Pre- and Post-Surgery Chemotherapy for Gallbladder Cancer

Recruiting at 366 trial locations

Overseen by Shishir K Maithel

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 2 & 3

Recruiting

Sponsor: ECOG-ACRIN Cancer Research Group

Disqualifiers: Metastatic disease, Inoperable disease, Pregnancy, others

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This phase II/III trial compares the effect of adding chemotherapy before and after surgery versus after surgery alone (usual treatment) in treating patients with stage II-III gallbladder cancer. Chemotherapy drugs, such as gemcitabine and cisplatin, 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 chemotherapy before surgery may make the tumor smaller; therefore, may reduce the extent of surgery. Additionally, it may make it easier for the surgeon to distinguish between normal and cancerous tissue. Giving chemotherapy after surgery may kill any remaining tumor cells. This study will determine whether giving chemotherapy before surgery increases the length of time before the cancer may return and whether it will increase a patient's life span compared to the usual approach.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of this drug for gallbladder cancer?

Research shows that the combination of gemcitabine and cisplatin improved the quality of life and performance status in patients with advanced gallbladder cancer. In one study, 64% of patients responded positively to this drug combination, with manageable side effects and no treatment-related deaths. ^{1 2 3 4 5}

Is the combination of gemcitabine and cisplatin generally safe for humans?

The combination of gemcitabine and cisplatin has been used in various cancers, including gallbladder and pancreatic cancer, with manageable side effects. Common side effects include blood-related issues and gastrointestinal reactions, but severe adverse effects are rare, allowing patients to maintain a good quality of life during treatment. ^{1 4 6 7 8}

How is the chemotherapy treatment for gallbladder cancer unique?

This treatment uses a combination of cisplatin and gemcitabine, which is a standard approach for advanced gallbladder cancer, but it is unique because it is given both before and after surgery to potentially improve outcomes. ^{1 3 9 10 11}

Research Team

Shishir K Maithel

Principal Investigator

ECOG-ACRIN Cancer Research Group

Eligibility Criteria

This trial is for adults with stage II-III gallbladder cancer who've had a cholecystectomy within the last 12 weeks. They should be in good physical condition (ECOG 0-1), have normal organ function, and no severe concurrent diseases. Pregnant or breastfeeding women can't participate, and those able to conceive must use contraception.

Inclusion Criteria

My hepatitis B virus load is undetectable with treatment.

My kidney function, measured by creatinine levels or clearance, is within the normal range.

I am HIV positive, on treatment, and my viral load is undetectable.

Exclusion Criteria

My cancer is limited and potentially removable by surgery.

You do not have any signs of recent fluid buildup in your abdomen.

My cancer has not spread to multiple organs beyond the liver.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Neoadjuvant Chemotherapy

Patients receive gemcitabine and cisplatin before surgery to potentially shrink the tumor

12 weeks

4 cycles of treatment every 21 days

Surgery

Surgical resection of part of the liver, lymph nodes, and possibly bile ducts

1 day

1 surgical visit

Adjuvant Chemotherapy

Patients receive gemcitabine and cisplatin after surgery to eliminate remaining cancer cells

12-24 weeks

4-8 cycles of treatment every 21 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

Every 3 months for 2 years, then every 6 months for 1 year

Treatment Details

Interventions

• Cisplatin (Platinum-based Chemotherapy)
• Gemcitabine Hydrochloride (Nucleoside Analog)
• Lymphadenectomy (Surgery)
• Partial Hepatectomy (Surgery)

Trial Overview The study compares adding chemotherapy before and after surgery to just after surgery for treating gallbladder cancer. It tests if pre-surgery chemo using gemcitabine hydrochloride and cisplatin makes tumors smaller, eases surgical removal, prevents recurrence better, and extends life compared to the usual treatment.

Participant Groups

Group I: Arm II (neoadjuvant therapy, surgery, adjuvant therapy) Experimental Treatment 4 Interventions

Patients receive gemcitabine IV over 30 minutes and cisplatin over 30 minutes-24 hours on days 1 and 8. Treatment repeats every 21 days for 4 cycles in the absence of disease progression or unacceptable toxicity. Approximately 4-8 weeks after completion of chemotherapy, patients whose disease has not spread to other places in the body (metastasized), then undergo surgery as in Arm I. Patients with successful surgery then resume treatment with gemcitabine IV and cisplatin IV on days 1 and 8. Treatment repeats every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity.

Group II: Arm I (surgery, adjuvant therapy) Active Control 4 Interventions

Within 4 weeks of randomization, patients undergo surgery to remove part of the liver, the lymph nodes around the liver, and possibly the bile ducts. Patients then receive gemcitabine IV over 30 minutes and cisplatin IV over 30 minutes-24 hours on days 1 and 8. Treatment repeats every 21 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity.

Cisplatin is already approved in Canada, Japan for the following indications:

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?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

Dr. Peter J. O'Dwyer

ECOG-ACRIN Cancer Research Group

Chief Executive Officer since 2012

MD from University of Pennsylvania

Dr. Mitchell D. Schnall

ECOG-ACRIN Cancer Research Group

Chief Medical Officer since 2012

MD, PhD from University of Pennsylvania

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Dr. Douglas R. Lowy

National Cancer Institute (NCI)

Chief Executive Officer since 2023

MD from New York University School of Medicine

Dr. Monica Bertagnolli

National Cancer Institute (NCI)

Chief Medical Officer since 2022

MD from Harvard Medical School

Findings from Research

In a case study of 2 patients with unresectable advanced gallbladder cancer, treatment with gemcitabine and cisplatin led to a rapid improvement in their performance status.

Both patients reported maintaining a good quality of life (QOL) during the course of their treatment, suggesting that this combination therapy may be beneficial for managing symptoms in advanced stages of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Two Cases of Unresectable Advanced Gallbladder Cancer in Which Gemcitabine and Cisplatin Therapy Improved the QOL]. Nagano, H., Yoshioka, S., Sato, M., et al.[2022]

In a study of 11 patients with advanced gallbladder cancer, gemcitabine combined with cisplatin resulted in a 64% overall response rate, with one patient achieving complete remission and six achieving partial responses.

The treatment was well-tolerated with manageable toxicity, and the median overall survival was 42 weeks, suggesting that this combination therapy could be a promising option for patients with a poor prognosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine and Cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. Malik, IA., Aziz, Z., Zaidi, SH., et al.[2022]

In a study of 396 patients with locally advanced or metastatic gallbladder cancer, those who continued chemotherapy beyond 6-8 cycles had a significantly improved median overall survival of 14.88 months compared to those who did not continue, highlighting the potential benefit of continuation chemotherapy.

The study identified key prognostic factors for overall survival, including the burden of metastases and the ability to receive second-line chemotherapy, which can help guide treatment decisions for patients undergoing first-line palliative chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of advanced Gall bladder cancer in the real world-can continuation chemotherapy improve outcomes? Ostwal, V., Pinninti, R., Ramaswamy, A., et al.[2020]

In a study of 20 patients with advanced gallbladder carcinoma, combined chemotherapy using gemcitabine and carboplatin resulted in a 36.7% overall response rate, with 21% achieving a complete response and 15.7% a partial response.

The treatment demonstrated mild toxicity, with only a small percentage of patients experiencing severe anemia, neutropenia, or thrombocytopenia, indicating that this chemotherapy regimen is both effective and relatively safe for patients with advanced disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of gemcitabine and carboplatin combination chemotherapy in gallbladder carcinoma. Julka, PK., Puri, T., Rath, GK.[2022]

A mini-PDX model using tumor samples from 12 gallbladder cancer patients showed significant variability in how different chemotherapy drugs worked, helping to tailor treatment plans.

Patients whose chemotherapy was guided by the PDX model had significantly longer overall survival (18.6 months) and disease-free survival (17.6 months) compared to those receiving standard chemotherapy, indicating that personalized treatment can lead to better outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Guided chemotherapy based on patient-derived mini-xenograft models improves survival of gallbladder carcinoma patients. Zhan, M., Yang, RM., Wang, H., et al.[2022]

A 54-year-old woman with inoperable advanced gallbladder cancer showed a positive response to combined chemotherapy with gemcitabine and cisplatin, leading to disease stabilization for over a year.

The treatment was well-tolerated, with no severe side effects reported, allowing the patient to maintain a good quality of life during the therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[A case of inoperable advanced gallbladder cancer that has maintained stable disease status for a long period with gemcitabine and cisplatin therapy]. Takayanagi, N., Chiba, H., Sagawa, T., et al.[2022]

Cis-diamminedichloroplatinum (II) demonstrated significant efficacy as a single-agent treatment for advanced genitourinary tumors, achieving complete responses in 16.7% of testicular cancer patients and partial responses in 50% of the same group, based on a study of 112 patients with various genitourinary tumors.

The treatment was associated with common adverse reactions such as gastrointestinal issues, nephrotoxicity, and myelosuppression, but also included occasional ototoxicity and peripheral neuropathies, indicating a need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Phase II study of cis-diamminedichloroplatinum (II) in genitourinary cancer]. [2013]

The combination of gemcitabine and low-dose cisplatin shows promising activity in treating metastatic and locally advanced pancreatic cancer, with a median progression-free survival of 4.4 months and median overall survival of 6.7 months based on a study of 58 patients.

While 66% of patients experienced significant toxicities, primarily hematologic, this treatment regimen is considered a viable first-line option for patients who cannot receive standard treatments like gemcitabine plus nab-paclitaxel, especially those with BRCA1 and/or BRCA2 mutations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Biweekly gemcitabine and low-dose cisplatin in the treatment of locally advanced or metastatic pancreatic cancer patients: a single institute experience. Lundberg, J., Reardon, J., Blazer, M., et al.[2022]

Olfactomedin 4 (OLFM4) is identified as a key gene contributing to cisplatin (CDDP) resistance in gallbladder cancer (GBC), with its expression linked to poor patient prognosis.

Depleting OLFM4 not only reduced GBC cell proliferation and invasion but also sensitized these cells to CDDP treatment, suggesting that targeting OLFM4 could enhance the effectiveness of chemotherapy in GBC.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

OLFM4 depletion sensitizes gallbladder cancer cells to cisplatin through the ARL6IP1/caspase-3 axis. Lin, Z., Yang, S., Zhou, Y., et al.[2022]

References

1. Japan pubmed.ncbi.nlm.nih.gov

[Two Cases of Unresectable Advanced Gallbladder Cancer in Which Gemcitabine and Cisplatin Therapy Improved the QOL]. [2022]

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

Gemcitabine and Cisplatin is a highly effective combination chemotherapy in patients with advanced cancer of the gallbladder. [2022]

3. China pubmed.ncbi.nlm.nih.gov

Treatment of advanced Gall bladder cancer in the real world-can continuation chemotherapy improve outcomes? [2020]

4. Singapore pubmed.ncbi.nlm.nih.gov

A phase II study of gemcitabine and carboplatin combination chemotherapy in gallbladder carcinoma. [2022]

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

Guided chemotherapy based on patient-derived mini-xenograft models improves survival of gallbladder carcinoma patients. [2022]

6. Japan pubmed.ncbi.nlm.nih.gov

[A case of inoperable advanced gallbladder cancer that has maintained stable disease status for a long period with gemcitabine and cisplatin therapy]. [2022]

7. Japan pubmed.ncbi.nlm.nih.gov

[Phase II study of cis-diamminedichloroplatinum (II) in genitourinary cancer]. [2013]

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

Biweekly gemcitabine and low-dose cisplatin in the treatment of locally advanced or metastatic pancreatic cancer patients: a single institute experience. [2022]

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

OLFM4 depletion sensitizes gallbladder cancer cells to cisplatin through the ARL6IP1/caspase-3 axis. [2022]

10. Japan pubmed.ncbi.nlm.nih.gov

Gemcitabine-cisplatin versus gemcitabine-oxaliplatin doublet chemotherapy in advanced gallbladder cancers: a match pair analysis. [2022]

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

Gemcitabine, Cisplatin, and Nab-Paclitaxel as a First-Line Therapy for Advanced Biliary Tract Cancers. [2023]