Sponsor: City of Hope Medical Center (other)
Phase: 1
Start date: Sept. 19, 2022
Planned enrollment: 12
No investigational drugs.
Goal: Assess the safety and tolerability of adding pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivery of nab-paclitaxel to standard systemic gemcitabine and cisplatin in biliary tract cancer with peritoneal metastases, and generate preliminary signals of efficacy and feasibility.
Patients: Adults (≥18 years) with histologically or cytologically confirmed intrahepatic or extrahepatic cholangiocarcinoma or gallbladder cancer, ECOG 0–1, radiologically or laparoscopically evident peritoneal metastases, adequate organ function, and no prior systemic therapy for advanced disease. Key exclusions include extensive liver involvement (≥50%), CNS metastases, significant neuropathy (≥grade 2), active infections requiring recent antibiotics, and recent adjuvant therapy (<6 months).
Design: Single-arm, open-label, phase 1 safety study with descriptive secondary efficacy and feasibility endpoints; planned enrollment 12. No randomization or blinding. Follow-up at 4 weeks post-treatment and then every 3 months.
Treatments: Systemic gemcitabine IV and cisplatin IV on days 1 and 8 of 21-day cycles, with intraperitoneal nab-paclitaxel delivered as PIPAC on day 3 of cycles 1, 3, and 5; up to 8 cycles unless progression or unacceptable toxicity. Nab-paclitaxel (albumin-bound paclitaxel) is a microtubule inhibitor facilitating paclitaxel delivery without solvents; when administered via PIPAC, it is aerosolized under pressure during laparoscopy to enhance peritoneal tissue penetration and distribution while potentially reducing systemic exposure. Clinical results for nab-paclitaxel via PIPAC in biliary tract cancer are not yet established; this trial seeks safety data and pharmacologic rationale rather than efficacy proof.
Outcomes: Primary: Incidence and characterization of treatment-related adverse events by NCI CTCAE v5.0 within the first 6 weeks. Secondary: Efficacy by PCI at laparoscopy, RECIST responses on CT, and PGRS on peritoneal biopsies at each PIPAC; postoperative complications by Clavien-Dindo within 4 weeks after each PIPAC; overall and progression-free survival; quality of life and symptoms by EQ-5D-5L and MDASI; functional status via daily step counts. Exploratory: Tumor subclonal evolution and microenvironment, with immune profiling; pharmacokinetic and pharmacodynamic assessments of intraperitoneal nab-paclitaxel.
Burden on patient: Moderate to high. Patients undergo standard-of-care IV chemotherapy on days 1 and 8 each cycle plus three scheduled laparoscopic procedures for PIPAC (cycles 1, 3, and 5), each requiring anesthesia, hospital visits, and peritoneal biopsies. Additional assessments include serial CT imaging, repeated laboratory monitoring, adverse event evaluations, and quality-of-life questionnaires at multiple time points. Functional monitoring with a wrist pedometer is low burden, but exploratory PK/PD sampling and tissue acquisition during laparoscopy add procedural and travel demands beyond standard gemcitabine/cisplatin care.
Inclusion Criteria:
* Documented informed consent of the participant and/or legally authorized representative
* Assent, when appropriate, will be obtained per institutional guidelines
* Agreement to allow the use of archival tissue from diagnostic tumor biopsies
* If unavailable, exceptions may be granted with study principal investigator (PI) approval
* Age: \>= 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
* Histologically or cytologically confirmed intrahepatic cholangiocarcinoma or extrahepatic cholangiocarcinoma or gallbladder cancer
* Documented metastatic disease on computed tomography (CT) imaging or magnetic resonance imaging (MRI). CT scan or MRI to assess measurable disease must have been completed within 28 days prior to registration
* Visible peritoneal metastatic disease on cross-sectional imaging or diagnostic laparoscopy (does not have to be measurable by Response Evaluation Criteria in Solid Tumors \[RECIST\] 1.1)
* Fully recovered from acute toxic effects (except alopecia, hearing loss, or non-clinically significant laboratory abnormalities) =\< grade 1 of prior anti-cancer therapy
* Complete medical history and physical exam (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Absolute neutrophil count (ANC) \>= 1,500/mcL (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Platelets \>= 100,000/mcL (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Hemoglobin \>= 8 g/dL (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Serum albumin \>= 2.8 g/dL (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Total bilirubin =\< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease, then direct bilirubin \< 1.5 mg/dL) (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Aspartate aminotransferase (AST) =\< 5 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Alanine aminotransferase (ALT) =\< 5 x ULN (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Calculated creatinine clearance of \>= 45 mL/min per 24 hour urine test or the Cockcroft-Gault formula (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* Seronegative for human immunodeficiency virus (HIV) antigen (Ag)/antibody (Ab) combo (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* If seropositive, patient may be eligible if they are stable on antiretroviral therapy, have a CD4 T cell count \>= 200/µL, and have an undetectable viral load
* Documented virology status of hepatitis, confirmed by hepatitis B virus (HBV) and hepatitis C virus (HCV) tests (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* For patients with active HBV, HBV deoxyribonucleic acid (DNA) \< 500 IU/mL during screening, initiation of anti-HBV treatment at least 14 days prior to day 1 of cycle 1, and willingness to continue anti-HBV treatment during the study (per standard of care)
* If seropositive for HCV, nucleic acid quantification must be performed. Viral load must be undetectable
* Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (performed within 28 days prior to day 1 of protocol therapy unless otherwise stated)
* If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
* Agreement by females and males of childbearing potential\* to use an effective method of birth control (e.g. licensed hormonal/barrier methods or surgery intended to prevent pregnancy \[or with a side effect of pregnancy prevention\]) or abstain from heterosexual activity for the course of the study through at least 14 months after the last dose of protocol therapy
* Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for \> 1 year (women only)
Exclusion Criteria:
* Any prior systemic therapy treatment for advanced cholangiocarcinoma or gallbladder cancer
* Any prior adjuvant therapy (chemotherapy, radiation therapy, biological therapy, immunotherapy) completed \< 6 months prior to registration
* Strong CYP3A4 inducers/inhibitors within 14 days prior to day 1 of protocol therapy
* Bowel obstruction requiring nasogastric tube, percutaneous endoscopic gastrostomy, or exclusive total parenteral nutrition
* Evidence of liver metastases with \>= 50% liver occupation
* Any history of, or current, brain or subdural metastases
* Life expectancy \< 3 months
* History of peripheral neuropathy \>= grade 2 measured by NCI CTCAE version 5.0 ("moderate symptoms, limiting instrumental activities of daily living")
* Treatment with therapeutic oral or IV antibiotics within 14 days prior to day 1 cycle 1 of treatment
* Patients receiving prophylactic antibiotics are eligible, provided the signs of active infection have resolved
* Any prior malignancy except adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for two years
* History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agents (platinum-based compounds, etc.)
* Clinically significant uncontrolled illness
* Females only: Pregnant or breastfeeding
* Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
* Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)
Duarte, California, 91010, United States
[email protected] / 626-471-9200
Status: Recruiting