Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT).
1.1.1 To reduce therapy associated toxicity for patients with non-metastatic hepatoblastoma (HB) and hepatocellular carcinoma (HCC) without adversely affecting long term outcomes.
1.1.1.1 GroupA:To determinetheevent-freesurvival(EFS)inpatientswithHB
whose tumor is completely resected at diagnosis and either receive no adjuvant chemotherapy (completely resected well differentiated fetal [WDF] histology HB) or 2 cycles of standard dose cisplatin monotherapy (completely resected non-well differentiated fetal histology HB 100 mg/m2/cycle given 3 weeks apart).
1.1.1.2 Group B: To demonstrate that 4 to 6 cycles of interval compressed lower dose cisplatin monotherapy (80 mg/m2/cycle; 320-480 mg/m2 total) is adequate for Low Risk HB.
a. In patients who are resected after 2 cycles of cisplatin monotherapy, to compare EFS following a randomized comparison of 2 versus 4 post-operative cycles of cisplatin monotherapy.
b. In patients whose tumors are deemed unresectable after 2 cycles of cisplatin monotherapy, to determine the proportion of tumors rendered completely resectable by an additional 2 or 4 cycles of chemotherapy.
1.1.1.3 Group C: To compare in a randomized fashion, EFS in patients with Intermediate Risk HB treated with 6 cycles of cisplatin/5- fluorouracil/vincristine/doxorubicin (C5VD) chemotherapy versus 6 cycles of interval compressed cisplatin monotherapy (100 mg/m2/dose).
1.1.1.4 Group E: To determine the EFS in patients with HCC whose tumor is completely resected at diagnosis who receive no adjuvant chemotherapy (completely resected HCC arising in the context of underlying liver disease) or 4 cycles of cisplatin/doxorubicin (PLADO) (completely resected de novo HCC).
1.1.2 To improve the EFS of patients with High Risk HB (Group D) by treating them with interval compressed cisplatin and doxorubicin based induction regimen followed by response-adapted consolidation therapy.
1.1.2.1 Group D1 In patients whose metastatic disease resolves with the
administration of SIOPEL 4 Induction therapy, to determine if the promising pilot results observed in SIOPEL 4 can be validated in a large international study.
1.1.2.2 Group D Arm CE & Arm VI In patients whose metastatic disease does not resolve with the administration of SIOPEL 4 Induction therapy, to determine in a randomized comparison which post induction treatment (irinotecan and vincristine alternating with carboplatin and doxorubicin or carboplatin and etoposide alternating with carboplatin and doxorubicin) results in superior outcomes.
1.1.3 In patients with unresectable/metastatic HCC at diagnosis (Group F), to determine whether the addition of gemcitabine and oxaliplatin (GEMOX + sorafenib) to a cisplatin, doxorubicin and sorafenib backbone improves chemotherapy response, resectability and survival.
ETOPOSIDE
OXALIPLATIN
VINCRISTINE
GEMCITABINE
CARBOPLATIN
DOXORUBICIN
IRINOTECAN
Chemotherapy single agent systemic
- Rutgers Cancer Institute of New Jersey
- RWJBarnabas Health
- Newark Beth Israel Medical Center
Inclusion Criteria
- Patients in Group F must have a body surface area (BSA) >= 0.6 m^2
- Patients must have a performance status corresponding to Eastern Cooperative Oncology
Group (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, except as noted
below; patients with a diagnosis of hepatocellular neoplasm, not otherwise specified,
should be classified and treated per hepatoblastoma treatment arms; note that rapid
central pathology review is required in some cases; 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
immunohistochemistry (IHC) according to the practices at the institution
- Patients with histology consistent with pure SCU must have positive INI1/SMARCB1
staining
- For all Group A patients, WDF status as determined by rapid review will be used to
further stratify patients to Group A1 or A2
- For Groups B, C and D, rapid review is required if patients are either >= 8 years
of age or have an alphafetoprotein (AFP) =< 100 at diagnosis
- For all Groups E and F patients, rapid central pathology review is required
- 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
- Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60
mL/min/1.73 m^2 or
- A serum creatinine based on age/gender as follows:
- Age: maximum serum creatinine (mg/dL)
- 1 month to < 6 months: 0.4 (male and female)
- 6 months to < 1 year: 0.5 (male and female)
- 1 to < 2 years: 06 (male and female)
- 2 to < 6 years: 0.8 (male and female)
- 6 to < 10 years: 1 (male and female)
- 10 to < 13 years: 1.2 (male and female)
- 13 to < 16 years: 1.5 (male), 1.4 (female)
- >= 16 years: 1.7 (male), 1.4 (female)
- Total bilirubin =< 5 x upper limit of normal (ULN) for age
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
< 10 x upper limit of normal (ULN) for age
- Shortening fraction of >= 28% by echocardiogram (for patients on
doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks prior
to study enrollment) or
- Ejection fraction of >= 47% by echocardiogram or radionuclide angiogram (for patients
on doxorubicin-containing regimens [Groups C, D, E2, and F] assessed within 8 weeks
prior to study enrollment)
- Group F patients only: QT/corrected QT (QTc) interval =< 450 milliseconds for males
and =< 470 milliseconds for females (assessed within 8 weeks prior to study
enrollment)
- Normal pulmonary function tests (including diffusion capacity of the lung for carbon
monoxide [DLCO]) if there is clinical indication for determination (e.g. dyspnea at
rest, known requirement for supplemental oxygen) (for patients receiving chemotherapy
[Groups A, B, C, D, E2, F]); for patients who do not have respiratory symptoms or
requirement for supplemental oxygen, pulmonary function tests (PFTs) are NOT required
- All patients and/or their parents or legal guardians must sign a written informed
consent
- All institutional, Food and Drug Administration (FDA), and National Cancer Institute
(NCI) requirements for human studies must be met
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
- 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
- These criteria apply ONLY to patients who may receive chemotherapy (all groups other
than Group 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
Please note that we have obtained the inclusion and exclusion criteria information from the National Institutes of Health’s clinical trials web site ClinicalTrials.gov. The listed criteria may not necessarily reflect recent amendments to the protocol and the current criteria.
For further information about clinical trials, please contact us at 732-235-7356.