Official Title
Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)
Summary:
This partially randomized phase II/III trial studies how well, in combination with surgery,
cisplatin and combination chemotherapy works in treating children and young adults with
hepatoblastoma or hepatocellular carcinoma. Drugs used in chemotherapy, such as cisplatin,
doxorubicin, fluorouracil, vincristine sulfate, carboplatin, etoposide, irinotecan,
sorafenib, gemcitabine and oxaliplatin, work in different ways to stop the growth of tumour
cells, either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. Giving combination chemotherapy may kill more tumour cells than one type of
chemotherapy alone.
Trial Description
Primary Outcome:
- Event-free survival (EFS)
- Percentage of Group B2 participants with resectable tumours
- Response rate for Group F patients
PRIMARY OBJECTIVES:
-
To reduce therapy associated toxicity for patients with non-metastatic hepatoblastoma (HB)
and hepatocellular carcinoma (HCC) without adversely affecting long term outcomes.
- To determine the event-free survival (EFS) in patients with HB whose tumour 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/m^2/cycle given 3
weeks apart). (Group A)
- To demonstrate that 4 to 6 cycles of interval compressed lower
dose cisplatin monotherapy (80 mg/m^2/cycle; 320-480 mg/m^2 total) is adequate for low risk
HB. (Group B)
- 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. (Group B)
- In patients whose tumours are deemed unresectable after
2 cycles of cisplatin monotherapy, to determine the proportion of tumours rendered completely
resectable by an additional 2 or 4 cycles of chemotherapy. (Group B)
- 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/m^2/dose). (Group C)
- To determine the
EFS in patients with HCC whose tumour 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).
(Group E)
- To improve the EFS of patients with high risk HB by treating them with interval
compressed cisplatin and doxorubicin based induction regimen followed by response-adapted
consolidation therapy. (Group D)
- In patients whose metastatic disease resolves with the
administration of Societe Internationale d'Oncologie Pediatrique (SIOPEL) 4 Induction
therapy, to determine if the promising pilot results observed in SIOPEL 4 can be validated in
a large international study. (Group D1)
- 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 sulfate [vincristine]
alternating with carboplatin and doxorubicin or carboplatin and etoposide alternating with
carboplatin and doxorubicin) results in superior outcomes. (Group D Arm CE & Arm VI)
- In
patients with unresectable/metastatic HCC at diagnosis, to determine whether the addition of
gemcitabine and oxaliplatin (GEMOX + sorafenib) to a cisplatin, doxorubicin and sorafenib
backbone improves chemotherapy response, resectability and survival. (Group F)
EXPLORATORY OBJECTIVES:
- To determine if the Childhood Hepatic tumour International Consortium (CHIC) hepatoblastoma
risk stratification analysis of very low risk (Group A), low risk (Group B), intermediate
risk (Group C) and high risk (Group D) groups stratifies patients allowing appropriate
utilization of varying intensity chemotherapy regimens and surgical resection strategies.
- To define the prognostic relevance of a positive microscopic margin in Group A-D resected
HB specimens.
- To define the frequency of histologically detectable multifocal lesions in liver
explants and resected specimens in which multifocal disease was detected at diagnosis and
disappeared on cross sectional imaging following treatment with chemotherapy.
- To define the prognostic relevance in HB of a 'small cell undifferentiated' tumour
component and percentage of tumour necrosis in post chemotherapy specimens.
- To determine the prognostic impact on EFS and overall survival (OS) of biopsy technique in
liver tumours unresectable at diagnosis.
- To determine the 3-year EFS and OS of HB patients who undergo liver transplantation vs
extreme resection in Group C and D patients.
- To determine the 3-year EFS and OS of Group D patients who undergo pulmonary
metastasectomy.
- To determine the 3-year EFS and OS of patients who undergo liver transplantation for
HCC.
- To determine the frequency of relapse in non-metastatic HCC in children treated by liver
transplantation versus conventional resection.
- To determine the concordance of Pretreatment Extent of Disease (PRETEXT) and
Post-treatment Extent of disease (POSTTEXT) based surgical guidelines and the surgical
intervention performed.
- To collect for future analysis, HB and HCC tumour specimens that can be molecularly
characterized to validate newly identified molecular and immunohistochemical biomarkers
correlating with known clinical prognostic factors and outcome.
- To evaluate the hepatoblastoma molecular risk-predictive model (HB-MRP) to risk stratify
hepatoblastoma patients in the context of the current AHEP1531 trial.
- To collect for future analysis samples to assess the pharmacogenomics (PG) related to
cisplatin therapy in pediatric and adolescent liver tumour patients and correlate PG with
Boston Grading Scale for ototoxicity.
- To collect for future analysis samples such that novel biomarkers of renal toxicity
(urine neutrophil gelatinase-associated lipocalin [NGAL], cystatin C and Kim1) from cisplatin
therapy can be correlated with pharmacogenomics, other associated toxicities, and outcomes.
- To determine which system (Children's Oncology Group [COG] PRETEXT, SIOPEL PRETEXT, or a
new hybrid definition of PRETEXT) of the annotation factors for V, P, E, F and R provides the
best prognostic information for determining response to chemotherapy, guiding risk based
therapy, predicting surgical resectability, and EFS.
- To determine the concordance between institutional and expert panel review assessment of
PRETEXT and POSTTEXT stage in an international cooperative group setting.
OUTLINE:
GROUP A (VERY LOW RISK HB): Patients are assigned to 1 of 2 groups.
GROUP A1 (WDF): Patients undergo observation.
GROUP A2 (NON-WDF): Patients receive cisplatin (CDDP) intravenously (IV) over 6 hours on day
1 following surgery. Treatment repeats every 21 days for up to 2 cycles in the absence of
disease progression or unacceptable toxicity.
GROUP B (LOW RISK HB): Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats
every 14 days for up to 2 cycles in the absence of disease progression or unacceptable
toxicity. Patients are then assigned to 1 of 2 groups
GROUP B1 (RESECTABLE): Patients receive 2 cycles of cisplatin, undergo surgery, then are
randomized to 1 of 2 arms (2 vs 4 additional cycles of cisplatin).
GROUP B1 ARM 4-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats
every 14 days for up to 4 total cycles (2 pre-surgery, 2 post-surgery) in the absence of
disease progression or unacceptable toxicity.
GROUP B1 ARM 6-CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats
every 14 days for up to 6 total cycles (2 pre-surgery, 4 post-surgery) in the absence of
disease progression or unacceptable toxicity.
GROUP B2 (UNRESECTABLE): Patients receive cisplatin IV over 6 hours on day 1. Treatment
repeats every 14 days for up to 6 total cycles (4 pre-surgery, 2 post-surgery). Patients with
resectable tumours undergo surgery, then all patients continue with 2 additional cycles of
cisplatin.
GROUP C (INTERMEDIATE RISK HB): Patients are randomized to 1 of 2 arms.
GROUP C ARM CDDP: Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats
every 14 days for up to 6 cycles in the absence of disease progression or unacceptable
toxicity. Patients undergo surgery after cycle 2 or 4.
GROUP C ARM C5VD: Patients receive cisplatin IV over 6 hours on day 1, 5-fluorouracil IV over
1-15 minutes, vincristine sulfate IV over 1 minute on days 1, 8, and 15 and doxorubicin IV
over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for up to 6 cycles in the
absence of disease progression or unacceptable toxicity. Patients undergo surgery after cycle
2 or 4.
GROUP D (HIGH RISK HB): SIOPEL-4 IV INDUCTION: Patients receive cisplatin IV over 6 hours on
days 1, 8, and 15 (for cycles 1 and 2) and days 1 and 8 (for cycle 3) and doxorubicin IV over
1-15 minutes on days 8 and 9 (for cycles 1 and 2) and days 1 and 2 (for cycle 3). Cycles 1
and 2 are 28 days; cycle 3 is 21 days. Patients are then assigned to 1 of 2 arms.
GROUP D1: CONSOLIDATION THERAPY: Patients with lung complete remission (either with
chemotherapy and/or surgery) receive carboplatin IV over 1 hour on day 1 and doxorubicin IV
over 1-15 minutes on days 1 and 2. Treatment repeats every 21 days for 3 cycles in the
absence of disease progression or unacceptable toxicity.
GROUP D2: Patients with residual metastatic disease are randomized to 1 of 2 arms.
GROUP D2 ARM CE: Patients receive carboplatin IV over 1 hour on days 1 and 2, doxorubicin IV
over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5, and carboplatin IV over 1 hour
and etoposide IV over 2 hours on day 1 and 2 of cycles 2, 4 and 6. Treatments repeat every 21
days for 6 cycles in the absence of disease progression or unacceptable toxicity.
GROUP D2 ARM VI: Patients receive carboplatin IV over 1 hour on days 1 and 2 and doxorubicin
IV over 1-15 minutes on days 1 and 2 during cycles 1, 3 and 5. Patients also receive
vincristine sulfate IV over 1 minute on days 1 and 8 and irinotecan IV over 60-90 minutes
once daily (QD) on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for 6
cycles in the absence of disease progression or unacceptable toxicity.
GROUP E (RESECTED HCC): Patients are assigned to 1 of 2 groups.
GROUP E1: Patients with HCC secondary to underlying hepatic disease undergo observation only.
GROUP E2 (PLADO): Patients with de novo HCC receive cisplatin IV over 6 hours on day 1 and
doxorubicin IV over 1-15 minutes on days 1 and 2 following surgery. Treatments repeat every
21 days for 4 cycles in the absence of disease progression or unacceptable toxicity.
GROUP F (UNRESECTED AND/OR METASTATIC HCC): Patients are randomized to 1 of 2 arms.
GROUP F ARM 1 (PLADO): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV
over 1-15 minutes on days 1 and 2 and sorafenib orally (PO) twice daily (BID) on days 3-21.
Treatments repeat every 21 days for up to 3 cycles in the absence of disease progression or
unacceptable toxicity. Patients may undergo surgery, if tumours are resectable, or receive an
additional 3 cycles of the treatment.
GROUP F ARM 2 (P/GEMOX): Patients receive cisplatin IV over 6 hours on day 1, doxorubicin IV
over 1-15 minutes on days 1 and 2 and sorafenib PO BID on days 3-14 of cycles 1 and 3.
Patients also receive gemcitabine IV over 90 minutes on day 1, oxaliplatin IV over 2 hours on
day 1 and sorafenib PO on days 1-14 of cycles 2 and 4. Patients may undergo surgery, if
tumours are resectable, or receive an additional 4 cycles of the treatment.
After completion of study treatment, patients are followed up for a minimum of 2 years.
View this trial on ClinicalTrials.gov
