Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
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| ClinicalTrials.gov Identifier: NCT03533582 |
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Recruitment Status :
Recruiting
First Posted : May 23, 2018
Last Update Posted : May 23, 2023
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Sponsor:
Children's Oncology Group
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Children's Oncology Group
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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.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Childhood Hepatocellular Carcinoma Childhood Malignant Liver Neoplasm Fibrolamellar Carcinoma Hepatoblastoma Hepatocellular Malignant Neoplasm, Not Otherwise Specified | Drug: Carboplatin Drug: Cisplatin Drug: Doxorubicin Drug: Etoposide Drug: Fluorouracil Drug: Gemcitabine Drug: Irinotecan Other: Laboratory Biomarker Analysis Drug: Oxaliplatin Other: Patient Observation Procedure: Resection Drug: Sorafenib Drug: Vincristine Sulfate | Phase 2 Phase 3 |
Show detailed description
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 537 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Pediatric Hepatic Malignancy International Therapeutic Trial (PHITT) |
| Actual Study Start Date : | May 23, 2018 |
| Estimated Primary Completion Date : | June 30, 2025 |
| Estimated Study Completion Date : | June 30, 2025 |
Resource links provided by the National Library of Medicine
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Group A1 (WDF)
Patients undergo observation.
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Other: Laboratory Biomarker Analysis
Correlative studies Other: Patient Observation Undergo watchful waiting
Other Names:
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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.
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Drug: Cisplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
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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.
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Drug: Cisplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
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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.
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Drug: Cisplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Procedure: Resection Undergo surgical resection
Other Name: Surgical Resection |
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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.
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Drug: Cisplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Procedure: Resection Undergo surgical resection
Other Name: Surgical Resection |
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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.
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Drug: Cisplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
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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.
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Drug: Cisplatin
Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Fluorouracil Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Vincristine Sulfate Given IV
Other Names:
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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.
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Drug: Cisplatin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Procedure: Resection Undergo surgical resection
Other Name: Surgical Resection |
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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. |
Drug: Carboplatin
Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
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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. |
Drug: Carboplatin
Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Etoposide Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
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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. |
Drug: Carboplatin
Given IV
Other Names:
Drug: Cisplatin Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Irinotecan Given IV Other: Laboratory Biomarker Analysis Correlative studies Drug: Vincristine Sulfate Given IV
Other Names:
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Active Comparator: GROUP E1
Patients undergo observation only.
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Drug: Doxorubicin
Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Other: Patient Observation Undergo watchful waiting
Other Names:
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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.
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Drug: Cisplatin
Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies |
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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.
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Drug: Cisplatin
Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Sorafenib Given PO
Other Names:
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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.
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Drug: Cisplatin
Given IV
Other Names:
Drug: Doxorubicin Given IV
Other Names:
Drug: Gemcitabine Given IV
Other Names:
Other: Laboratory Biomarker Analysis Correlative studies Drug: Oxaliplatin Given IV
Other Names:
Procedure: Resection Undergo surgical resection
Other Name: Surgical Resection Drug: Sorafenib Given PO
Other Names:
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Primary Outcome Measures :
- Event-free survival (EFS) [ Time Frame: 3 years ]EFS is defined as the time from randomization (or registration into the trial for non-randomized patients) to the first failure event where the failure events are defined as: 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. Patients who have not had an event will be censored at their last follow-up date. EFS for group A, group B1, group C, group D1, group D2 and E will be presented.
- Percentage of Group B2 participants with resectable tumors [ Time Frame: 6 months ]Group B patients who are unresectable after cycles 1 & 2 of cisplatin treatment will be assigned to Group B2. These patients will receive cycles 3-6 of cisplatin treatment.
- Response rate for Group F patients [ Time Frame: Up to 5 years ]Response is defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Patients who are not assessable for response - e.g. because of early stopping of treatment or death - will be classified as non-responders.
Other Outcome Measures:
- Failure free survival [ Time Frame: 3 years ]Failure free survival is defined as the time from randomization (or registration into the trial for non-randomized patients) to first failure event. Failure events are: progression of existing disease or occurrence of disease at new sites, death from any cause prior to disease progression, diagnosis of a second malignant neoplasm, or failure to go to resection.
- Overall survival [ Time Frame: 3 years ]Overall survival is defined as the time from randomization (or registration for non-randomized patients) to death from any cause.
- Percentage of patients experiencing grade 3 or higher adverse events [ Time Frame: 8 months ]The percentage of patients experiencing grade 3 or higher toxicity will be reported, where adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
- Percentage of patients with chemotherapy-related cardiac, nephro- and oto-toxicity [ Time Frame: Up to 5 years ]Adverse events are graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.
- Percentage of patients with hearing loss [ Time Frame: Up to 5 years ]Hearing loss will be measured according to the SIOP Boston Scale for ototoxicity.
- Best response [ Time Frame: Up to 5 years ]Response in hepatocellular carcinoma (HCC) will be defined as complete (CR) or partial (PR) response according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria. Response in HB will be defined as CR or PR based on radiological response (RECIST v1.1) and AFP decline.
- Percentage of participants who are surgically resectable [ Time Frame: Up to 5 years ]Surgical resectability is defined as complete resection, partial resection or transplant following randomization (or enrollment for non-randomized patients).
- Percentage of participants with adherence to surgical guidelines [ Time Frame: Up to 5 years ]Adherence to surgical guidelines is defined as the local clinician's surgical decision to resect or not compared to the current SIOPEL surgical guidelines.
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| Ages Eligible for Study: | up to 30 Years (Child, Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Criteria
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
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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
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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
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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
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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
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- 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
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Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2 or
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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)
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- 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)
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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
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Group F:
- Patients with peripheral sensitive neuropathy with functional impairment
- Patients with a personal or family history of congenital long QT syndrome
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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
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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
Information from the National Library of Medicine
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03533582
Locations
Show 204 study locations
Sponsors and Collaborators
Children's Oncology Group
National Cancer Institute (NCI)
Investigators
| Principal Investigator: | Gregory M Tiao | Children's Oncology Group |
| Responsible Party: | Children's Oncology Group |
| ClinicalTrials.gov Identifier: | NCT03533582 |
| Other Study ID Numbers: |
AHEP1531 NCI-2017-01910 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ) AHEP1531 ( Other Identifier: Children's Oncology Group ) AHEP1531 ( Other Identifier: CTEP ) U10CA180886 ( U.S. NIH Grant/Contract ) |
| First Posted: | May 23, 2018 Key Record Dates |
| Last Update Posted: | May 23, 2023 |
| Last Verified: | July 2022 |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
Additional relevant MeSH terms:
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Carcinoma Neoplasms Liver Neoplasms Hepatoblastoma Neoplasms, Glandular and Epithelial Neoplasms by Histologic Type Digestive System Neoplasms Neoplasms by Site Digestive System Diseases Liver Diseases Neoplasms, Complex and Mixed Cisplatin Carboplatin Gemcitabine Doxorubicin |
Liposomal doxorubicin Fluorouracil Oxaliplatin Irinotecan Etoposide Vincristine Etoposide phosphate Sorafenib Daunorubicin Podophyllotoxin Antineoplastic Agents Antimetabolites, Antineoplastic Antimetabolites Molecular Mechanisms of Pharmacological Action Antibiotics, Antineoplastic |