The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been endorsed by the ANZCTR. Before participating in a study, talk to your health care provider and refer to this information for consumers
Trial details imported from ClinicalTrials.gov

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




Registration number
NCT03533582
Ethics application status
Date submitted
11/05/2018
Date registered
22/05/2018
Date last updated
16/01/2019

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
Elevated Alpha-Fetoprotein 0 0
Hepatoblastoma 0 0
SMARCB1 Gene Mutation 0 0
Condition category
Condition code
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: 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 courses 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 up to 4 courses 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 up to 6 courses in the absence of disease progression or unacceptable toxicity.

Experimental: GROUP B2 (UNRESECTABLE) - Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 2 courses. Patients with resectable tumors undergo surgery, then all patients continue with 2 additional courses of cisplatin.

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 courses in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after course 2.

Experimental: GROUP C ARM CDDP - Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients undergo surgery after course 2.

Experimental: GROUP D1 - SIOPEL-4 INDUCTION: Patients receive cisplatin IV over 6 hours on days 1, 8, and 15 (for courses 1 and 2) and days 1 and 8 (for course 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 courses 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 courses 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 courses 1 and 2) and days 1 and 8 (for course 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 courses 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 courses 1, 3 and 5, and etoposide IV over 2 hours on day 1 and 2 of courses 2, 4 and 6. Treatments repeat every 21 days for up to 6 courses 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 courses 1 and 2) and days 1 and 8 (for course 3) and doxorubicin IV over 1-15 minutes on days 8 and 9. Treatment repeats every 28 days for up to 3 courses 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 courses 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 courses 2, 4 and 6. Treatments repeat every 21 days for up to 6 courses 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 up to 4 courses 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 courses in the absence of disease progression or unacceptable toxicity. Patients may undergo surgery, if tumors are resectable, or receive an additional 3 courses 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 courses 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 courses 2 and 4. Patients may undergo surgery, if tumors are resectable, or receive an additional 4 courses 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: Drugs: Sorafenib
Given PO

Treatment: Drugs: Vincristine Sulfate
Given IV

Intervention code [1] 0 0
Treatment: Drugs
Intervention code [2] 0 0
Other interventions
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Event-free survival (EFS) - Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of each failure event and in total, survival curves will be estimated by the method of Kaplan-Meier, EFS estimates at 3 and 5 years with 95% confidence intervals (CI), median EFS with CI will be reported if appropriate. A Cox proportional hazards model with EFS as an outcome measure and treatment and stratification factors as covariates will be constructed. This model will be used in the context of a Bayesian analysis and a log Hazard Ratio (HR) will be derived. Bayesian Normal-Normal conjugate analysis of the data will be used to compare treatments. The analysis will use non-informative prior to represent no information about prior beliefs regarding relative treatment difference.
Timepoint [1] 0 0
From date of randomization until progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, or diagnosis of a second malignant neoplasm, assessed up to 5 years
Primary outcome [2] 0 0
Response in hepatocellular carcinoma (HCC), defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria - The main analysis will be based on a log-binomial model for a Bernoulli response variable. This model will be used in the context of a Bayesian analysis. A non-informative null centered proper prior distributions for the parameters will be used. Response rate (RR) and 95% credible interval (CrI) will be presented. Posterior probabilities for the pre-specified values of interest will be provided. Additionally, the posterior probabilities of RR being larger than 0.7, 0.8, 0.9, 1, 1.1, 1.2 and 1.3 will be also provided.
Timepoint [2] 0 0
Up to 5 years
Secondary outcome [1] 0 0
Failure free survival - Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of each failure event and in total, survival curves will be estimated by the method of Kaplan-Meier. Bayesian Normal-Normal conjugate analysis of the data will be used to compare treatments. The analysis will use non-informative prior to represent no information about prior beliefs regarding relative treatment difference.
Timepoint [1] 0 0
From date of randomization until the date of first documented progression, date of death from any cause, diagnosis of a second malignant neoplasm or failure to go to resection, whichever came first, assessed up to 5 years
Secondary outcome [2] 0 0
Overall survival
Timepoint [2] 0 0
From date of randomization (or registration for non-randomized patients) until the date of death from any cause, assessed up to 5 years
Secondary outcome [3] 0 0
Incidence of adverse events - Will be categorized and graded using Common Terminology Criteria for Adverse Events (CTCAE).
Timepoint [3] 0 0
Up to 5 years
Secondary outcome [4] 0 0
Chemotherapy-related cardiac, nephro- and oto-toxicity - Will be recorded in relation to each cycle of treatment and will be categorized and graded using Common Terminology Criteria for Adverse Events.
Timepoint [4] 0 0
Up to 5 years
Secondary outcome [5] 0 0
Hearing loss measured according to the SIOP Boston Scale for oto-toxicity - Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: the number (and proportion) of patients at each the SIOP Boston Scale for oto-toxicity category (i.e. grade 0 to grade 4) and the number (and proportion) of patients who are not assessable for this outcome, (i.e. because of early stopping of treatment, additional treatments to protocol treatment, progression prior to the response assessment or death). The number (and proportion) of patients experiencing any grade hearing loss. Grades 1 to grade 4 will be combined in this analysis. The above will be presented for each assessment time point (EOT and at least 1 year and 2 years of follow up).
Timepoint [5] 0 0
Up to 5 years
Secondary outcome [6] 0 0
Best response defined as compete response (CR) or partial response (PR) based on radiological response (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and AFP decline - Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: best response will be calculated by taking best RECIST category (i.e. CR, PR, stable disease [SD], progressive disease [PD]) for each patient. CR and PR patients will then be grouped into responders. The number (and proportion) of patients at each best response RECIST category (i.e. CR, PR, SD, PD) and the number (and proportion) of patients who are not assessable for response, e.g. because of early stopping of treatment, progression prior to the response assessment or death. The number (and proportion) of responders (CR and PR) and non-responders.
Timepoint [6] 0 0
Up to 5 years
Secondary outcome [7] 0 0
Surgical resectability defined as complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients) - Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: The number (and proportion) of patients undergoing complete resection, partial resection or transplant. Time to complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients) will be analyzed using the Kaplan-Meier method.
Timepoint [7] 0 0
Up to 5 years
Secondary outcome [8] 0 0
Adherence to surgical guidelines defined as the local clinician?s surgical decision to resect or not compared to the current SIOPEL surgical guidelines - Descriptive analysis for each non-randomized and randomized question (by treatment arm and overall) will include: The number (and proportion) of patients at each combination of SIOPEL surgical guideline (to resect or not) and local clinician?s surgical decision. The degree of agreement will be measured by Cohen?s kappa with CI.
Timepoint [8] 0 0
Up to 5 years

Eligibility
Key inclusion criteria
- 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; 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

- 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) >= 70
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])
< 10x upper limit of normal (ULN) for age

- Shortening fraction of >= 27% by echocardiogram (for patients on
doxorubicin-containing regimens [Groups C, D, E, and F]), or

- Ejection fraction of >= 50% by radionuclide angiogram (for patients on
doxorubicin-containing regimens (Groups C, D, E, and F)

- 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 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
Gender
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

- This criteria apply ONLY to patients who will receive chemotherapy (all groups other
than Group E1):

- Female patients who are pregnant; 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
Recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,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
Women's and Children's Hospital-Adelaide - North Adelaide
Recruitment hospital [5] 0 0
Royal Children's Hospital - Parkville
Recruitment hospital [6] 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
5006 - North Adelaide
Recruitment postcode(s) [5] 0 0
3052 - Parkville
Recruitment postcode(s) [6] 0 0
6009 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Alabama
Country [2] 0 0
United States of America
State/province [2] 0 0
Alaska
Country [3] 0 0
United States of America
State/province [3] 0 0
Arizona
Country [4] 0 0
United States of America
State/province [4] 0 0
Arkansas
Country [5] 0 0
United States of America
State/province [5] 0 0
California
Country [6] 0 0
United States of America
State/province [6] 0 0
Colorado
Country [7] 0 0
United States of America
State/province [7] 0 0
Connecticut
Country [8] 0 0
United States of America
State/province [8] 0 0
Delaware
Country [9] 0 0
United States of America
State/province [9] 0 0
District of Columbia
Country [10] 0 0
United States of America
State/province [10] 0 0
Florida
Country [11] 0 0
United States of America
State/province [11] 0 0
Georgia
Country [12] 0 0
United States of America
State/province [12] 0 0
Hawaii
Country [13] 0 0
United States of America
State/province [13] 0 0
Illinois
Country [14] 0 0
United States of America
State/province [14] 0 0
Indiana
Country [15] 0 0
United States of America
State/province [15] 0 0
Iowa
Country [16] 0 0
United States of America
State/province [16] 0 0
Kentucky
Country [17] 0 0
United States of America
State/province [17] 0 0
Louisiana
Country [18] 0 0
United States of America
State/province [18] 0 0
Maine
Country [19] 0 0
United States of America
State/province [19] 0 0
Maryland
Country [20] 0 0
United States of America
State/province [20] 0 0
Massachusetts
Country [21] 0 0
United States of America
State/province [21] 0 0
Michigan
Country [22] 0 0
United States of America
State/province [22] 0 0
Minnesota
Country [23] 0 0
United States of America
State/province [23] 0 0
Mississippi
Country [24] 0 0
United States of America
State/province [24] 0 0
Missouri
Country [25] 0 0
United States of America
State/province [25] 0 0
Nevada
Country [26] 0 0
United States of America
State/province [26] 0 0
New Hampshire
Country [27] 0 0
United States of America
State/province [27] 0 0
New Jersey
Country [28] 0 0
United States of America
State/province [28] 0 0
New York
Country [29] 0 0
United States of America
State/province [29] 0 0
North Carolina
Country [30] 0 0
United States of America
State/province [30] 0 0
Ohio
Country [31] 0 0
United States of America
State/province [31] 0 0
Oklahoma
Country [32] 0 0
United States of America
State/province [32] 0 0
Oregon
Country [33] 0 0
United States of America
State/province [33] 0 0
Pennsylvania
Country [34] 0 0
United States of America
State/province [34] 0 0
South Carolina
Country [35] 0 0
United States of America
State/province [35] 0 0
South Dakota
Country [36] 0 0
United States of America
State/province [36] 0 0
Tennessee
Country [37] 0 0
United States of America
State/province [37] 0 0
Texas
Country [38] 0 0
United States of America
State/province [38] 0 0
Utah
Country [39] 0 0
United States of America
State/province [39] 0 0
Vermont
Country [40] 0 0
United States of America
State/province [40] 0 0
Virginia
Country [41] 0 0
United States of America
State/province [41] 0 0
Washington
Country [42] 0 0
United States of America
State/province [42] 0 0
West Virginia
Country [43] 0 0
United States of America
State/province [43] 0 0
Wisconsin

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 cisplatin and combination
chemotherapy works in treating children and young adults with hepatoblastoma or liver cancer
after surgery. 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 after surgery may kill more tumor cells.
Trial website
https://clinicaltrials.gov/show/NCT03533582
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Gregory 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

No data has been provided for results reporting
Summary results
Not applicable