Combination Chemotherapy for Liver Cancer

Recruiting at 215 trial locations

Age: < 65

Sex: Any

Trial Phase: Phase 3

Sponsor: Children's Oncology Group

Must not be taking: Investigational drugs, Anticancer agents, St. John's wort

Disqualifiers: Prior chemotherapy, Uncontrolled infection, Organ transplant, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 6-8 months

537 Participants Needed

Trial Summary

What is the purpose of this trial?

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.

Do I need to stop my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, you cannot be on other anticancer agents or certain drugs like St. John's wort if you are in Group D. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drugs used in the combination chemotherapy for liver cancer?

Research shows that cisplatin-based chemotherapy, often combined with other drugs like irinotecan and gemcitabine, has been effective in improving survival and quality of life in patients with advanced non-small cell lung cancer. These findings suggest potential benefits of similar drug combinations for other cancers, including liver cancer. ^{1 2 3 4 5}

Is the combination chemotherapy for liver cancer safe for humans?

Carboplatin, a drug used in combination chemotherapy, is generally considered safer than its counterpart cisplatin, as it causes less kidney damage and has fewer side effects like nausea and hearing loss. However, it can still cause blood-related side effects, such as a decrease in platelets, which are important for blood clotting. ^{6 7 8 9 10}

What makes this liver cancer treatment unique?

This treatment is unique because it combines multiple chemotherapy drugs, including cisplatin, doxorubicin, and others, which have shown effectiveness in other cancers, to potentially enhance their effects against liver cancer. The combination aims to target the cancer cells more effectively by using different mechanisms of action from each drug. ^{1 3 11 12 13}

Research Team

Gregory M Tiao

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for children and young adults with hepatoblastoma or liver cancer who have undergone surgery. They must be newly diagnosed, have proper organ function, not received prior cancer treatments except certain surgeries, and agree to contraception if of childbearing potential. Those with uncontrolled infections or on other cancer drugs can't join.

Inclusion Criteria

I am too ill for a biopsy but meet all other trial requirements.

My kidney function is normal or near normal.

For all Group A patients, WDF status as determined by rapid review will be used to further stratify patients to Group A1 or A2

Exclusion Criteria

Patients who are currently receiving other anticancer agents

I have had a liver transplant for liver cancer but no other organ transplants.

Patients with hypersensitivity to any drugs on their expected treatment arm

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cisplatin and combination chemotherapy, with treatment cycles varying by risk group and tumor resectability

6-8 months

Multiple visits for chemotherapy administration

Surgery

Surgical resection of tumors, performed after initial chemotherapy cycles

1-2 weeks

1 visit for surgery

Follow-up

Participants are monitored for safety, effectiveness, and long-term outcomes after treatment

Up to 5 years

Regular follow-up visits

Treatment Details

Interventions

• Cisplatin
• Doxorubicin, Fluorouracil, Vincristine Sulfate, Etoposide, Irinotecan, Sorafenib, Gemcitabine, Oxaliplatin, Carboplatin
• Resection

Trial Overview The study tests how well cisplatin combined with other chemotherapy drugs works after surgery in treating liver cancers in the young. It's a phase II/III trial where these drugs are given to see if they're better at killing tumor cells than one drug alone.

Participant Groups

Group I: GROUP F ARM 2 (P/GEMOX) Experimental Treatment 7 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group II: GROUP F ARM 1 (PLADO) Experimental Treatment 4 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group III: GROUP E2 (PLADO) Experimental Treatment 3 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group IV: GROUP D2 ARM VI Experimental Treatment 6 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group V: GROUP D2 ARM CE Experimental Treatment 5 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group VI: GROUP D1 Experimental Treatment 4 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group VII: GROUP C ARM CDDP Experimental Treatment 3 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group VIII: GROUP C ARM C5VD Experimental Treatment 5 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group IX: GROUP B2 ARM II Experimental Treatment 2 Interventions

Patients receive cisplatin IV over 6 hours on day 1. Treatment repeats every 14 days for up to 6 total cycles. Patients may optionally undergo blood sample collection on study.

Group X: GROUP B2 ARM I Experimental Treatment 3 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group XI: GROUP B1 ARM 6-CDDP Experimental Treatment 3 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group XII: GROUP B1 ARM 4-CDDP Experimental Treatment 2 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group XIII: GROUP A2 (NON-WDF) Experimental Treatment 2 Interventions

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. Patients may optionally undergo blood sample collection on study.

Group XIV: Group A1 (WDF) Active Control 2 Interventions

Patients undergo observation. Patients may optionally undergo blood sample collection on study.

Group XV: GROUP E1 Active Control 3 Interventions

Patients undergo observation only. Patients may optionally undergo blood sample collection on study.

Cisplatin is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in United States as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Canada as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Approved in Japan as Platinol for:

• Testicular cancer
• Ovarian cancer
• Cervical cancer
• Bladder cancer
• Head and neck cancer
• Esophageal cancer
• Lung cancer
• Mesothelioma
• Brain tumors
• Neuroblastoma

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Findings from Research

Cisplatin-based chemotherapy significantly improves survival and symptom control in stage IV non-small cell lung cancer patients with good performance status, suggesting its effectiveness as a primary treatment option.

Combination regimens including cisplatin and at least one other active drug (like ifosfamide or gemcitabine) are recommended, with four to six cycles proposed for patients who respond well, while non-platinum options can be considered for those unable to tolerate platinum-based treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Stage IV NSCLC. Place of chemotherapy]. Meert, AP.[2013]

Cisplatin combined with either a vinca alkaloid or etoposide is highly effective in reducing mortality for patients with non-small cell lung cancer, as shown in meta-analyses comparing chemotherapy to supportive care.

Recent studies indicate that combining cisplatin-based chemotherapy with new agents and radiotherapy can significantly prolong survival and improve outcomes for patients with locally advanced non-small cell lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Chemotherapy for non-small cell lung cancer]. Shinkai, T., Saijo, N.[2018]

Less than 25% of patients with non-small cell lung cancer (NSCLC) have early-stage disease that can be surgically removed, highlighting the need for effective treatments for advanced stages.

Cisplatin-based chemotherapy, especially in combination with newer agents like gemcitabine and paclitaxel, has shown improved survival rates and response rates exceeding 35% in advanced NSCLC, indicating its efficacy in managing this disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on European randomized studies in non-small cell lung cancer. Giaccone, G., Manegold, C., Rosell, R., et al.[2007]

Cisplatin and carboplatin are both effective platinum-based chemotherapy agents, but they differ significantly in their side effects; cisplatin can cause severe kidney damage and neurotoxicity, while carboplatin is safer for renal function and has less neurotoxicity.

Carboplatin's toxicity profile allows for dose adjustments based on renal function, making it a more manageable option for patients, whereas cisplatin requires hydration protocols to mitigate its harmful effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative adverse effect profiles of platinum drugs. McKeage, MJ.[2018]

In a phase II trial involving 37 patients with advanced non-small cell lung cancer, the combination of carboplatin and gemcitabine showed promising efficacy, with 8.1% achieving complete response and 24.3% achieving partial response after treatment.

The treatment was well-tolerated, with mild hematological toxicity, and a median survival of 10 months, suggesting that this regimen could be a viable palliative option for patients with this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Carboplatin and gemcitabine in the palliative treatment of stage IV non-small cell lung cancer: definitive results of a phase II trial. Tassinari, D., Fochessati, F., Arcangeli, V., et al.[2022]

In a randomized phase II trial involving 78 patients with extensive-stage small-cell lung cancer (ES-SCLC), the combination of pemetrexed with carboplatin showed a median survival time of 10.4 months and a response rate of 39.5%, indicating it is an effective treatment option.

Both pemetrexed/cisplatin and pemetrexed/carboplatin combinations were well-tolerated, with manageable hematologic toxicities, suggesting that these treatments can be safely administered as first-line therapy for ES-SCLC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of pemetrexed combined with either cisplatin or carboplatin in untreated extensive-stage small-cell lung cancer. Socinski, MA., Weissman, C., Hart, LL., et al.[2015]

References

1. France pubmed.ncbi.nlm.nih.gov

[Stage IV NSCLC. Place of chemotherapy]. [2013]

2. Ireland pubmed.ncbi.nlm.nih.gov

A phase II trial of fractionated irinotecan plus carboplatin for previously untreated extensive-disease small cell lung cancer. [2018]

3. United States pubmed.ncbi.nlm.nih.gov

A phase II study of irinotecan plus cisplatin for patients with advanced stage IIIB or IV NSCLC previously treated with nonplatinum-based chemotherapy. [2018]

4. Japan pubmed.ncbi.nlm.nih.gov

[Chemotherapy for non-small cell lung cancer]. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

An update on European randomized studies in non-small cell lung cancer. [2007]

6. New Zealand pubmed.ncbi.nlm.nih.gov

Comparative adverse effect profiles of platinum drugs. [2018]

7. United States pubmed.ncbi.nlm.nih.gov

In vitro effects of platinum compounds on renal cellular respiration in mice. [2018]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Gender difference in Cisplatin-induced nephrotoxicity in a rat model: greater intensity of damage in male than female. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Carboplatin and gemcitabine in the palliative treatment of stage IV non-small cell lung cancer: definitive results of a phase II trial. [2022]

10. Netherlands pubmed.ncbi.nlm.nih.gov

Preclinical antitumor and toxicologic profile of carboplatin. [2019]

11. Japan pubmed.ncbi.nlm.nih.gov

[Trials on expanding the clinical application of cisplatin]. [2013]

12. Japan pubmed.ncbi.nlm.nih.gov

[A case of Carboplatin and pemetrexed combination chemotherapy for synchronous double cancers of hepatocellular carcinoma and primary lung cancer]. [2019]

13. United States pubmed.ncbi.nlm.nih.gov

Randomized phase II trial of pemetrexed combined with either cisplatin or carboplatin in untreated extensive-stage small-cell lung cancer. [2015]