Safety of pressurized intraperitoneal aerosolized chemotherapy in biliary cancer patients with peritoneal metastases

ABSTRACT

Biliary tract cancers are a rare diagnosis with a rising incidence. Up to 20% of patients have peritoneal metastases, resulting in symptoms of ascites, abdominal pain and potential bowel obstruction. A standard of care systemic treatment comprises gemcitabine, cisplatin and durvalumab (gem/cis/durva). However, the clinical benefit among patients with peritoneal metastases remains unknown. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy directly to the peritoneal space, which could potentially improve efficacy with minimal systemic toxicity. We describe the design of a Phase I study investigating PIPAC with nab-paclitaxel plus systemic gem/cis/durva among biliary tract cancer patients with peritoneal metastases who have not received prior systemic treatment. The primary end point is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva.

Clinical Trial Registration: NCT05285358 (ClinicalTrials.gov)

Plain language summary

Article highlights.

Biliary tract cancers

• Biliary tract cancers include cholangiocarcinoma (intra-hepatic and extra-hepatic) and gallbladder cancer.

• Up to 20% of patients will have peritoneal metastases, which can cause ascites, abdominal pain and potential bowel obstruction.

Systemic treatment landscape

• Standard of care first-line systemic treatment comprises gemcitabine, cisplatin and anti-PD-1/L1 immunotherapy (e.g. durvalumab).

• The addition of nab-paclitaxel to the combination of gemcitabine plus cisplatin showed promising results in a Phase II single-arm study, but a Phase III randomized study showed no significant improvement in efficacy with the triplet combination compared with gemcitabine plus cisplatin alone, potentially due to increased toxicity.

• The benefit of systemic treatment among patients with peritoneal metastases has not been thoroughly investigated.

Pressurized intraperitoneal aerosolized chemotherapy (PIPAC)

• PIPAC delivers chemotherapy in an aerosolized form directly to the intraperitoneal space, allowing for lower doses of chemotherapy to be used; this may increase peritoneal tumor uptake and reduce systemic uptake, potentially reducing toxicities.

• Multiple studies in Europe and one study in the United States have demonstrated the feasibility and safety of PIPAC with multiple chemotherapies (including nab-paclitaxel) among patients with a variety of cancer diagnoses and peritoneal metastases.

Phase I study of PIPAC in patients with advanced biliary tract cancer

• NCT05285358 is a Phase I single-arm study investigating PIPAC with nab-paclitaxel in combination with systemic gemcitabine, cisplatin and durvalumab in patients with advanced biliary tract cancer and peritoneal metastases who have not previously received systemic therapy.

• The primary objective is safety of PIPAC with nab-paclitaxel in combination with systemic chemotherapy (gemcitabine plus cisplatin) and immunotherapy (durvalumab).

1. Introduction

1.1. Biliary tract cancer

Biliary tract cancers (BTCs) are a heterogeneous group of cancers that arise in the bile ducts [1]. They include cholangiocarcinoma (intra-hepatic and extra-hepatic) and gallbladder cancer [1,2]. Although BTCs are a rare diagnosis, accounting for approximately 3% of all adult cancer diagnoses [2], their incidence is rising [3]. Resectable disease can be treated with surgery; however, many patients present with metastatic disease [2–6]. Of patients with metastatic disease, 10%–20% have peritoneal metastases [7]. Patients with peritoneal metastases often experience poor quality of life, with symptoms of ascites, abdominal pain and potential bowel obstruction [8]. Systemic therapies may have poor penetration to peritoneal metastases and treatment for metastatic peritoneal disease is palliative, with a poor prognosis [8,9].

1.2. Systemic treatment landscape

Prior to 2010, there were no definitive first-line standard of care systemic treatment options for patients with advanced BTC [10]. ABC-02 was a randomized controlled Phase III trial comparing gemcitabine plus cisplatin (gem-cis) versus single-agent gemcitabine in patients with advanced unresectable or metastatic cholangiocarcinoma (intra-hepatic or extra-hepatic), gallbladder cancer, or ampullary carcinoma [10]. Patients on the gem-cis arm received 1000 mg/m² of body surface area gemcitabine plus 25 mg/m² cisplatin on Days 1 and 8 of 3-week cycles (204 patients); patients on the gemcitabine arm received 1000 mg/m² gemcitabine on Days 1, 8 and 15 of 4-week cycles (206 patients). All patients received treatment for up to 24 weeks or until disease progression or unacceptable toxicity. Median overall survival (OS) was 11.7 months (95% confidence interval [CI] 9.5–14.3) for the gem-cis arm compared with 8.1 months (95% CI 7.1–8.7) for gemcitabine (hazard ratio [HR] 0.64, 95% CI 0.52–0.80, p < 0.001) (Table 1). Progression-free survival (PFS) also improved on the gem-cis arm compared with gemcitabine (median PFS 8.0 months vs 5.0 months, HR 0.63, 95% CI 0.51–0.77, p < 0.001). The incidence of adverse events (AEs) was similar between treatment arms; common grade 3–4 AEs included decreased neutrophil count (25.3% gem-cis vs 16.6% gemcitabine), abnormal liver function (16.7% vs 27.1%), fatigue (18.7% vs 16.6%) and infection (18.2% vs 19.1%). Taken together, these data resulted in the approval of gem-cis as a first-line systemic treatment for patients with advanced BTC.

Table 1.

Summary of results from clinical trials evaluating systemic treatment options for patients with advanced biliary tract cancers.

Reference	ABC-02		NCT02392637	SWOG 1815		TOPAZ-1		KEYNOTE-966
	[10]		[11]	[12]		[13]		[14]
Treatment	Gemcitabine + cisplatin (n = 204)	Gemcitabine (n = 206)	Gemcitabine + cisplatin + nab-paclitaxel (n = 60)	Gemcitabine + cisplatin + nab-paclitaxel (n = 294)	Gemcitabine + cisplatin (n = 147)	Gemcitabine + cisplatin + durvalumab (n = 341)	Gemcitabine + cisplatin + placebo (n = 344)	Gemcitabine + cisplatin + pembrolizumab (n = 533)	Gemcitabine + cisplatin + placebo (n = 536)
Median OS, months (95% CI)	11.7 (9.5–14.3)	8.1 (7.1–8.7)	19.2 (13.2-NE)	14.0 (12.6–16.3)	12.7 (9.5–16.6)	12.8 (11.1–14.0)	11.5 (10.1–12.5)	12.7 (11.5–13.6)	10.9 (9.9–11.6)
HR (95% CI), p-value	0.64 (0.52–0.80), p < 0.001		NR	0.93 (0.74–1.19), p = 0.65		0.80 (0.66–0.97), p = 0.021		0.83 (0.72–0.95), p = 0.0034
Median PFS, months (95% CI)	8.0 (6.6–8.6)	5.0 (4.0–5.9)	11.8 (6.0–15.6)	8.2 (6.7–9.2)	6.4 (5.5–8.5)	7.2 (6.7–7.4)	5.7 (5.6–6.7)	6.5 (5.7–6.9)	5.6 (5.1–6.6)
HR (95% CI), p-value	0.63 (0.51–0.77), p < 0.001		NR	0.92 (0.72–1.16), p = 0.43		0.75 (0.63–0.89), p = 0.001		0.86 (0.75–1.00), p = 0.023
ORR, %	26.1	15.5	45	31	22	26.7	18.7	29	29
DCR, %	81.4	71.8	84	77	69	85.3	82.6	75	76
Any-grade AEs, %	NR	NR	NR	NR	NR	99.4	98.8	99.1	99.6
Any-grade TRAEs, %	NR	NR	NR	NR	NR	92.9	90.1	93.2	93.6
Grade 3–4 AEs, %	70.7	68.8	58	NR	NR	75.7	77.8	79.4	74.9
Grade 3–4 TRAEs, %	NR	NR	NR	NR	NR	62.7	64.9	69.8	68.7
Grade 5 TRAEs, n	1	0	0	NR	NR	2	1	8	3

AE: Adverse event; CI: Confidence interval; DCR: Disease control rate; HR: Hazard ratio; NE: Not estimable; NR: Not reported; ORR: Objective response rate; OS: Overall survival; PFS: Progression-free survival; TRAE: Treatment-related adverse event

Since the approval of gem-cis, studies have investigated if the addition of nanoparticle albumin-bound (nab)-paclitaxel to this regimen can increase efficacy [11]. Shroff et al. performed a Phase II single-arm study investigating the combination of gemcitabine, cisplatin and nab-paclitaxel in patients with advanced BTC [11]. Sixty patients received gemcitabine, cisplatin and nab-paclitaxel on Days 1 and 8 of 3-week cycles until disease progression or unacceptable toxicity. The starting treatment doses were 1000 mg/m² gemcitabine, 25 mg/m² cisplatin and 125 mg/m² nab-paclitaxel (high-dose). A high incidence of grade 3–4 hematologic AEs in the first 32 patients resulted in permanent dose reductions of gemcitabine and nab-paclitaxel to 800 mg/m² and 100 mg/m², respectively, for the remaining 28 patients (reduced-dose). Neutropenia was the most common grade ≥3 AE, occurring in 32% of high-dose patients. However, grade ≥3 neutropenia was still recorded for 35% of reduced-dose patients (33% of all patients). Median OS for all patients was 19.2 months (95% CI 13.2-not estimable); median PFS was 11.8 months (95% CI 6.0–15.6) (Table 1).

To further investigate the combination of gemcitabine, cisplatin and nab-paclitaxel, the SWOG Cancer Research Network performed SWOG 1815, a Phase III randomized open-label study comparing gemcitabine plus cisplatin plus nab-paclitaxel versus gem-cis in patients with advanced BTC [12]. Patients received 800 mg/m² gemcitabine, 25 mg/m² cisplatin and 100 mg/m² nab-paclitaxel (triplet, 294 patients) or 1000 mg/m² gemcitabine and 25 mg/m² cisplatin (gem-cis, 147 patients) on Days 1 and 8 of 3-week cycles until disease progression. The hazard rate of the triplet in comparison to gem-cis did not significantly improve either OS (HR 0.93, 95% CI 0.74–1.19, p = 0.65) or PFS (HR 0.92, 95% CI 0.72–1.16, p = 0.43) (Table 1). The incidence of grade ≥3 hematologic AEs was higher in the triplet arm (60% vs 45%, p = 0.003); common grade 3–4 hematologic AEs included neutropenia (37% triplet vs 28% gem-cis), anemia (33% vs 22%), leukopenia (25% vs 10%) and thrombocytopenia (20% vs 15%). SWOG 1815 did not support the use of systemic gemcitabine, cisplatin and nab-paclitaxel for patients with advanced BTC.

The TOPAZ-1 randomized, double-blind, placebo-controlled Phase III trial compared gemcitabine plus cisplatin plus durvalumab (gem/cis/durva) to gemcitabine plus cisplatin plus placebo among patients with previously untreated advanced BTC [13]. All patients received 1000 mg/m² gemcitabine plus 25 mg/m² cisplatin on Days 1 and 8 of 3-week cycles for up to 8 cycles. Patients received 1500 mg durvalumab or placebo on Day 1 of each 3-week cycle. After 8 cycles, patients continued to receive 1500 mg durvalumab or placebo on Day 1 of 4-week cycles until disease progression or unacceptable toxicity. Addition of durvalumab significantly improved OS (HR 0.80, 95% CI 0.66–0.97, p = 0.021) and PFS (HR 0.75, 95% CI 0.63–0.89, p = 0.001) (Table 1). Subgroup analyses of TOPAZ-1 suggested that patients with locally advanced disease may derive greater benefit from treatment compared with patients with metastatic disease. Patients with peritoneal metastases were not specifically analyzed, and the clinical benefit and safety of gem/cis/durva among this particular population remains relatively unknown. Similar to TOPAZ-1, the Phase III KEYNOTE-966 trial reported improved OS for patients who received combination gemcitabine, cisplatin and pembrolizumab compared with patients who received gemcitabine, cisplatin and placebo (HR 0.83, 95% CI 0.72–0.95, p = 0.0034) (Table 1) [14]. TOPAZ-1 and KEYNOTE-966 established gem-cis in combination with anti-PD-1/L1 immunotherapy as a safe and effective first-line treatment for patients with advanced BTC; both combinations have been approved by the United States (US) Food and Drug Administration (FDA). However, an unmet need remains among patients with advanced BTCs to maximize treatment efficacy while minimizing off-target effects, AEs and dose reductions, particularly in the setting of peritoneal metastases.

1.3. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC)

Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) delivers chemotherapy in an aerosolized form directly to the intraperitoneal space [15–17]. This procedure allows for lower doses of chemotherapy to be used while achieving high peritoneal tumor uptake throughout the peritoneal cavity and low systemic uptake [15,18]. Alyami et al. reported that PIPAC improved the peritoneal carcinomatosis index (PCI) in 64.5% of patients with colorectal, gastric, ovarian, mesothelioma, or pseudomyxoma peritoneal cancer and peritoneal carcinomatosis who received three instances of PIPAC [19]. Demtröder et al. reported a 71% objective tumor response in 17 patients with colorectal peritoneal metastases who received PIPAC with oxaliplatin; only four patients experienced grade 3 AEs and no grade 4 or 5 AEs were reported [20]. Nadiradze et al. reported a median OS of 15.4 months in 24 patients with gastric cancer and peritoneal metastases who received ≥1 PIPAC with cisplatin and doxorubicin; grade ≥3 AEs were observed in 9 patients (37.5%) and there were no treatment-related deaths [21]. Ceelen et al. performed a Phase I first-in-human dose-finding study of PIPAC with nab-paclitaxel in 23 patients with breast, gastrointestinal, or ovarian cancer and peritoneal metastases [22]. Patients received three instances of PIPAC with nab-paclitaxel at escalating doses of 35 mg/m², 70 mg/m², 90 mg/m², 112.5 mg/m², or 140 mg/m². Among patients who received two or more instances of PIPAC, histological responses were observed in 35% of patients; an additional 35% of patients had stable peritoneal metastatic disease. Based on these findings, the recommended dose of PIPAC with nab-paclitaxel for patients with hepatobiliary functional impairment is 112.5 mg/m².

Previous studies of PIPAC have been conducted in Europe, where the treatment modality remains investigational [23]. A first-in-US Phase I study is testing the feasibility and safety of PIPAC in patients with colorectal/appendiceal, ovarian, or gastric cancer and peritoneal carcinomatosis (NCT04329494). In the colorectal/appendiceal arm, patients received up to three instances of PIPAC with oxaliplatin in combination with systemic 5-fluorouracil and leucovorin; the primary end point was safety [24]. No dose-limiting toxicities (DLTs) were observed in 12 patients. Median PFS for the 12 patients was 2.9 months; however, six of 12 patients maintained a best overall response of stable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for ≥3 months and were able to receive three PIPAC procedures in 6-week cycles. This study demonstrated the feasibility of using PIPAC in the US for patients with metastatic peritoneal disease.

1.4. Study rationale

Given the approval of gem/cis/durva as a standard of care first-line treatment for patients with advanced BTCs [13] and the demonstrated safety of PIPAC administration among patients with peritoneal metastases (including PIPAC with nab-paclitaxel [22]), we are evaluating PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva to determine its safety and tolerability in patients with advanced BTC and peritoneal metastases who have not received prior systemic therapy. Secondary end points include measures of clinical activity.

Patients receive up to three instances of PIPAC with nab-paclitaxel at 90 mg/m². Given that Ceelen et al. recommended PIPAC with nab-paclitaxel at 112.5 mg/m² in the context of a single-agent therapy [22], we will use the next-highest dose of 90 mg/m² for our study of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva.

The primary objective is safety of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva as measured by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Secondary objectives include preliminary efficacy as measured by RECIST 1.1, Peritoneal Regression Grading Score (PRGS), PCI, median OS and median PFS. Additional secondary end points include post-operative surgical complications, PIPAC technical failure rate and patient-reported health status/quality of life.

2. Phase I study of PIPAC in patients with advanced biliary tract cancer

2.1. Study design

NCT05285358 is a Phase I non-randomized study of PIPAC with nab-paclitaxel combined with standard of care first-line systemic treatment (gem/cis/durva) in patients with advanced BTC and peritoneal metastases who have not received prior systemic therapy. It is designed as a dose de-escalation study with two dose levels for PIPAC with nab-paclitaxel. Dose level (DL) 1 will use 90 mg/m² nab-paclitaxel and DL-1 (if needed) will use 70 mg/m². The doses of gem/cis/durva will remain the same for both dose levels. The study will enroll a maximum of 12 DLT-evaluable patients using a modified Phase I queue (IQ) 3 + 3 design [25]. More than 12 patients (but no more than 18) may be enrolled to achieve 12 DLT-evaluable patients.

2.2. Eligibility criteria

Full inclusion and exclusion criteria are defined in Table 2. Key inclusion criteria include a diagnosis of histologically or cytologically confirmed cholangiocarcinoma (intra-hepatic or extra-hepatic) or gallbladder cancer with documented metastatic disease and visible peritoneal disease on imaging or laparoscopy. Key exclusion criteria include any prior systemic therapy for advanced cholangiocarcinoma or gallbladder cancer, receipt of adjuvant therapy (chemotherapy, radiation therapy, biological therapy, immunotherapy) within six months prior to registration, prior exposure to immune-mediated therapy, or evidence of liver metastases with ≥50% liver occupation.

Table 2.

Eligibility criteria.

Inclusion criteria

- Age ≥18 years   - ECOG performance status of 0 or 1   - Histologically or cytologically confirmed intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, or gallbladder cancer   - Documented metastatic disease on CT scan or 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 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.   - ANC ≥1,500 cells/μL   - Platelets ≥100,000 cells/μL   - Hemoglobin ≥8 g/dL   - Serum albumin ≥2.8 g/dL   - Total bilirubin ≤1.5 × ULN (unless has Gilbert's disease, then direct bilirubin <1.5 mg/dL)   - AST ≤5 × ULN   - ALT ≤5 × ULN   - Calculated creatinine clearance ≥45 mL/min per 24-hour urine test or the Cockcroft-Gault formula   - Seronegative for HIV Ag/Ab combo     ○ If seropositive, patients may be eligible if they are stable on antiretroviral therapy, have a CD4 T cell count ≥200 cells/μL and have an undetectable viral load.   - Documented virology status of hepatitis, confirmed by HBV and HCV tests     ○ For patients with active HBV, HBV 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: negative urine or serum pregnancy test. 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 treatment for advanced cholangiocarcinoma or gallbladder cancer.   - Any prior adjuvant therapy (chemotherapy, radiation therapy, biological therapy, immunotherapy) completed <6 months prior to registration.   - Prior exposure to immune-mediated therapy, including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1 and anti-PD-L2 antibodies, excluding therapeutic anti-cancer vaccines.   - Any concurrent chemotherapy, investigational product, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.   - Receipt of live attenuated vaccine within 30 days prior to the first dose of protocol therapy. Note that patients, if enrolled, should not receive live vaccine while receiving protocol therapy and up to 30 days after the last dose of protocol therapy.   - Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab. The following are exceptions to this criterion:     ○ Intranasal, inhaled, or topical steroids or local steroid injections (e.g., intra-articular injection).     ○ Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or its equivalent.     ○ Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).   - Strong CYP3A4 inducers/inhibitors within 14 days prior to Day 1 of protocol therapy.   - Participation in another clinical study with an investigational product administered in the last 3 months.   - Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study or during the follow-up period of an interventional study.   - Prior randomization or treatment in a previous durvalumab clinical study, regardless of treatment arm assignment.   - 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 or spinal cord compression (including asymptomatic and adequately treated disease).   - 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 intravenous 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 or hypersensitivity reactions attributed to compounds of similar chemical or biologic composition to study agents (platinum-based compounds, etc.)   - History of allogeneic organ transplantation   - History of active primary immunodeficiency   - Active and uncontrolled infection, including tuberculosis (clinical evaluation that includes clinical history, physical examination and radiographic findings and tuberculosis testing in line with local practice) or human immunodeficiency virus (positive HIV 1/2 antibodies).
- Active or prior documented autoimmune or inflammatory disorders, including inflammatory bowel disease (e.g., colitis or Crohn's disease), diverticulitis (with the exception of diverticulosis), systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome (granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc.). The following are exceptions to this criterion:     ○ Patients with vitiligo or alopecia.     ○ Patients with hypothyroidism (e.g., following Hashimoto's disease) who are stable on hormone replacement.     ○ Any chronic skin condition that does not require systemic therapy.     ○ Patients without any active disease in the last 5 years may be included but only after consultation with the Study Physician.     ○ Patients with celiac disease controlled by diet alone.   - Clinically significant uncontrolled illness, including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirements, substantially increase the risk of incurring AEs, or compromise the ability of the patient to give written informed consent.   - 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).

Ab: Antibody; AE: Adverse event; Ag: Antigen; ALT: Alanine aminotransferase; ANC: Absolute neutrophil count; AST: Aspartate aminotransferase; CT: Computed tomography; CTCAE: Common Terminology Criteria for Adverse Events; ECOG: Eastern Cooperative Oncology Group; HBV: Hepatitis B virus; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; IU: International unit; MRI: Magnetic resonance imaging; NCI: National Cancer Institute; RECIST: Response Evaluation Criteria in Solid Tumors; ULN: Upper limit of normal

2.3. Interventions

Gemcitabine (800 mg/m²) and cisplatin (25 mg/m²) will be administered intravenously on Days 1 and 8 of 3-week cycles; durvalumab (1500 mg) will be administered intravenously on Day 1. Patients will receive PIPAC with nab-paclitaxel (90 mg/m²) on Day 3 of Cycles 1, 3 and 5. If DLTs occur that determine that DL1 is not well-tolerated, DL-1 will be tested with 70 mg/m² PIPAC with nab-paclitaxel. The DLT window for each patient is 42 days after the first PIPAC. After eight 3-week cycles, durvalumab (1500 mg) will be continued on Day 1 of 4-week cycles until disease progression or unacceptable toxicity. Dose modifications and delays after the start of therapy are permitted, along with granulocyte colony stimulating factor treatment as needed. Patients may also receive additional prophylactic and supportive care as clinically indicated per institutional policies. Patients will undergo computed tomography or magnetic resonance imaging scans for response assessment at baseline and every 8 weeks until the patient comes off study. Patients will be followed for PFS and OS for up to 1 year after stopping all treatments. The study schema is shown in Figure 1.

Figure 1.

Study schema.

AE: Adverse event; DLT: Dose-limiting toxicity; IP: Intraperitoneal; IV: Intravenous; PIPAC: Pressurized intraperitoneal aerosolized chemotherapy; Q3W: Every 3 weeks; Q4W: Every 4 weeks.

Blood samples, tissue biopsies (tumor and normal) and ascites/peritoneal fluid will be collected at each PIPAC/treatment cycle to investigate secondary and exploratory objectives, including assessment of response, PIPAC pharmacokinetics/pharmacodynamics, analyses of tumor/circulating tumor DNA and circulating peritoneal fluid, and assessment of changes in the immune microenvironment. Patients will also complete EQ-5D-5L and MD Anderson Symptom Inventory surveys and wear a wristband fitness tracker to investigate patient functional status changes during and after treatment.

2.4. End points

All end points are listed in Table 3. The primary end point is AEs graded by NCI CTCAE version 5.0. AEs will be monitored during treatment and for 4 weeks after the last dose of treatment with any agent. DLTs are defined as any of the following events during the 6 weeks after the first PIPAC attributable to treatment: any grade 3 or 4 non-hematologic toxicity (NCI CTCAE version 5.0) excluding Grade 3 untreated or inadequately treated nausea, vomiting, abdominal pain and diarrhea, Grade 3 fatigue that returns to Grade 2 or less within 7 days, Grade 3 laboratory/metabolic abnormalities, other than ALT or AST, that are not considered clinically significant or are easily correctable, vitiligo or alopecia of any AE grade, Grade 3 infusion-related reaction (first occurrence and in the absence of steroid prophylaxis) that resolves within 6 hours with appropriate clinical management, Grade 3 toxicities that are a one-grade increase over baseline, or Grade 3 peripheral neuropathy; surgical complication of Clavien-Dindo grade III-B or higher; Grade 4 thrombocytopenia; Grade 4 neutropenia lasting more than 7 days or associated with fever or infection; or delay of more than 21 days from the planned date for the second cycle of PIPAC due to PIPAC-related AEs.

Table 3.

Study end points.

Primary end point   - Adverse events defined by NCI CTCAE version 5.0 Secondary end points   - Efficacy, measured by RECIST 1.1, Peritoneal Regression Grading Score and Peritoneal Carcinomatosis Index   - Post-operative surgical complications, measured by Clavien-Dindo classification 4 weeks after each PIPAC   - Overall survival, measured by time from initiation of treatment to death   - Progression-free survival, measured by time from initiation of treatment to progression   - Patient-reported health status/quality of life and symptoms before treatment and at 6-week intervals until the patient comes off study, as measured by the EQ-5D-5L and MDASI   - Functional status, as measured by the number of daily steps before and after treatments (wristband pedometer) Exploratory end point   - Nab-paclitaxel concentrations in plasma and tissues

CTCAE: Common Terminology Criteria for Adverse Events; MDASI: MD Anderson Symptom Inventory; NCI: National Cancer Institute; PIPAC: Pressurized intraperitoneal aerosolized chemotherapy; RECIST: Response Evaluation Criteria in Solid Tumors.

Secondary end points include objective response per RECIST 1.1, PRGS at each PIPAC, PCI at time of laparoscopy, post-operative surgical complications, PFS, OS, PIPAC technical failure rate, EQ-5D-5L and MD Anderson Symptom Inventory responses before/during treatment and number of daily steps taken before/during treatment. Nab-paclitaxel concentrations in plasma and tissues will be investigated as an exploratory end point.

2.5. Sample size

The study follows a modified IQ 3 + 3 design to limit risk, with expansion to approximately 12 patients to confirm tolerability and investigate biological correlatives. The queue-based modification of the IQ 3 + 3 design has previously been implemented in studies to reduce the duration of dose exploration [25]. This is not a DLT rate–targeting design, but one where dose exploration is modified to allow for more rapid study completion with asynchronous patient accrual and issues with screen failures or inevaluable patients without exceeding the risk limits of the 3 + 3 design. The recommended Phase II dose can be lower than the maximum tolerated dose, but not higher. The DLT window is currently set at 42 days; patients will be followed during subsequent treatment cycles for late-developing AEs that can also be factored into limiting dose escalation at the discretion of the principal investigator.

To describe the operating characteristics of the IQ 3 + 3 design in this setting and demonstrate that it is not more aggressive than the traditional 3 + 3 design, we present two scenarios (Table 4). In scenario 1 (high toxicity) the “true” probability of a DLT on DL1 is 40% and 20% on DL-1, whereas in scenario 2 (lower toxicity) the probability of a DLT on DL1 is 15% and 5% on DL-1. Given these scenarios, we assumed a maximum screening duration of 30 days and a uniform distribution for when screening would complete, with a screen failure probability of 30%. The inevaluable rate was assumed to be 20%, with a uniform beta distribution over the cycle. The time to DLT was modeled as a beta distribution during cycle 1 (42 days) with parameters 1.5 and 1 and an interarrival time of 42 days.

Table 4.

Dose-limiting toxicity risk assessment comparison.

Scenario 1:	No Dose	DL-1	DL1
True Risk of DLT	–	20%	40%
Probable MTD IQ 3 + 3	0.33	0.50	0.17
Probable MTD 3 + 3	0.31	0.50	0.19

Scenario 2:	No Dose	DL-1	DL1
True Risk of DLT	–	5%	15%
Probable MTD IQ 3 + 3	0.01	0.25	0.74
Probable MTD 3 + 3	0.01	0.24	0.74

DL1: Dose level 1; DL-1: Dose level -1; DLT: Dose-limiting toxicity; IQ: Phase I queue; MTD: Maximum tolerated dose. “No Dose” means that DL-1 was not well-tolerated.

In scenario 1, the expected number of patients during dose exploration is 8.5 evaluable patients, with 98% probability of completing with 12 evaluable patients. The expected duration of the dose-finding phase is 23.2 months with the IQ 3 + 3 design versus 25.9 months with the standard 3 + 3 design. There is a slightly lower chance of selecting DL1 in scenario 1 with the IQ 3 + 3 design compared with the traditional 3 + 3 design (17% vs 19%). For scenario 2, with lower toxicity assumed (5%, 15%), the expected number of evaluable patients is 6.62, with 99% probability of completing with 12 evaluable patients. The expected duration of the dose-finding phase in scenario 2 is 18.6 months with the IQ 3 + 3 design versus 20.9 months with the traditional 3 + 3 design. The operating characteristics in this lower toxicity scenario between the IQ 3 + 3 and the standard 3 + 3 designs are nearly identical.

Once the initial safety assessment is complete, accrual may continue until a maximum of 12 DLT-evaluable patients are accrued (but not to exceed 18 total patients); additional patients will better establish the safety/tolerability of PIPAC with nab-paclitaxel in combination with systemic gem/cis/durva and provide further correlative data. If at any time during the expansion the observed DLT rate is 30% or higher, the study will suspend accrual pending review by the institutional Data and Safety Monitoring Committee, Institutional Review Board, and US FDA consultations.

2.6. Data collection & analysis

Data for this trial will be collected using institutional electronic data capture systems compliant with the US Code of Federal Regulations, Title 21, Part 11. Study personnel will enter data from source documents corresponding to a subject's visit into the protocol-specific electronic Case Report Form. All patients who initiate treatment will be included in data summaries. Baseline demographic and clinical characteristics will be described using summary statistics.

Toxicities observed during the first 42 days after each patient's first PIPAC will be summarized by type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment and reversibility or outcome. Adverse events that occur during additional PIPAC cycles and subsequent non-PIPAC cycles will be summarized by grade and attribution. With at least 12 patients, the probability of observing any specific AE of interest that occurs with an incidence of 20% is greater than 93%. Post-surgical complications will be assessed by Clavien-Dindo classification and will be strictly descriptive in nature [26]. The window for post-surgical complications will be 28 days post-PIPAC procedure.

Efficacy will be analyzed using RECIST 1.1, PRGS, PCI and patient-reported outcomes. All four criteria will be analyzed separately. The proportion of successes for RECIST 1.1, PRGS and PCI will be estimated by the number of successes divided by the total number of patients initiating therapy. Efficacy per RECIST 1.1 and PCI is defined as the percentage of evaluable patients achieving a best response of complete response, partial response, or stable disease. Efficacy per PRGS is defined as the percentage of evaluable patients who achieved a decrease in PRGS over successive biopsies. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson. Patient-reported outcomes will be summarized with descriptive statistics. Progression-free survival at 1 year will be described using the Kaplan-Meier method.

Unsuccessful attempts at PIPAC will be summarized in narrative form, as will any PIPAC-associated occupational hazard events experienced by healthcare personnel within 7 days of the procedure. The technical failure rate and device malfunction rate will be calculated. Candidates for cytoreduction and hyperthermic intraperitoneal chemotherapy will not be counted as technical failures. Any patient who has a device malfunction will be followed for three months for safety. A summary of toxicities experienced in patients with device malfunctions will be compiled and reviewed for any safety signals.

Correlative studies in the context of this Phase I study are hypothesis-generating and no attempt will be made to adjust for multiple comparisons. Any conclusions will include a statement about the exploratory nature of these investigations.

2.7. Ethics

This study will be conducted in conformance with the principles set forth in The Belmont Report: Ethical Principles and Guidelines for the Protection of Human Subjects of Research (US National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, April 18, 1979) and the Declaration of Helsinki. This study has been reviewed and approved by the City of Hope Institutional Review Board (IRB #21679). Study progress, compliance, toxicity, safety and accrual will be reviewed by the institutional Data and Safety Monitoring Committee; the institutional Office of Clinical Trials Monitoring will provide additional supervision per institutional guidelines. Participating clinicians will obtain written informed consent from either the prospective participant or his/her guardian or legal representative before study participation.

3. Conclusion

First-line systemic treatment for patients with advanced BTCs comprises gemcitabine, cisplatin and anti-PD-1/L1 immunotherapy (durvalumab or pembrolizumab), although the impact of these regimens among patients with peritoneal metastases is unknown. The addition of nab-paclitaxel may improve outcomes, but its role for patients with BTC needs further investigation. PIPAC with nab-paclitaxel has been demonstrated to be safe and tolerable among patients with peritoneal metastases. NCT05285358 was designed to investigate the unmet need for improved treatment options specifically for patients with advanced BTC and peritoneal metastases by combining PIPAC with nab-paclitaxel and systemic gemcitabine, cisplatin and durvalumab. Enrollment began in June 2023 and is ongoing.

Funding Statement

This manuscript was funded by research grants from the PHASE ONE Foundation and Kure It Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contributions

All authors (D Li, C Crook, V Chung, G Brar, M Fakih, A Barzi, L Melstrom, G Singh, Y Fong, P Frankel, M Raoof) meet the criteria for authorship set forth by the International Committee of Medical Journal Editors: substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data for the work; drafting the work or revising it critically for important intellectual content; final approval of the version to be published; and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All listed authors agreed to the journal it will be submitted to and all authors were involved in reviewing and agreeing to all versions of the submission.

Financial disclosure

This manuscript was funded by research grants from the PHASE ONE Foundation and Kure It Cancer Research. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Competing interests disclosure

D Li has received research funding from AstraZeneca and has received honoraria and advisory/consulting fees from AbbVie, Adagene, AstraZeneca, Coherus, Delcath Systems, Eisai, Exelixis, Genentech, Ipsen, Merck, QED, Servier, Sumitomo Pharma Oncology, TerSera, TransThera Biosciences and TriSalus Life Sciences. C Crook reports no conflicts of interest. V Chung has received research funding from Merck and has served in a consulting or advisory role for Perthera. G Brar reports no conflicts of interest. M Fakih has received research funding from AgenusBio, Amgen, Genentech/imCORE and Verastem and has received honoraria and advisory/consulting fees from AbbVie, Adagene, AstraZeneca, Bayer, Bristol-Myers Squibb, Eisai, Entos, GlaxoSmithKline, Guardant Health, Incyte, Janssen, Merck, Mirati Therapeutics, Nouscom, Pfizer, Roche/Genentech, Seattle Genetics, Taiho and Xenthera. A Barzi has received research funding from Bayer and Merck, holds a leadership role at Cardiff Oncology and has received honoraria and advisory/consulting fees from Bayer Technology System, BioTheranostics, Daiichi Sankyo/AstraZeneca, Helsinn Therapeutics/QED Therapeutics and Merrion. L Melstrom reports no conflicts of interest. G Singh holds patents on a device unrelated to the current study. Y Fong holds stock and other ownership interests in Imugene (self) and Pfizer (immediate family member), holds patents/royalties/other intellectual property on viral vectors licensed to Imugene and Merck and has received advisory/consulting fees from Imugene, Medtronic, Sovato Health and Vergent Bioscience. P Frankel holds stock in Geron and serves on an external data and safety monitoring committee for Johnson & Johnson/Janssen. M Raoof has received research funding from Exact Sciences. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Writing disclosure

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval from City of Hope for the research described (IRB #21679). In addition, informed consent has been obtained from the participants involved.