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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03533582




Registration number
NCT03533582
Ethics application status
Date submitted
11/05/2018
Date registered
23/05/2018
Date last updated
22/04/2024

Titles & IDs
Public title
Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
Scientific title
Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT)
Secondary ID [1] 0 0
NCI-2017-01910
Secondary ID [2] 0 0
AHEP1531
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Childhood Hepatocellular Carcinoma 0 0
Childhood Malignant Liver Neoplasm 0 0
Fibrolamellar Carcinoma 0 0
Hepatoblastoma 0 0
Hepatocellular Malignant Neoplasm, Not Otherwise Specified 0 0
Condition category
Condition code
Cancer 0 0 0 0
Non melanoma skin cancer
Cancer 0 0 0 0
Kidney
Cancer 0 0 0 0
Liver
Oral and Gastrointestinal 0 0 0 0
Other diseases of the mouth, teeth, oesophagus, digestive system including liver and colon

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Carboplatin
Treatment: Drugs - Cisplatin
Treatment: Drugs - Doxorubicin
Treatment: Drugs - Etoposide
Treatment: Drugs - Fluorouracil
Treatment: Drugs - Gemcitabine
Treatment: Drugs - Irinotecan
Other interventions - Laboratory Biomarker Analysis
Treatment: Drugs - Oxaliplatin
Other interventions - Patient Observation
Treatment: Surgery - Resection
Treatment: Drugs - Sorafenib
Treatment: Drugs - Vincristine Sulfate

Active Comparator: Group A1 (WDF) - Patients undergo observation.

Experimental: GROUP A2 (NON-WDF) - Patients receive cisplatin 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.

Experimental: GROUP B1 ARM 4-CDDP - Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for 4 cycles (2 pre-surgery, 2 post-surgery) in the absence of disease progression or unacceptable toxicity.

Experimental: GROUP B1 ARM 6-CDDP - Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for 6 cycles (2 pre-surgery, 4 post-surgery) in the absence of disease progression or unacceptable toxicity.

Experimental: GROUP B2 ARM I - 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). After cycle 4, patients undergo surgery, then continue with 2 additional cycles of cisplatin.

Experimental: GROUP B2 ARM II - Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles.

Experimental: 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.

Experimental: 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.

Experimental: GROUP D1 - SIOPEL-4 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 during cycles 1 and 2 and days 1 and 2 during cycle 3. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: 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 up to 3 cycles in the absence of disease progression or unacceptable toxicity.

Experimental: GROUP D2 ARM CE - 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. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
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 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 up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Experimental: GROUP D2 ARM VI - 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. Treatment repeats every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity.
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 90 minutes QD on days 1 to 5 of cycles 2, 4 and 6. Treatments repeat every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Active Comparator: GROUP E1 - Patients undergo observation only.

Experimental: GROUP E2 (PLADO) - Patients 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.

Experimental: 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 PO 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 tumors are resectable, or receive an additional 3 cycles of the treatment.

Experimental: 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 tumors are resectable, or receive an additional 4 cycles of the treatment.


Treatment: Drugs: Carboplatin
Given IV

Treatment: Drugs: Cisplatin
Given IV

Treatment: Drugs: Doxorubicin
Given IV

Treatment: Drugs: Etoposide
Given IV

Treatment: Drugs: Fluorouracil
Given IV

Treatment: Drugs: Gemcitabine
Given IV

Treatment: Drugs: Irinotecan
Given IV

Other interventions: Laboratory Biomarker Analysis
Correlative studies

Treatment: Drugs: Oxaliplatin
Given IV

Other interventions: Patient Observation
Undergo watchful waiting

Treatment: Surgery: Resection
Undergo surgical resection

Treatment: Drugs: Sorafenib
Given PO

Treatment: Drugs: Vincristine Sulfate
Given IV
Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Intervention code [3] 0 0
Treatment: Surgery
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free survival (EFS)
Timepoint [1] 0 0
3 years
Primary outcome [2] 0 0
Percentage of Group B2 participants with resectable tumors
Timepoint [2] 0 0
6 months
Primary outcome [3] 0 0
Response rate for Group F patients
Timepoint [3] 0 0
Up to 5 years

Eligibility
Key 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
Minimum age
No limit
Maximum age
30 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2/Phase 3
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
24/05/2018
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
30/06/2026
Actual
Sample size
Target
537
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,SA,VIC,WA
Recruitment hospital [1] 0 0
John Hunter Children's Hospital - Hunter Regional Mail Centre
Recruitment hospital [2] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [3] 0 0
The Children's Hospital at Westmead - Westmead
Recruitment hospital [4] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [5] 0 0
Women's and Children's Hospital-Adelaide - North Adelaide
Recruitment hospital [6] 0 0
Royal Children's Hospital - Parkville
Recruitment hospital [7] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2310 - Hunter Regional Mail Centre
Recruitment postcode(s) [2] 0 0
2031 - Randwick
Recruitment postcode(s) [3] 0 0
2145 - Westmead
Recruitment postcode(s) [4] 0 0
4101 - South Brisbane
Recruitment postcode(s) [5] 0 0
5006 - North Adelaide
Recruitment postcode(s) [6] 0 0
3052 - Parkville
Recruitment postcode(s) [7] 0 0
6009 - Perth
Recruitment outside Australia
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United States of America
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Alabama
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Alaska
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Arizona
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Arkansas
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Colorado
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Connecticut
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Delaware
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District of Columbia
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Florida
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Georgia
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Idaho
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Illinois
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Indiana
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Nevada
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New Hampshire
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New Mexico
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New York
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North Carolina
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Ohio
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Oklahoma
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Oregon
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Pennsylvania
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Rhode Island
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South Carolina
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South Dakota
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Tennessee
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Texas
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Utah
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Vermont
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West Virginia
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Wisconsin
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Canada
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Alberta
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Canada
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Manitoba
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Canada
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Nova Scotia
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Canada
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Ontario
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Canada
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Quebec
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Saskatchewan
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New Zealand
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Auckland
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New Zealand
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Christchurch
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Puerto Rico
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San Juan
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Saudi Arabia
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Riyadh

Funding & Sponsors
Primary sponsor type
Other
Name
Children's Oncology Group
Address
Country
Other collaborator category [1] 0 0
Government body
Name [1] 0 0
National Cancer Institute (NCI)
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief 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 tumor
cells, either by killing the cells, by stopping them from dividing, or by stopping them from
spreading. Giving combination chemotherapy may kill more tumor cells than one type of
chemotherapy alone.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03533582
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Gregory M Tiao
Address 0 0
Children's Oncology Group
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03533582