Clinical trial NCT06800391: Metronomic Neoadjuvant Capecitabine and Cyclophosphamide in HUGE Pseudomyxoma Peritonei Patients
Official title: Metronomic Neoadjuvant Capecitabine and Cyclophosphamide in Huge (PCI>28) Pseudomyxoma Peritonei Patients Candidates to Cytoreductive Surgery (CRS) and Hypertermic Intraperitoneal Chemotherapy (HIPEC)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Pseudomyxoma Peritonei
Keywords: Pseudomyxoma peritonei
metronomic regimen
capecitabine
cyclophosphamide
cytoreductive surgery
HIPEC
peritoneal cancer index
Lead sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Sponsor class: OTHER
First posted: 2025-01-30
Enrollment: 31
Sex: ALL
Minimum age (years): 18
Maximum age (years): 76
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Capecitabine will be taken orally at dose of 1250 mg/m2 /day (625 mg/m2 BID), continuous daily dosing. Cycles are to be repeated every 28 days for a total of 6 cycles.

Cyclophosphamide 50 mg/day continuous daily dosing. Cycles are to be repeated every 28 days for a total of 6 cycles.
Primary purpose: TREATMENT

Brief summary: The goal of this clinical trial is to evaluate the safety and efficacy of neoadjuvant capecitabine and cyclophosphamide treatment in patients affected by huge Pseudomyxoma peritonei (PMP) (peritoneal cancer index \>28). Treatment consists of metronomic (low-dose medication for a prolonged time) of capecitabine plus cyclophosphamide for 6 months followed by standard of care cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The main question the trial aims to answer is which is the proportion of patients with complete cytoreduction at CRS/HIPEC after neoadjuvant metronomic approach with oral capecitabine and cyclophosphamide in patients affected by huge PMP.

Detailed description: Mucinous neoplasms are the most common appendiceal tumors, and the most common cause of Pseudomyxoma peritonei (PMP). The term PMP defines a clinical syndrome characterized by progressive accumulation of mucinous material within the abdominal-pelvic cavity, ultimately leading to patient death due to local-regional progression of the disease. The upfront cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is regarded as standard treatment for PMP.

However, not every PMP patient benefit from upfront CRS and HIPEC. A proportion of patients could be inoperable due to a lack of clinical conditions for clinical deterioration or comorbidites contra-indicating surgery, or an unresectable disease at the diagnosis. Up to 32% of cases could be present the so-called huge PMP (peritoneal cancer index \>28), where the proportion of patients with complete cytoreduction is low of their entire cohort of PMP patients. Moreover, CRS in huge PMPs generally requires very extensive surgical maneuvers such as total gastric or total colon resection. Hence, the patients suffer from a significant impact on postoperative quality of life due to nutritional issues.

Preoperative systemic chemotherapy might be an option for such advanced cases, as it can possibly reduce the tumor burden, allowing less extensive surgery with less visceral resections. Systemic treatment regimens are associated with relevant toxicity and highcosts. Metronomic schedules might be preferred because of their favorable safety profileand antiangiogenic and immunomodulatory properties.

In unresectable or progressive PMP, a single-center prospective uncontrolled trial showed the safety and promising activity results of a continuous metronomic regimen with capecitabine with cyclophosphamide. At a median follow-up of 22.4 months, median progression-free survival was 9.5 months, and the 1-year overall survival rate was 73.7%. Overall, the disease control rate was 87%, and 6 (27%) patients achieved disease control ≥12 months.

On this basis, a phase II, mono-institutional, single arm trial was designed, evaluating neoadjuvant metronomic capecitabine and cyclophosphamide in patients affected by huge Pseudomyxoma peritonei who are potentially candidates to cytoreductive surgery and HIPEC. The goal of the present study is to evaluate the surgical and oncological outcomes of neoadjuvant metronomic approach with oral capecitabine and cyclophosphamide in patients affected by huge PMP.

In details, after the identification of patients affected by PMP, the measurement of peritoneal cancer index will be assessed by chest and abdominal CT scan at the staging phase. Only patients with PCI\>28 will be recruited regardless of resectability. Once enrolled, the patients will receive staging laparoscopy in order to confirm the histological diagnosis, to accurately stage the disease with the surgical PCI, to be compared with the radiological PCI for accuracy evaluation, and to collect material for the translational analyses. Then the patients will receive a continuous treatment schedule of oral metronomic chemotherapy with capecitabine 1250 mg/m2/day (625 mg/m2 BID) continuously with cyclophosphamide 50 mg/day continuously, for a total of 6 four-weekly cycles. At the completion of the cycles, the patients will be restaged and, as long as they are considered operable, they will be submitted to standard of care cytoreductive surgery/HIPEC, in order to define the reaching of the primary endpoint of completeness of cytoreduction. A total number of 31 patients are planned to be included in the study according to the statistical design.

Eligibility criteria: Inclusion Criteria:

* Clinical/Histological diagnosis of pseudomyxoma peritonei (PMP);
* Peritoneal Cancer Index (PCI \>28) assessed by chest and abdominal CT scan at the staging phase;
* Age \>= 18 years and \<76 years;
* Performance Status (ECOG \<2);
* Adequate organ function including the following:
* Adequate bone marrow reserve: WBC count \>3.0x109/L, absolute neutrophyl count \>1.5x109/L, platelet count \>100x109/L, and hemoglobin \>10 g/dL;
* Hepatic: bilirubin \< 1.5 times the ULN, alkaline phosphatase, aspartate transaminase, and alanine transaminase \< 2.5 x UL;
* Renal: Creatinine clearance \>50 mL/min or serum creatinine \<1.5 x UNL;
* Patients compliance and geographic proximity that allows for adequate follow-up;
* Patients must sign an informed consent document (ICD);
* Male and female patients with reproductive potential must use an approved contraceptive method;

Exclusion Criteria:

* Peritoneal Cancer Index (PCI ≤28) assessed by chest and abdominal CT scan at the staging phase;
* DPD deficiency;
* Previous systemic chemotherapy and/or biological therapy;
* Administration of other experimental drugs during the study Pregnancy and breast-feeding;
* Serious or uncontrolled medical pathologies or active infections that would jeopardize the possibility of receiving the investigated treatment;
* Disorders that could influence the absorption of capecitabine (e.g. malabsorption), intestinal occlusion, Crohn's disease or ulcerative colitis;
* Psychiatric disorders, neurologic disease or other conditions that would make it impossible to comply with the protocol procedures;
* Positive anamnesis with regard to other neoplastic diseases except for the ones that have been cured for more than 5 years.

Primary outcomes:
measure: The proportion of patients with complete cytoreduction after neoadjuvant metronomic approach with oral capecitabine and cyclophosphamide in patients affected by huge PMP.
timeFrame: 6-8 months from the start of treatment
Secondary outcomes:
measure: Radiological objective tumor response rate.
timeFrame: Performed at baseline and 16 weeks from the start of treatment.
measure: Conversion rate
timeFrame: 6-8 months from the start of treatment
measure: Downsizing of the tumor measured by surgical Peritoneal Cancer index (PCI).
timeFrame: Performed after 16 weeks.
measure: Safety and tolerability of neoadjuvant metronomic chemotherapy.
timeFrame: 6-8 months.
measure: Major complications (NCI-CTCAE v5) associated with CRS and HIPEC
timeFrame: 30 days after surgery.
measure: Quality of life EQ-5D-5L
timeFrame: Before/after neoadjuvant metronomic chemotherapy, and 30 days after the surgery.
measure: Progression-free survival
timeFrame: After 24 months.
measure: Overall Survival.
timeFrame: After 48 months.
measure: Quality of life EORTC-QLQ-C30
timeFrame: Within 30 days after the date of surgery.
Other outcomes:
measure: Effect of neoadjuvant metronomic chemotherapy on the immunocompetence of tumor microenvironment
timeFrame: Through the study completion, an average of 3 years
Locations:
city: Milan
country: Italy
facility: Fondazione IRCCS Istituto Nazionale dei Tumori
Study officials:
affiliation: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
name: Alessandra Raimondi, MD
role: PRINCIPAL_INVESTIGATOR
References: