Pre- and Post-Surgery Chemotherapy for Gallbladder Cancer

Not currently recruiting at 395 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2 & 3

Sponsor: ECOG-ACRIN Cancer Research Group

Disqualifiers: Metastatic disease, Inoperable disease, Pregnancy, others

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

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

Compensation: Varies

Number of Visits: 12

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether adding chemotherapy before surgery treats stage II-III gallbladder cancer more effectively than administering it only after surgery. The chemotherapy drugs, gemcitabine (Gemcitabine Hydrochloride) and cisplatin (Cisplatin), aim to shrink the tumor, potentially making surgery easier and more effective. The study will assess if this approach can delay cancer's return and extend patients' lives. The trial seeks participants who discovered gallbladder cancer unexpectedly during routine gallbladder removal surgery. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering a chance to contribute to potential advancements in gallbladder cancer treatment.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that the combination of cisplatin and gemcitabine is generally well-tolerated by patients with advanced biliary tract cancer, including gallbladder cancer. One study found that the side effects of this treatment were mostly acceptable and manageable, typically handled with supportive care.

Another study indicated that adding durvalumab to this combination led to a high response rate, suggesting the treatment's effectiveness. However, the side effects remained similar to those of the cisplatin and gemcitabine combination alone.

Overall, these studies suggest that this chemotherapy mix is relatively safe for patients. It has been used successfully in treating similar types of cancer, supporting its use in clinical settings. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for gallbladder cancer because they explore both pre- and post-surgery chemotherapy approaches. Unlike conventional therapies that typically focus only on post-surgery treatment, this approach evaluates the impact of administering chemotherapy before surgery (neoadjuvant therapy) in Arm II. This could potentially shrink tumors, making surgery more effective. Additionally, both arms utilize a combination of cisplatin and gemcitabine, powerful drugs that work together to attack cancer cells more effectively. By integrating chemotherapy in both pre- and post-surgical phases, researchers hope to improve outcomes and survival rates compared to standard treatment options.

What evidence suggests that this trial's treatments could be effective for gallbladder cancer?

Research has shown that using gemcitabine with cisplatin can help treat biliary tract cancers, including gallbladder cancer. Studies found that patients receiving this combination lived, on average, 3.6 months longer than those who only received gemcitabine. Patients' overall survival time ranged from 4.6 to 11.7 months. This treatment effectively controls tumor growth for many patients. While some side effects occur, they are usually manageable. In this trial, one group of participants will receive this combination before and after surgery, while another group will receive it only after surgery. This evidence supports the potential benefit of using these drugs in both pre- and post-surgery settings for gallbladder cancer. ^{3 4 6 7 8}

Who Is on the Research Team?

Shishir K Maithel

Principal Investigator

ECOG-ACRIN Cancer Research Group

Are You a Good Fit for This Trial?

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.

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

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

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Cisplatin
• Gemcitabine Hydrochloride
• Lymphadenectomy
• Partial Hepatectomy

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.

How Is the Trial Designed?

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 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?

ECOG-ACRIN Cancer Research Group

Lead Sponsor

Trials

122

Recruited

160,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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]

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]

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]

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]

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 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]

In a study of 142 patients with locally advanced or metastatic gallbladder cancer, the combination treatment of gemcitabine, cisplatin, and nab-paclitaxel (GCNP) resulted in a high overall response rate of 67.6%, indicating its efficacy in managing this aggressive cancer.

The treatment not only improved response rates but also increased the likelihood of surgical resection, with 34% of patients initially deemed inoperable undergoing successful surgery after GCNP, suggesting a potential for better long-term outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine, Cisplatin, and Nab-Paclitaxel as a First-Line Therapy for Advanced Biliary Tract Cancers. Gedela, S., Munot, P., Vaidyanathan, A., et al.[2023]

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]

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]

In a study of 326 patients with advanced gallbladder cancer, gemcitabine-cisplatin (GC) showed a significantly longer median event-free survival (EFS) of 4.67 months compared to 3.88 months for gemcitabine-oxaliplatin (GO), suggesting GC may be more effective in delaying disease progression.

While both regimens are viable options, GC was associated with higher rates of anemia and thrombocytopenia, whereas GO had a higher incidence of peripheral neuropathy and hepatotoxicity, indicating that the choice of treatment may depend on the patient's overall health and tolerance to side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gemcitabine-cisplatin versus gemcitabine-oxaliplatin doublet chemotherapy in advanced gallbladder cancers: a match pair analysis. Ramaswamy, A., Ostwal, V., Pinninti, R., et al.[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]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4509359/

Gemcitabine Plus Cisplatin for Advanced Biliary Tract Cancer Median overall survival ranged from 4.6 to 11.7 months, and response rate ranged from 17.1% to 36.6%. Toxicities were generally acceptable and manageable.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa0908721

Cisplatin plus Gemcitabine versus Gemcitabine for Biliary ... Patients treated with cisplatin plus gemcitabine lived an average of 3.6 months longer than those treated with gemcitabine alone.

3. eviq.org.au eviq.org.au/medical-oncology/upper-gastrointestinal/pancreas-and-biliary/1200-biliary-and-gallbladder-advanced-cisplatin-an

Biliary and gallbladder advanced ciSplatin and gemcitabine RESULTS: After a median follow-up of 8.2 months and 327 deaths, the median overall survival was 11.7 months among the 204 patients in the cisplatin-gemcitabine ...

4. nature.com nature.com/articles/6605211

Gemcitabine alone or in combination with cisplatin ... In addition, 11 patients had stable disease on gemcitabine alone vs 17 on the combination (SD 35.5 vs 47.2%) The tumour control rate (CR+PR+SD) ...

5. bmccancer.biomedcentral.com bmccancer.biomedcentral.com/articles/10.1186/s12885-018-5211-y

Therapeutic outcomes and prognostic factors in unresectable ... Therapeutic outcomes and prognostic factors in unresectable gallbladder cancer treated with gemcitabine plus cisplatin. BMC Cancer 19, 10 (2019) ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11578849/

Efficacy, safety and differential outcomes of immune‐ ... The best overall response rate was 28.5% and disease control rate was 65.5%. While extrahepatic and intrahepatic BTC showed similar outcomes, mOS was ...

7. sciencedirect.com sciencedirect.com/science/article/pii/S0959804924008554

Durvalumab plus gemcitabine and cisplatin in advanced ... The TOPAZ-1 phase III trial showed a survival benefit with durvalumab plus gemcitabine and cisplatin in patients with advanced biliary tract cancer (BTC).

8. evidence.nejm.org evidence.nejm.org/doi/full/10.1056/EVIDoa2200015

Durvalumab plus Gemcitabine and Cisplatin in Advanced ... A phase 2 trial of durvalumab in combination with gemcitabine and cisplatin demonstrated promising efficacy, with an objective response rate of 72% and a ...