolomide at 100 mg/m2/day with VAL-413 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 VAL-413
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 VAL-413 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), or for patients with neuroblastoma, using International Neuroblastoma
Response Criteria. In addition, a palatability survey will be conducted on Day 1 or Day 4 of
the first cycle, which will allow patients to evaluate the taste of VAL-413. 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 VAL-413 and conventional irinotecan given orally.
Assessment of first-cycle toxicity will be used to identify the recommended phase II dose for
VAL-413. 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).
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
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 or irinotecan is allowed, although patients must not
have had disease progression while receiving either irinotecan 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
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
14. SGPT (ALT) ≤ 5 x upper limit of normal (ULN) for age
15. Serum albumin ≥ 2 g/dL
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
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
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.