Metronomic Neoadjuvant Capecitabine and Cyclophosphamide in HUGE Pseudomyxoma Peritonei Patients (REVERSE)

Metronomic Neoadjuvant Capecitabine and Cyclophosphamide in Huge (PCI>28) Pseudomyxoma Peritonei Patients Candidates to Cytoreductive Surgery (CRS) and Hypertermic Intraperitoneal Chemotherapy (HIPEC)

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.

Study Overview

• Status: Recruiting
• Conditions: Pseudomyxoma Peritonei
• Intervention / Treatment: Combination product: Capecitabine 1250 mg/m2 /day - Cyclophosphamide 50Mg/day

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.

• Study Type: Interventional
• Enrollment (Estimated): 31
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Alessandra Raimondi, MD; Phone Number: +39 02 2390 2581; Email: alessandra.raimondi@istitutotumori.mi.it
• Study Contact Backup: Name: Shigeki Kusamura, MD; Phone Number: +39 02 2390 3441; Email: shigeki.kusamura@istitutotumori.mi.it

Study Locations

• Italy
  • Milan, Italy, 20133
    • Recruiting
    • Fondazione IRCCS Istituto Nazionale dei Tumori
    • Contact: Alessandra Raimondi, MD; Phone Number: +39 02 2390 2581; Email: alessandra.raimondi@istitutotumori.mi.it
    • Contact: Shigeki Kusamura, MD; Phone Number: +39 02 2390 3441; Email: shigeki.kusamura@istitutotumori.mi.it
    • Principal Investigator: Alessandra Raimondi, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Capecitabine and Cyclophosphamide; Capecitabine (1250 mg/m2 /day) and Cyclophosphamide (50 mg/day) continuous daily dosing. Cycles are to be repeated every 28 days for a total of 6 cycles.	Combination product: Capecitabine 1250 mg/m2 /day - Cyclophosphamide 50Mg/day; Capecitabine (1250 mg/m2 /day) and Cyclophosphamide (50 mg/day) continuous daily dosing. Cycles are to be repeated every 28 days for a total of 6 cycles.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The proportion of patients with complete cytoreduction after neoadjuvant metronomic approach with oral capecitabine and cyclophosphamide in patients affected by huge PMP.	Use of Completeness of Cytoreduction score to evaluate the radicality of Cytoreductive Surgery. Patients with a residual disease <2.5 mm will be considered completely cytoreduced, otherwise incompletely cytoreduced. "Completeness of Cytoreduction Score" ranging from the best cc-0: no peritoneal nodule was seen, afterwards cc-1,tumor nodules persisting after cytoreduction are less than 2.5 mm in diameter, then cc-2, tumor nodules persisting after cytoreduction are between 2.5 mm and 2.5 cm in diameter to the worst cc-3, tumor nodules persisting after cytoreduction are greater than 2.5 cm	6-8 months from the start of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Radiological objective tumor response rate.	Objective tumor response rate will be defined by two independent radiologists by means of CT (computed tomography) scans. Tumour response will be determined semiquantitatively as either stable, reduced or progressed.	Performed at baseline and 16 weeks from the start of treatment.
Conversion rate	Conversion rate will be calculated dividing the number of resectable cases after the neoadjuvant chemotherapy by the number of resectable cases before neoadjuvant chemotherapy. Resectability will be evaluated with CT scans using Bouquot et al. methodology.	6-8 months from the start of treatment
Downsizing of the tumor measured by surgical Peritoneal Cancer index (PCI).	Downsizing of the tumor will be measured at the time of staging laparoscopy and CRS using Peritoneal Cancer Index (PCI). Peritoneal cancer index (PCI) ranging from the best 0 to the worst 39.	Performed after 16 weeks.
Safety and tolerability of neoadjuvant metronomic chemotherapy.	Incidence of Treatment-Emergent Adverse Event will be measured using NCI-CTCAE v5.	6-8 months.
Major complications (NCI-CTCAE v5) associated with CRS and HIPEC	Major complications associated with CRS and HIPEC will be measured using NCI-CTCAE v5.	30 days after surgery.
Quality of life EQ-5D-5L	Quality of life will be assessed through Patient reported outcomes (PRO) instrument. EuroQol EQ-5D-5L. The EQ-5D-5L uses for first 5 questions qualitative multiple choice answers with NO SCALE. For the last questions, a score from 0 to 100 indicates from the worst to the best outcome.	Before/after neoadjuvant metronomic chemotherapy, and 30 days after the surgery.
Progression-free survival	Progression-free Survival (PFS) is the time between the date of chemotherapy commencement and the date of Disease-Progression or Death, whichever occurs first.	After 24 months.
Overall Survival.	Overall Survival (OS) is the time between the date of chemotherapy commencement and date of Death or last follow up.	After 48 months.
Quality of life EORTC-QLQ-C30	Quality of life will be assessed through Patient reported outcomes (PRO) instrument. EORTC QLQ-C30 For questions 1-28 of EORTC QLQ-C30 a 4-point scale is used. It scores from 1 to 4: 1 ("Not at all"), 2 ("A little"), 3 ("Quite a bit")and 4 ("Very much"). Half points are not allowed. The range is 3. For the raw score, less points are considered to have a better outcome. For the questions 29 and 30 of EORTC QLQ-C30 a 7-points scale is used. It scores from 1 to 7: 1 ("very poor") to 7 ("excellent"). Half points are not allowed. The range is 6. First of all, raw score has to be calculated with mean values. Afterwards linear transformation is performed to be comparable. More points are considered to have a better outcome.	Within 30 days after the date of surgery.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Effect of neoadjuvant metronomic chemotherapy on the immunocompetence of tumor microenvironment	Conduction of biological studies with exploratory nature and therefore without the possibility to be categorized according to specific scale of range.	Through the study completion, an average of 3 years

Collaborators and Investigators

• Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Investigators: Principal Investigator: Alessandra Raimondi, MD, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Study record dates

Study Major Dates

• Study Start (Actual): November 22, 2024
• Primary Completion (Estimated): November 1, 2027
• Study Completion (Estimated): November 1, 2029

Study Registration Dates

• First Submitted: November 25, 2024
• First Submitted That Met QC Criteria: January 23, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 23, 2025
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: capecitabine; cytoreductive surgery; cyclophosphamide; HIPEC; Pseudomyxoma peritonei; metronomic regimen; peritoneal cancer index
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Carcinoma; Neoplasms, Cystic, Mucinous, and Serous; Adenocarcinoma, Mucinous; Pseudomyxoma Peritonei; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antirheumatic Agents; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Capecitabine; Cyclophosphamide
• Other Study ID Numbers: INT 135-24; 2024-514329-42-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No