Clinical Trials

Inclusion Criteria: 

All clinical and laboratory studies to determine eligibility must be performed within 7 days prior to enrollment unless otherwise indicated. Laboratory values used to assess eligibility must be no older than seven (7)  days at the start of therapy.

Laboratory tests need not be repeated if therapy starts within seven (7) days of obtaining labs to assess eligibility. Exception: repeat AFP MUST be sent within 48 hours prior to starting chemotherapy and  preferably on the same day that chemotherapy starts. However, the AFP result is NOT required prior to starting therapy.

If a post-enrollment lab value is outside the limits of eligibility, or laboratory values are > 7 days old, then the following laboratory evaluations must be re-checked within 48 hours prior to initiating therapy:

• CBC with differential, bilirubin, ALT (SGPT) and serum creatinine. If the recheck is outside the limits of eligibility, the patient may not receive protocol therapy and will be considered off protocol therapy.  Imaging studies, if applicable, must be obtained within 2 weeks prior to start of  protocol therapy (repeat the tumor imaging if necessary). For patients with upfront resection, imaging must be obtained within 28 days prior to the start of therapy (repeat tumor imaging if necessary).
• Patients must be ≤ 30 years of age at the time of diagnosis.
• Patients in Group F must have a Body Surface Area (BSA) ≥ 0.6 m2.
• Patients must have a performance status corresponding to ECOG scores of 0, 1, or 2. Use Karnofsky for patients > 16 years of age and Lansky 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.
• Patients must be newly diagnosed with histologically-proven primary pediatric hepatic malignancies including hepatoblastoma or hepatocellular carcinoma.
• Patients with a diagnosis of hepatocellular neoplasm, not otherwise specified, should be classified and treated per hepatoblastoma treatment arms.
  • Please note: All patients with histology as assessed by the institutional pathologist consistent with pure small cell undifferentiated (SCU) HB will be required to have testing for INI1/SMARCB1 by IHC according to  the practices at the institution.
• Patients with histology consistent with pure SCU must have positive INI1/SMARCB1 staining.
• In emergency situations when a patient meets all other eligibility criteria and has had baseline required observations, but is too ill to undergo a biopsy safely, the patient may be enrolled without a biopsy.  Clinical situations in which emergent treatment may be indicated include, but are not limited to, the following circumstances:
  • Anatomic or mechanical compromise of critical organ function by tumor (e.g., respiratory distress/failure, abdominal compartment syndrome, urinary obstruction, etc.).
  • Uncorrectable coagulopathy.  For a patient to maintain eligibility for AHEP1531 when emergent treatment is given, the following must occur:
    • The patient must have a clinical diagnosis of hepatoblastoma, including an elevated alphafetoprotein (AFP), and must meet all AHEP1531 eligibility criteria at the time of emergent treatment.
    • Patient must be enrolled on AHEP1531 prior to initiating protocol therapy.
• A patient will be ineligible if any chemotherapy is administered prior to AHEP1531 enrollment.
  • Note: If the patient receives AHEP1531 chemotherapy emergently PRIOR to undergoing a diagnostic biopsy, pathologic review of material obtained in the future during either biopsy or surgical resection must either confirm the diagnosis of hepatoblastoma or not reveal another pathological diagnosis to be included in the analysis of the study aims.
• Patients may have had surgical resection of the hepatic malignancy prior to enrollment. All other anti-cancer therapy for the current liver lesion is prohibited.
• Adequate renal function for patients receiving chemotherapy (Groups A2, B, C, D, E2, F), defined as:
  • Creatinine clearance or radioisotope GFR ≥ 60 mL/min/1.73 m2 or a serum creatinine based on age/gender as follows:
    • 1 month to < 6 months | Male 0.4 | Female 0.4
    • 6 months to < 1 year | Male 0.5 | Female 0.5
    • 1 to < 2 years | Male 0.6 | Female 0.6
    • 2 to < 6 years | Male 0.8 | Female 0.8
    • 6 to < 10 years | Male 1.0 | Female 1.0
    • 10 to < 13 years | Male 1.2 | Female 1.2
    • 13 to < 16 years | Male 1.5 | Female 1.4
    • ≥ 16 years | Male 1.7 | Female 1.4

  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the CDC.

• Adequate liver function defined as:
  • Total bilirubin ≤ 5 x upper limit of normal (ULN) for age; and
  • SGOT (AST) or SGPT (ALT) < 10 x upper limit of normal (ULN) for age.
• Adequate cardiac function for patients on doxorubicin-containing regimens (Groups C, D, E2, and F), which must be assessed within 8 weeks prior to study enrollment, is defined as:
  • Shortening fraction of ≥ 28% by echocardiogram; or
  • Ejection fraction of ≥ 47% by echocardiogram or radionuclide angiogram;
  • Group F patients only: QT/QTc interval ≤ 450 milliseconds for males and ≤ 470 milliseconds for females.
• Adequate pulmonary function for patients receiving chemotherapy (Groups A2, B, C, D, E2, F), defined as:
  • Normal pulmonary function tests (including DLCO) if there is clinical indication for determination (e.g., dyspnea at rest, known requirement for supplemental oxygen).
• For patients who do not have respiratory symptoms or requirement for supplemental oxygen, PFTs are NOT required.

Exclusion Criteria:

• Prior chemotherapy or tumor directed therapy (i.e., radiation therapy, biologic agents, local therapy (embolization, radiofrequency ablation, and laser); therefore, patients with a pre-disposition syndrome who have a prior malignancy are not eligible.
• Patients who are currently receiving another investigational drug.
• Patients who are currently receiving other anticancer agents.
• Patients with uncontrolled infection.
• Patients who previously received a solid organ transplant, other than those who previously received an orthotopic liver transplantation (OLT) as primary treatment of their hepatocellular carcinoma.
• Patients with hypersensitivity to any drugs on their expected treatment arm.
• Treatment Group specific exclusion criteria:
• Group C:
  • Patients who have known deficiency of dihydropyrimidine dehydrogenase (DPD).
• Group D:
  • Patients with chronic inflammatory bowel disease and/or bowel obstruction.
  • Patients with concomitant use of St. John’s wort, which cannot be stopped prior to the start of trial treatment.
• Group F:
  • Patients with peripheral sensitive neuropathy with functional impairment.
  • Patients with a personal or family history of congenital long QT syndrome.
• Pregnancy and Breast Feeding - These criteria apply ONLY to patients who will receive chemotherapy (all groups other than Groups A1 and E1).
• Female patients who are pregnant, since fetal toxicities and teratogenic effects have been noted for several of the study drugs.
• A pregnancy test is required for female patients of childbearing potential.
• Lactating females who plan to breastfeed their infants.
• Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation.
• Note for Group F:
  • Patients of childbearing potential should use effective birth control during treatment with sorafenib and for at least 2 weeks after stopping treatment.