PIPAC for the Treatment of Peritoneal Carcinomatosis in Patients With Ovarian, Uterine, Appendiceal, Colorectal, or Gastric Cancer

Study Overview
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Brief Summary
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This phase I trial studies the side effects of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in treating patients with ovarian, uterine, appendiceal, stomach (gastric), or colorectal cancer that has spread to the lining of the abdominal cavity (peritoneal carcinomatosis). Chemotherapy drugs, such as cisplatin, doxorubicin, oxaliplatin, leucovorin, fluorouracil, mitomycin, and irinotecan, 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. PIPAC is a minimally invasive procedure that involves the administration of intraperitoneal chemotherapy. The study device consists of a nebulizer (a device that turns liquids into a fine mist), which is connected to a high-pressure injector, and inserted into the abdomen (part of the body that contains the digestive organs) during a laparoscopic procedure (a surgery using small incisions to introduce air and to insert a camera and other instruments in the abdominal cavity for diagnosis and/or to perform routine surgical procedures). Pressurization of the liquid chemotherapy through the study device results in aerosolization (a fine mist or spray) of the chemotherapy intra-abdominally (into the abdomen). Giving chemotherapy through PIPAC may reduce the amount of chemotherapy needed to achieve acceptable drug concentration, and therefore potentially reduces side effects and toxicities.

Detailed Description
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PRIMARY OBJECTIVES: I. To evaluate the safety of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in 3 groups of patients: peritoneal carcinomatosis (PC) due to primary ovarian, uterine, or gastric carcinoma (Arm 1); PC due to primary colorectal or appendiceal carcinoma (Arm 2). II. To evaluate safety of PIPAC and identify the maximum tolerated dose (MTD) of PIPAC with MMC in patients with PC due to colorectal or appendiceal carcinoma (Arm 3). SECONDARY OBJECTIVES: I. Ability to proceed to cytoreduction with/without hyperthermic intraperitoneal chemotherapy (HIPEC) (Arm 3 patients). II. Efficacy will be assessed by: Ia. Response Evaluation Criteria in Solid Tumors (RECIST), if available, version 1.1 via computed tomography (CT) scan at baseline (week 10, and 6 weeks after completing treatment; and at 18 weeks). Ib. Peritoneal regression grading score (PRGS) via biopsy at each cycle (both pre-PIPAC and post-PIPAC peritoneal samples will be obtained). Ic. Peritoneal carcinomatosis index (PCI) at the time of laparoscopy. II. Post-operative surgical complications by Claven-Dindo classification evaluated at 4, 10, and 16 weeks (4 weeks after each PIPAC). III. Progression-free survival. IV. PIPAC technical failure rate. V. Patient-reported health state/quality of life and symptoms before treatment and at 6, 12, and 18 weeks as measured by the European Quality of Life Five Dimension Five Level Scale Questionnaire (EQ-5D-5L) and MD Anderson Symptom Inventory (MDASI). VI. Functional status, as measured by the number of daily steps before and after treatments (Vivofit 4 wristband pedometer - Garmin Company). EXPLORATORY OBJECTIVE: I. Correlative/translational studies to characterize the tumor microenvironment, subclonal evolution, genomics, and pharmacokinetics of peritoneal tumors. OUTLINE: Patients are assigned to 1 of 3 arms. ARM I: Patients with ovarian, uterine, or gastric cancer, undergo PIPAC with doxorubicin intraperitoneally (IP), followed by cisplatin IP. Treatment repeats every 4-6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients with colorectal or appendiceal cancer undergo PIPAC with oxaliplatin IP. For cycles 2 and 3, patients receive leucovorin intravenously (IV) over 10 minutes and fluorouracil IV over 15 minutes 1-24 hours before undergoing PIPAC. Treatment repeats every 4-6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. ARM III: Patients with colorectal or appendiceal cancer who have undergo at least 4 months (or 8 cycles) of first-line standard of care chemotherapy but have not progressed on second line chemotherapy undergo PIPAC with mitomycin IP. Patients also receive standard of care irinotecan IV over 90 on day 1, leucovorin IV over 30 minutes on day 1, and fluorouracil IV on days 1-2 during weeks 2, 4, 8, 10, 14 and 16. Treatment repeats every 4-6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 12 weeks for up to 3 years.

Official Title
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Safety and Efficacy of Pressurized Intraperitoneal Aerosolized Chemotherapy (PIPAC) in Ovarian, Uterine, Appendiceal, Colorectal, and Gastric Cancer Patients With Peritoneal Carcinomatosis (PC)

Conditions
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Metastatic Gastric Carcinoma, Metastatic Malignant Solid Neoplasm, Clinical Stage IV Gastric Cancer AJCC v8, Clinical Stage IVA Gastric Cancer AJCC v8, Clinical Stage IVB Gastric Cancer AJCC v8, Malignant Uterine Neoplasm, Metastatic Appendix Carcinoma, Metastatic Colorectal Carcinoma, Metastatic Malignant Neoplasm in the Peritoneum, Metastatic Ovarian Carcinoma, Pathologic Stage IV Gastric Cancer AJCC v8, Peritoneal Carcinomatosis, Postneoadjuvant Therapy Stage IV Gastric Cancer AJCC v8, Stage IV Appendix Carcinoma AJCC v8, Stage IV Colorectal Cancer AJCC v8, Stage IV Ovarian Cancer AJCC v8, Stage IV Uterine Corpus Cancer AJCC v8, Stage IVA Appendix Carcinoma AJCC v8, Stage IVA Colorectal Cancer AJCC v8, Stage IVA Ovarian Cancer AJCC v8, Stage IVA Uterine Corpus Cancer AJCC v8, Stage IVB Appendix Carcinoma AJCC v8, Stage IVB Colorectal Cancer AJCC v8, Stage IVB Ovarian Cancer AJCC v8, Stage IVB Uterine Corpus Cancer AJCC v8, Stage IVC Appendix Carcinoma AJCC v8, Stage IVC Colorectal Cancer AJCC v8

Intervention / Treatment
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* Procedure: Biopsy
* Drug: Cisplatin
* Drug: Doxorubicin
* Drug: Fluorouracil
* Device: Intraperitoneal Chemotherapy
* Drug: Irinotecan
* Drug: Leucovorin
* Drug: Mitomycin
* Drug: Oxaliplatin
* Other: Quality-of-Life Assessment
* Other: Questionnaire Administration


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Documented informed consent of the participant and/or legally authorized representative Patients must have histologically confirmed ovarian, uterine, gastric, appendiceal or colorectal cancer with PC Prior IP chemotherapy is permitted Eastern Cooperative Oncology Group (ECOG) performance status (PS) =< 2 Absolute neutrophil count (ANC) >= 1500/mm^3 Platelets >= 100,000/mm^3 Hemoglobin >= 9 g/dl Serum total bilirubin =< 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) and aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 x ULN, unless liver metastases (Arm 1) are present or unless patients is know to have chronic liver disease (hepatitis) in which case AST and ALT must be =< 5 x ULN Alkaline phosphatase =< 2 x ULN Serum creatinine (sCr) =< 1.5 x ULN, or creatinine clearance (Ccr) >= 40 ml/min as calculated by the Cockcroft-Gault formula No contraindications for a laparoscopy The peritoneal disease does not have to be measurable by RECIST 1.1 but needs to be visible on cross sectional imaging or diagnostic laparoscopy Patients must have progressed on at least one evidence-based chemotherapeutic regimen (Arm 1 and 2). For Arm 3, patients should have stable or responsive disease on at least 4 months first-line systemic chemotherapy For patients with a known history of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a known history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Women of childbearing potential (WOCBP) and male patients with WOCBP partner must be using an adequate method of contraception to avoid pregnancy throughout the study and for up to 12 weeks after the last dose of investigational product in such a manner that the risk of pregnancy is minimized. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or is not postmenopausal. Post menopause is define as: Amenorrhea >= 12 consecutive months without another cause or For women with irregular menstrual periods and on hormone replacement therapy (HRT), a documented serum follicle stimulating hormone (FSH) level > 35 mIU/mL Women who are using oral contraceptives, other hormonal contraceptives (vaginal products, skin patches, or implanted or injectable products), or mechanical products such as an intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy, or are practicing abstinence or where their partner is sterile (e.g., vasectomy) should be considered to be of childbearing potential INCLUSION TO PROCEED WITH PIPAC: Laparoscopy findings must meet all of the below criteria in order to proceed to PIPAC: PIPAC access is feasible There is room for aerosol therapy There is no evidence of impending bowel obstruction =< 5 L of ascites Not a candidate for cytoreduction and HIPEC Exclusion Criteria: Gastric and colorectal/appendiceal: Extra-peritoneal metastatic disease Arm 1 (ovarian, uterine, gastric): Previous treatment with maximum cumulative doses of doxorubicin, daunorubicin, epirubicin, idarubicin, and/or other anthracyclines and anthracenediones Arm 2 (colorectal/appendiceal): Known dihydropyrimidine dehydrogenase deficiency (DPD) deficiency Arm 2 (colorectal/appendiceal): Bowel obstruction requiring nasogastric tube, percutaneous endoscopic gastrostomy or exclusive total parenteral nutrition Arm 2 (colorectal/appendiceal): Prior unanticipated severe reaction or hypersensitivity to platinum based compounds Arm 2 (colorectal/appendiceal): Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), with the exception of alopecia, hearing loss, or non-clinically significant laboratory abnormalities. Grade 2 peripheral neuropathy is permitted Arm 2 (colorectal/appendiceal): Life expectancy of less than 6 months Arm 2 (colorectal/appendiceal): Chemotherapy or surgery within the last 4 weeks prior to enrollment (6 weeks for prior bevacizumab therapy). Five half-lives for other anti-cancer agents Arm 2 (colorectal/appendiceal): Previous anaphylactic reaction to the chemotherapy drug used Arm 2 (colorectal/appendiceal): Patients may not be receiving any other investigational or concurrent anti-cancer agents Arm 2 (colorectal/appendiceal): Ascites due to decompensated liver cirrhosis; portal vein thrombosis Arm 2 (colorectal/appendiceal): Simultaneous tumor debulking with gastrointestinal resection Arm 2 (colorectal/appendiceal): Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias, severe renal impairment, myelosuppression, or severe hepatic impairment Arm 2 (colorectal/appendiceal): Immunocompromised patients such as those with an immunosuppressive medication or a known disease of the immune system Arm 2 (colorectal/appendiceal): Involvement in the planning and conduct of the study Arm 2 (colorectal/appendiceal): Pregnancy Arm 2 (colorectal/appendiceal): Patients with psychiatric illness/social situations that would limit compliance with study requirements Arm 2 (colorectal/appendiceal): New York Heart Association (NYHA) class 3 or 4; myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months Arm 2 (colorectal/appendiceal): Major systemic infection requiring antibiotics 72 hours or less prior to the first dose of study drug Arm 2 (colorectal/appendiceal): Exclusive total parenteral nutrition Arm 2 (colorectal/appendiceal): Prior intra-abdominal aerosol chemotherapy Arm 3 (colorectal/appendiceal): Progression on first- AND second-line systemic therapy Arm 3 (colorectal/appendiceal): Hematologic toxicities requiring significant dose reductions while on systemic chemotherapy Arm 3 (colorectal/appendiceal): Intolerance to prior 5-FU at 2400mg/m^2 IV every 2 weeks or to irinotecan at 180mg/m^2. Intolerance is defined as the need of significant dose reduction or treatment interruption of > 1 week due to toxicity Arm 3 (colorectal/appendiceal): Known DPD deficiency Arm 3 (colorectal/appendiceal): Bowel obstruction requiring nasogastric tube, percutaneous endoscopic gastrostomy or exclusive total parenteral nutrition Arm 3 (colorectal/appendiceal): Patients who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities > grade 1), with the exception of alopecia, hearing loss, or non-clinically significant laboratory abnormalities. Grade 2 peripheral neuropathy is permitted Arm 3 (colorectal/appendiceal): Life expectancy of less than 6 months Arm 3 (colorectal/appendiceal): Chemotherapy or surgery within the last 2 weeks prior to enrollment (6 weeks for prior bevacizumab therapy). Five half-lives for other anti-cancer agents Arm 3 (colorectal/appendiceal): Previous anaphylactic reaction to the chemotherapy drug used Arm 3 (colorectal/appendiceal): Patients may not be receiving any other investigational anti-cancer agents Arm 3 (colorectal/appendiceal): Ascites due to decompensated liver cirrhosis; portal vein thrombosis Arm 3 (colorectal/appendiceal): Simultaneous tumor debulking with gastrointestinal resection Arm 3 (colorectal/appendiceal): Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, severe myocardial insufficiency, recent myocardial infarction, severe arrhythmias, severe renal impairment, myelosuppression, or severe hepatic impairment Arm 3 (colorectal/appendiceal): Immunocompromised patients such as those with an immunosuppressive medication or a known disease of the immune system Arm 3 (colorectal/appendiceal): Involvement in the planning and conduct of the study Arm 3 (colorectal/appendiceal): Pregnancy Arm 3 (colorectal/appendiceal): Patients with psychiatric illness/social situations that would limit compliance with study requirements Arm 3 (colorectal/appendiceal): New York Heart Association (NYHA) class 3 or 4; myocardial infarction, acute coronary syndrome, diabetes mellitus with ketoacidosis or chronic obstructive pulmonary disease (COPD) requiring hospitalization in the preceding 6 months Arm 3 (colorectal/appendiceal): Major systemic infection requiring antibiotics 72 hours or less prior to the first dose of study drug Arm 3 (colorectal/appendiceal): Exclusive total parenteral nutrition Arm 3 (colorectal/appendiceal): Prior intra-abdominal aerosol chemotherapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (PIPAC, doxorubicin, cisplatin)<br>Patients with ovarian, uterine, or gastric cancer, undergo PIPAC with doxorubicin IP, followed by cisplatin IP. Treatment repeats every 4-6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Drug: Cisplatin<br>* Given via PIPAC<br>* Other names: Platosin;Drug: Doxorubicin<br>* Given via PIPAC<br>* Other names: Hydroxyldaunorubicin;Device: Intraperitoneal Chemotherapy<br>* Undergo PIPAC<br>* Other names: Intraperitoneal Therapy;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm II (PIPAC, oxaliplatin, leucovorin, fluorouracil)<br>Patients with colorectal or appendiceal cancer undergo PIPAC with oxaliplatin IP. For cycles 2 and 3, patients receive leucovorin IV over 10 minutes and fluorouracil IV over 15 minutes 1-24 hours before undergoing PIPAC. Treatment repeats every 4-6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Device: Intraperitoneal Chemotherapy<br>* Undergo PIPAC<br>* Other names: Intraperitoneal Therapy;Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Oxaliplatin<br>* Given via PIPAC<br>* Other names: SR-96669;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|
| Experimental: Arm III (PIPAC, mitomycin, FOLFIRI)<br>Patients with colorectal or appendiceal cancer who have undergo at least 4 months (or 8 cycles) of first-line standard of care chemotherapy but have not progressed on second line chemotherapy undergo PIPAC with mitomycin IP. Patients also receive standard of care irinotecan IV over 90 on day 1, leucovorin IV over 30 minutes on day 1, and fluorouracil IV on days 1-2 during weeks 2, 4, 8, 10, 14 and 16. Treatment repeats every 4-6 weeks for up to 3 cycles in the absence of disease progression or unacceptable toxicity. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Drug: Fluorouracil<br>* Given IV<br>* Other names: Ro-2-9757;Device: Intraperitoneal Chemotherapy<br>* Undergo PIPAC<br>* Other names: Intraperitoneal Therapy;Drug: Irinotecan<br>* Given IV<br>Drug: Leucovorin<br>* Given IV<br>* Other names: Folinic acid;Drug: Mitomycin<br>* Given via PIPAC<br>* Other names: NCI-C04706;Other: Quality-of-Life Assessment<br>* Ancillary studies<br>* Other names: Quality of Life Assessment;Other: Questionnaire Administration<br>* Ancillary studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicities | Assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Summarized by type (organ affected or laboratory determination), severity, time of onset, duration, probable association with the study treatment, and reversibility or outcome. | Up to 18 weeks | 
| Incidence of adverse events | Assessed using CTCAE v.5.0. Summarized by grade and attribution. Post-surgical complications will be assessed by Clavien-Dindo classification. | From day 1 of protocol therapy until week 18 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of evaluable patients who have achieved complete response (CR), partial response (PR), or stable disease (SD) | Assessed by Response Evaluation Criteria in Solid Tumors criteria version 1.1 via computed tomography (CT) scan. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach by Clopper and Pearson. | At baseline, following the second cycle (week 10), and 6 weeks after completing treatment (at 18 weeks/off-study) | 
| Percentage of evaluable patients who have achieved CR, PR, or SD | Assessed by Peritoneal Carcinomatosis Index. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach by Clopper and Pearson. | At the time of laparoscopy (or CT imaging if laparoscopy is not planned during surgery) | 
| Percentage of evaluable patients who have achieved a decrease in Peritoneal Regression Grading Score over successive biopsies | The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach by Clopper and Pearson. | Up to 18 weeks | 
| Progression-free survival | Described using the Kaplan-Meier method. | Time from first pressurized intraperitoneal aerosolized chemotherapy (PIPAC) procedure, assessed up to 1 year | 
| Post-surgical complications | Assessed by Clavien-Dindo classification. Results will be strictly descriptive in nature. | At 4 weeks after each PIPAC | 
| PIPAC technical failure rate |  | Up to 3 years | 
| Functional status | Measured by the number of daily steps before and after treatments (Vivofit 4 wristband pedometer - Garmin Company). | Up to 18 weeks | 
| Cytoreductive surgery rate (Arm 3) |  | Up to 18 weeks |