Investigation of Mitomycin C PIPAC - FOLFIRI Combination for Unresectable Appendiceal or Colorectal Peritoneal Metastases Treatment (IMPACT): A Multicenter, Randomized, Open-Label, Phase 3 Trial
Investigation of Mitomycin C PIPAC - FOLFIRI Combination for Unresectable Appendiceal or Colorectal Peritoneal Metastases Treatment (IMPACT): A Multicenter, Randomized, Open-Label, Phase 3 Trial
This phase III trial studies how well pressurized intraperitoneal aerosolized chemotherapy (PIPAC) with mitomycin works versus (vs) standard chemotherapy (leucovorin calcium, fluorouracil, and irinotecan hydrochloride [FOLFIRI regimen] plus bevacizumab) in treating patients with appendix or colorectal cancer that cannot be removed by surgery (unresectable) and has spread from where it first started (primary site) to the abdominal cavity (peritoneal metastases). PIPAC is a new therapeutic approach that is minimally invasive, does not require surgery (laparotomy), and can be frequently repeated. Chemotherapy is delivered as a pressurized mist directly inside the abdominal cavity (peritoneum) during a minimally invasive surgery called a laparoscopy. The pressure helps the chemotherapy absorb into the cancer tissue and spread more evenly. Mitomycin is an antibiotic used as a chemotherapy drug. It stops or slows the growth of cancer cells and other rapidly growing cells by damaging their deoxyribonucleic acid (DNA). Standard chemotherapy drugs, such as those in the FOLFIRI regimen, are given via infusion into a vein (intravenously), and work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Another standard intravenous drug, bevacizumab, is in a class of medications called antiangiogenic agents. It works by stopping the formation of blood vessels that bring oxygen and nutrients to tumor. This may slow the growth and spread of tumor. Giving mitomycin via PIPAC in combination with the standard FOLFIRI regimen, with or without bevacizumab, may work better than standard FOLFIRI plus bevacizumab alone in treating patients with unresectable appendix or colorectal cancer with peritoneal metastases.
PRIMARY OBJECTIVE:
I. Evaluate the overall survival of patients treated with mitomycin PIPAC (MMC-PIPAC) in combination with systemic FOLFIRI in comparison to those treated with systemic FOLFIRI/bevacizumab as a 2nd line therapy in patients with appendiceal or colorectal cancer with peritoneal metastases.
SECONDARY OBJECTIVES:
I. Compare progression-free survival between the two arms. II. Rate of completion of cytoreductive surgery.
III. Evaluate the Objective response rate by arm, assessed by:
IIIa. Peritoneal Regression Grading Score (PRGS) via histologic assessment of biopsies performed at each PIPAC cycle; IIIb. Laparoscopic Peritoneal Carcinomatosis Index (PCI) reduction; IIIc. Radiographic response by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1; IIId. Tumor marker (CEA) response rate. IV. Patient-reported health state/quality of life and symptoms before treatment, at 6 months and at 1-year, as measured by European Organisation for the Research and Treatment of Cancer-Quality of Life Questionnaire (EORTC-QLQ30) and EORTC-Colorectal Cancer (CR29) for each arm.
EXPLORATORY OBJECTIVES:
I. Characterization of sub-clonal and tumor microenvironment evolution in response to therapy with a particular focus on immune and fibroblast subsets in the tumor and immune subsets in peripheral blood.
II. Correlating cell free DNA, ribonucleic acid (RNA), proteins and/or metabolites in blood and peritoneal fluid with burden of disease, survival and response to therapy.
III. Develop artificial intelligence and machine learning approaches for the characterization of peritoneal metastases by correlating video/photographic imaging features of peritoneal metastases to histologic features.
IV. Establish the feasibility of generating patient-derived xenografts, organoids, and cell lines from pre-treated colorectal and appendiceal cancer peritoneal metastases (City of Hope [COH] only).
V. Characterization of stool and tissue microbiome of patients on the study protocol.
OUTLINE: Patients are randomized to 1 of 2 arms.
ARM I: Patients receive mitomycin via PIPAC during on day 1 of each cycle. Cycles repeat every 6 weeks for 3 cycles in the absence of disease progression or unacceptable toxicity. Beginning 2 weeks after each mitomycin PIPAC treatment, patients receive FOLFIRI regimen, consisting of irinotecan intravenously (IV) over 90 minutes on day 1 of each cycle, leucovorin IV over 30 minutes on day 1 of each cycle, and fluorouracil IV over 46-48 hours on day 1 of each cycle (i.e., weeks 2, 4, 8, 10, 14, 16, etc). Cycles of FOLFIRI regimen repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after last cycle of mitomycin PIPAC, patients may also receive bevacizumab IV over 30-90 minutes at the discretion of the treating physician. Cycles of bevacizumab repeat every 2 weeks in the absence of disease progression or unacceptable toxicity.
ARM II: Patients receive FOLFIRI regimen, consisting of irinotecan IV over 90 minutes on day 1 of each cycle, leucovorin IV over 30 minutes on day 1 of each cycle, and fluorouracil IV over 46-48 hours on day 1 of each cycle. Cycles repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Beginning 4 weeks after standard laparoscopy, patients also receive bevacizumab IV over 30-90 minutes on day 1 of each cycle. Cycles of bevacizumab repeat every 2 weeks in the absence of disease progression or unacceptable toxicity. Patients who experience disease progression may cross-over to Arm I (NOTE: Cross-over patients do not receive FOLFIRI regimen).
All patients also undergo computed tomography (CT), collection of blood, ascites, and urine samples, as well as biopsies throughout the study. Patients may also undergo magnetic resonance imaging (MRI) during screening.
After completion of study treatment, patients are followed up at 4 weeks and then every 8-12 weeks until death.
Inclusion Criteria:
Documented informed consent of the participant and/or legally authorized representative
Agreement to allow the use of archival tissue from diagnostic tumor biopsies
Age: ≥ 18 years
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
Histologically or cytologically confirmed appendiceal or colorectal cancer peritoneal metastases
No extraperitoneal metastases except lung ≤ 5 lesions with largest ≤ 1cm as identified on CT imaging 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 (v1.1)
Completed at least 4 months (8 cycles) of first-line standard-of-care oxaliplatin-based systemic therapy without progression of disease. Or completed less than 4 months of oxaliplatin based therapy due to intolerance and without progressive disease. Or progressed on first-line standard-of-care oxaliplatin-based systemic therapy. Permissible first-line systemic therapies include leucovorin calcium, fluorouracil, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (XELOX) or fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFOXIRI). Receipt of anti-EGFR, anti-VEGF, or anti-BRAF therapy in the first-line is acceptable. Mismatch repair-deficient patients are permissible if they have progressed on first-line immunotherapy
Not a candidate for cytoreductive surgery as determined by site investigator
Fully recovered from the acute toxic effects of prior anti-cancer therapy to Common Terminology Criteria for Adverse Events (CTCAE) grade 1 or lower except alopecia, hearing loss, neuropathy, or non-clinically significant laboratory abnormalities
Complete medical history and physical exam (To be performed within 28 days prior to Day 1 of protocol therapy)
Absolute neutrophil count (ANC) ≥ 1,500/mcL (To be performed within 28 days prior to Day 1 of protocol therapy)
Platelets ≥ 100,000/mcL (To be performed within 28 days prior to Day 1 of protocol therapy)
Hemoglobin ≥ 8 g/dL (To be performed within 28 days prior to Day 1 of protocol therapy)
Serum albumin ≥ 2.8 g/dL (To be performed within 28 days prior to Day 1 of protocol therapy)
Total bilirubin ≤ 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease, then direct bilirubin < 1.5 mg/dL) (To be performed within 28 days prior to Day 1 of protocol therapy)
Aspartate aminotransferase (AST) ≤ 5 x ULN (To be performed within 28 days prior to Day 1 of protocol therapy)
Alanine aminotransferase (ALT) ≤ 5 x ULN (To be performed within 28 days prior to Day 1 of protocol therapy)
Calculated creatinine clearance of ≥ 45 mL/min per 24-hour urine test or the Cockcroft-Gault formula (To be performed within 28 days prior to Day 1 of protocol therapy)
Women of childbearing potential (WOCBP): Negative urine or serum pregnancy test (To be performed within 28 days prior to Day 1 of protocol therapy)
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
CROSS-OVER ARM INCLUSION: Documented informed consent of the participant and/or legally authorized representative
CROSS-OVER ARM INCLUSION: Agreement to allow the use of archival tissue from diagnostic tumor biopsies
CROSS-OVER ARM INCLUSION: Age: ≥ 18 years
CROSS-OVER ARM INCLUSION: ECOG performance status of 0 or 1
CROSS-OVER ARM INCLUSION: No extraperitoneal metastases except lung ≤ 5 lesions with largest ≤ 1cm as identified on CT imaging or MRI. CT scan or MRI to assess measurable disease must have been completed within 28 days prior to registration
CROSS-OVER ARM INCLUSION: Progression on Control Arm of the Study as determined by RECIST v1.1. Non-radiographic progression will need to be assessed on a case-by-case basis by central review
CROSS-OVER ARM INCLUSION: Fully recovered from the acute toxic effects of prior anti-cancer therapy to CTCAE grade 1 or lower except alopecia, hearing loss, neuropathy, or non-clinically significant laboratory abnormalities
CROSS-OVER ARM INCLUSION: Complete medical history and physical exam (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: ANC ≥ 1,500/mcL (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: Platelets ≥ 100,000/mcL (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: Hemoglobin ≥ 8 g/dL (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: Serum albumin ≥ 2.8 g/dL (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: Total bilirubin ≤ 1.5 X ULN (unless has Gilbert's disease, then direct bilirubin <1.5 mg/dL) (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: AST ≤ 5 x ULN (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: ALT ≤ 5 x ULN (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: Calculated creatinine clearance of ≥ 45 mL/min per 24-hour urine test or the Cockcroft-Gault formula (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (To be performed within 28 days prior to Day 1 of protocol therapy)
CROSS-OVER ARM INCLUSION: 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
Exclusion Criteria:
More than 8 cycles of first line irinotecan therapy
Progression on irinotecan
Receipt of any second-line systemic chemotherapy (Note: Sequential administration of FOLFOX followed by FOLFIRI is considered second line therapy. However, FOLFOXIRI followed by FOLFIRI is considered first line as long as no more than 8 cycles of irinotecan are given)
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
Strong CYP3A4 inducers/inhibitors within 14 days prior to Day 1 of protocol therapy
Prior peritoneal-directed chemotherapy (Prior cytoreductive surgery is permitted)
Participation in another clinical study with an investigational product administered in the last 2 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
Low-grade appendiceal mucinous neoplasm or low-grade appendiceal mucinous adenocarcinoma
Extraperitoneal metastases (except lung ≤ 5 lesions with largest being ≤ 1cm)
Any history of bowel obstruction requiring nasogastric tube, percutaneous endoscopic gastrostomy, or need for total parenteral nutrition. Even if the bowel obstruction resolved with conservative measures, the patient would be excluded. The exception is if the bowel obstruction was surgically addressed with ostomy, resection or bypass. This exception should be documented
Fused mesenteric disease-causing mesenteric shortening and bowel sequestration ("cauliflowering")
Bulky mesenteric disease where chemotherapy is unlikely to penetrate the tumor
Contraindication to laparoscopy
Rapid weight loss (> 10% in < 3 months)
Ascites (> 2L drained per month)
Adhesions involving > 50% of abdominal cavity on diagnostic laparoscopy
Life expectancy < 6 months
Treatment with therapeutic oral or IV antibiotics within 14 days prior to Day 1 Cycle 1 of treatment
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 or other 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)
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 (ILD), serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, 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)
CROSS-OVER ARM EXCLUSION: 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
CROSS-OVER ARM EXCLUSION: Strong CYP3A4 inducers/inhibitors within 14 days prior to Day 1 of protocol therapy
CROSS-OVER ARM EXCLUSION: Participation in another clinical study with an investigational product administered in the last 2 months other than the current study
CROSS-OVER ARM EXCLUSION: 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
CROSS-OVER ARM EXCLUSION: Extraperitoneal metastases (except lung ≤ 5 lesions with largest being ≤ 1cm)
CROSS-OVER ARM EXCLUSION: Any history of bowel obstruction requiring nasogastric tube, percutaneous endoscopic gastrostomy, or need for total parenteral nutrition. Even if the bowel obstruction resolved with conservative measures, the patient would be excluded. The exception is if the bowel obstruction was surgically addressed with ostomy, resection or bypass. This exception should be documented
CROSS-OVER ARM EXCLUSION: Fused or bulky mesenteric disease-causing mesenteric shortening and bowel sequestration
CROSS-OVER ARM EXCLUSION: Contraindication to laparoscopy
CROSS-OVER ARM EXCLUSION: Rapid weight loss (> 10% in < 3 months)
CROSS-OVER ARM EXCLUSION: Ascites (> 2L drained per month)
CROSS-OVER ARM EXCLUSION: Adhesions involving > 50% of abdominal cavity on diagnostic laparoscopy
CROSS-OVER ARM EXCLUSION: Life expectancy < 6 months
CROSS-OVER ARM EXCLUSION: Treatment with therapeutic oral or IV antibiotics within 14 days prior to Day 1 Cycle 1 of treatment
Goodyear, Arizona 85338, United States
mraoof@coh.org626-218-5484
mraoof@coh.org626-218-5484
mraoof@coh.org626-218-5484
mraoof@coh.org626-218-5484
mraoof@coh.org626-218-5484