Randomized Phase II/III Trial of Cisplatin, Gemcitabine Hydrochloride, and Paclitaxel Albumin-Bound as Neoadjuvant Therapy in Resectable Biliary Tract Cancers
- Trial ID
- 2023-503295-25-00
- Protocol
- PURITY
- Sponsor
- Fondazione GONO G.I.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of neoadjuvant GAP (Cisplatin, Gemcitabine, and Nabpaclitaxel) followed by surgery compared to an upfront surgical approach in terms of 12-month progression-free survival (PFS) in patients with resectable biliary tract cancers. This is clinically relevant as it aims to determine whether the neoadjuvant chemotherapy regimen can improve survival outcomes in a population at high risk for recurrence.
Secondary objectives include:
- Estimating the efficacy of neoadjuvant GAP followed by surgery compared to upfront surgery in terms of progression-free survival (PFS), event-free survival (EFS), recurrence-free survival (RFS), and overall survival (OS).
- Evaluating the activity of neoadjuvant GAP in achieving radical surgery (R0, R0+R1 resection rate) compared to upfront surgery.
- Estimating the impact of the neoadjuvant strategy on patients' quality of life using patient-reported outcome (PRO) questionnaires.
- Evaluating the activity of neoadjuvant GAP in terms of overall response rate (ORR) according to RECIST 1.1 criteria, assessed by both investigator and blinded independent central review (BICR) in patients with measurable disease.
- Retrospectively evaluating the resectability of the primary tumor as assessed by a central review committee.
- Evaluating the safety profile, adverse events, and surgical morbidity or mortality of neoadjuvant GAP compared to upfront surgery.
Participants
The clinical trial involves participants diagnosed with **resectable biliary tract cancers**, including gallbladder carcinoma and various forms of cholangiocarcinoma, but excluding mixed tumor entities with hepatocellular carcinoma and ampullary cancers. The study population comprises both male and female subjects aged 18 to 74 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, indicating they are fully active or restricted in physically strenuous activity but ambulatory. Participants must have no prior tumor resection for biliary tract cancer and must be free of distant metastases as confirmed by imaging techniques. The trial includes individuals with adequate hematologic, liver, and renal function, and excludes those with complete dihydropyrimidine dehydrogenase enzyme deficiency. The sponsor has not provided information regarding the total number of participants. The selection process involves a multidisciplinary team assessment to ensure the technical resectability of the cancer. Participants are required to adhere to specific lifestyle considerations, such as abstaining from donating eggs or sperm and using effective contraceptive methods during and after the study period. The trial population includes a vulnerable population, indicating additional ethical considerations in the study design.
Plans and Procedures
The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy of neoadjuvant chemotherapy using a combination of **cisplatin**, **gemcitabine hydrochloride**, and **paclitaxel albumin-bound** followed by surgery, compared to an upfront surgical approach in patients with resectable biliary tract cancers. The primary objective is to assess the 12-month progression-free survival rate. The trial is expected to run until January 31, 2029, with recruitment starting on July 1, 2023.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, histological confirmation of non-metastatic resectable carcinoma of the biliary tract, and adequate organ function. Following the screening, participants will be randomized into either the neoadjuvant chemotherapy group or the immediate surgery group. The neoadjuvant group will receive chemotherapy for a maximum treatment period of 63 days, with follow-up visits scheduled to monitor treatment response and adverse events.
Subsequent follow-up visits will occur at regular intervals to assess progression-free survival, event-free survival, and overall survival, among other secondary endpoints. The end-of-study visit will evaluate the overall response rate and resectability rate. Participants are expected to be involved in the study for the duration of the treatment and follow-up period, which may extend up to several years depending on individual response and survival outcomes.
Conditions that may lead to early termination from the study include disease progression that precludes definitive surgery, treatment discontinuation due to adverse events, or withdrawal of consent. Participants must comply with study protocols, including the use of effective contraceptive methods and agreement not to donate eggs or sperm during the study and for a specified period afterward. The study aims to provide valuable insights into the effectiveness of neoadjuvant chemotherapy in improving outcomes for patients with high-risk resectable biliary tract cancers.
Treatment
The clinical trial involves the administration of several **experimental medications**. **Cisplatin** is provided as a concentrate for solution for infusion. It is administered via infusion with a maximum daily dose of 25 mg/m² and a total maximum dose of 150 mg/m² over a treatment period of 63 days. The active substance is of chemical origin, and the formulation is not pediatric-specific.
**Gemcitabine Hydrochloride** is also administered as a concentrate for solution for infusion. The dosing regimen includes a maximum daily dose of 800 mg/m² and a total maximum dose of 4800 mg/m², with the treatment period extending up to 63 days. This medication is similarly of chemical origin and is not formulated for pediatric use.
**Capecitabine** is utilized as an auxiliary treatment in the study. It is administered orally with a maximum daily dose of 2500 mg/m² and a total maximum dose of 280,000 mg/m² over a treatment period of 8 weeks. The active substance is of chemical origin, and the formulation is not intended for pediatric patients.
**Paclitaxel Albumin-Bound** is provided as a powder for dispersion for infusion. The administration route is infusion, with a maximum daily dose of 100 mg/m² and a total maximum dose of 600 mg/m² over a 63-day treatment period. The active substance is categorized under Specified Substance Group 1, and the formulation is not pediatric-specific.
In addition to the experimental medications, the study may include non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments, although specific details are not provided. Participant compliance with the dosing schedules is monitored throughout the trial to ensure adherence to the treatment protocols.
Efficacy
The efficacy of the clinical trial will be assessed primarily through the evaluation of the 12-month **progression-free survival (PFS)** rate. This primary endpoint measures the proportion of patients who are alive and free from disease progression or post-resection recurrence at the 12-month timepoint from randomization. This endpoint is considered the primary measure in the phase II part of the study and a secondary measure in the phase III part.
Secondary endpoints include several additional measures of efficacy: **progression-free survival (PFS)**, which tracks the time from randomization to disease progression, post-resection recurrence, or death from any cause; **event-free survival (EFS)**, which measures the time from randomization to events such as disease progression that precludes definitive surgery, treatment discontinuation, post-resection recurrence, a second primary cancer, or death; **relapse-free survival (RFS)**, which is the time from surgery to disease recurrence or death in patients undergoing surgery with curative intent; and **overall survival (OS)**, which is the time from randomization to death from any cause, with censoring for patients still alive at the time of analysis.
Additional secondary endpoints include the **R0 resection rate**, the percentage of patients achieving a microscopically margin-free complete surgical removal of all residual disease, and the **R0+R1 resection rate**, which includes patients with macroscopic removal of the tumor but positive microscopic margins. **Quality of life (QLQ)** will be assessed using Patient Reported Outcome instruments, with comparisons of mean score changes from baseline and time to deterioration in specific domains. The **overall response rate (ORR)**, defined by the percentage of patients achieving a complete or partial response according to RECIST 1.1 criteria, will be evaluated based on investigator assessment and a blinded independent central review of CT scan images.
Other measures include the **resectability rate**, evaluating the conversion to resectability in the neoadjuvant arm, and the **toxicity rate**, which is the percentage of patients experiencing specific adverse events according to National Cancer Institute Common Toxicity Criteria. The **perioperative morbidity and mortality rate** will also be assessed, defined as the percentage of patients experiencing serious perioperative morbidity or mortality according to the Clavien-Dindo classification.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Patient able and willing to provide written informed consent and to comply with the study protocol and with the planned surgical procedures.
- Estimated life expectancy > 3 months.
- Adequate baseline hematologic function characterized by the following at screening: a) ANC >=1.5x10^9/L, b) platelets >= 100x10^9/L, c) hemoglobin >=9g/dl. Note: prior transfusions for patients with low hemoglobin are allowed.
- Adequate liver function characterized by the following at screening: a) Serum total bilitubin <= 1.5xULN and < 2mg/dL.Note: Subjects with Serum total bilirubin >=1.5xULN and conjugated bilirubin <=40% of total bilirubin are allowed. b) Serum transaminases (AST and/or ALT) < 3 x ULN.
- Adequate renal function, i.e. serum creatinine <= 1.5 institutionalULN and calculated by Cockroft-Gault formula or directly measured creatinine clearance >= 50mL/min
- Adequate coagulation functions as defined by International Normalized Ratio (INR) <= 1.5,and a partial thromboplastin time (PTT) <= 5 seconds above the ULN (unless receiving anticoagulation therapy).
- No presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency with DPYD gene testing mandatory at screening as per national guidelines
- Females of childbearing potential must agree to remain abstinent (refrain from sexual intercourse) or use highly effective contraceptive methods, as defined in APPENDIX V of the full protocol, during the treatment period and for at least 7 months after the last administration of study treatments.
- Males must agree to remain abstinent (refrain from sexual intercourse) or use highly effective contraceptive methods, as defined in APPENDIX V of the full protocol.
- Female and male patients >= 18 years and < 75 years.
- Histologically or cytologically confirmed non metastatic resectable carcinoma of biliary tract (BTC), including gallbladder carcinoma (GBC), intrahepatic, periperihilar or distal Cholangiocarcinoma (CCA). Mixed tumor entities with hepatocellular carcinoma and ampullary cancers are excluded.
- Availability of a tumoral sample
- ECOG performance status of 0-1.
- No prior tumor resection for BTC.
- Exclusion of distant metastases by CT or MRI of abdomen, pelvis, and thorax and PET scan.
- Technically resectable BTC as per local Multidisciplinary Team (MDT) assessment, including a core team with at least one medical oncologist, one surgeon, one radiologist, one endoscopist/gastroenterologist and one pathologist, all with expertise > 3 years on biliary tract cancer and hepatobiliary oncology..
- High risk for recurrence defined as the presence of at least one of the following risk features, as evaluated at baseline (pre-surgery)
- Negative serum pregnancy test within 7 days of starting study treatment in premenopausal women and women <1 year after the onset of menopause.
- A participant must agree not to donate eggs/sperm for future use for the purposes of assisted reproduction during the study and for a period of 7 months after receiving the last dose of study treatment. Female and male participants should consider preservation of eggs/sperm prior to study treatment as anti-cancer treatments may impair fertility.
Exclusion Criteria
- Known allergy or hypersensitivity to cisplatin, gemcitabine, nab-paclitaxel or fluoropyrimidine and their excipients.
- Any known additional malignancy that is progressing or requires active treatment, or history of other malignancy within 2 years of study entry except for curatively treated basal cell carcinoma of the skin, in situ carcinoma of the cervix, and prostate cancer.
- Locally unresectable tumor according to local MDT (including radiological evidence suggesting inability to resect with curative intent whilst maintaining adequate vascular inflow and outflow, and sufficient future liver remnant).
- Evidence of distant metastases at any site.
- Tumors requiring multi-step surgical procedures such as two-stage hepatectomy or Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS) due to liver volumetry-based assessment of anticipated inadequate future liver remnant.
- Cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic decompensation in the year before enrolment.
- Know active uncontrolled hepatitis B or hepatitis C. Patients with a past or resolved HBV infection are eligible. Patients with chronic disease controlled by antiviral therapy or requiring prophylactic treatment are eligible.
- Chronic or current active infectious disease requiring systemic antibiotics or antifungal treatment within 2 weeks prior to enrollment.
- Known uncontrolled HIV infection. HIV-positive patients are eligible if their CD4+ cell count amounts to 300 cells per μL or more; HIV viral load must be undetectable per standard of care assay, and they must be compliant with antiretroviral treatment.
- Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication.
- Pregnant or breast-feeding patient, or patient is planning to become pregnant within 7 months after the end of treatment.
- Any other concurrent antineoplastic treatment including radiotherapy.
- Previous or concurrent systemic (eg cytotoxic or targeted or other experimental drugs) therapy for BTC.
- Prior surgery or locoregional therapy for BTC.
- Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV, unstable angina pectoris, history of myocardial infarction in the last three months, significant arrhythmia).
- Presence of psychiatric disorder precluding understanding of information of trial related topics and giving informed consent.
- Any serious underlying medical conditions (judged by the investigator), that could impair the ability of the patient to participate in the trial
- Presence of complete dihydropyrimidine dehydrogenase (DPD) enzyme deficiency with DPYD gene testing mandatory at screening as per national guidelines.
- Rare hereditary problems of galactose intolerance, total lactase deficiency or glucosegalactose malabsorption.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Italy | Recruiting | 01 Jul 2023 | 108 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
GEMCITABINE HYDROCHLORIDE | Test | — | INFUSION | 800 | 63 | SUB02324MIG |
CISPLATIN | Test | — | INFUSION | 25 | 63 | SUB07483MIG |
PACLITAXEL ALBUMIN-BOUND | Test | — | INFUSION | 100 | 63 | SUB127678 |
CAPECITABINE | Other | PHF00009MIG | ORAL | 2500 | 8 | SCP2172075 |