This phase I trial tests the safety, side effects and best dose of nab-paclitaxel pressurized intraperitoneal aerosolized chemotherapy (PIPAC) in combination with second-line chemotherapy, paclitaxel and ramucirumab, and tests how well they work in treating stomach cancer that has spread from where it first started to the tissue that lines the abdominal wall and organs (peritoneal metastases). Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Nab-paclitaxel is an albumin-stabilized nanoparticle formulation of paclitaxel which may have fewer side effects and work better than other forms of paclitaxel. PIPAC delivers chemotherapy, such as nab-paclitaxel, that has been turned into a fine mist (aerosolized) at a high pressure directly into the abdominal cavity. Aerosolized chemotherapy delivered directly into the peritoneal space has been shown to deliver higher drug concentrations to the tumor. Ramucirumab is a monoclonal antibody that may prevent the growth of new blood vessels that tumors need to grow. Giving nab-paclitaxel PIPAC in combination with paclitaxel and ramucirumab may be safe, tolerable, and/or effective in treating gastric cancer patients with peritoneal metastases.
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of nab-paclitaxel PIPAC when given in combination with standard-of-care second-line systemic therapy (paclitaxel, ramucirumab). II. To assess the safety and tolerability of nab-paclitaxel PIPAC plus systemic paclitaxel and ramucirumab, and accompanying dose modification plan, by evaluation of toxicities including: type, frequency, severity, attribution, time course and duration. SECONDARY OBJECTIVES: I. To evaluate the anti-tumor activity of nab-paclitaxel when given in combination with standard-of-care second-line systemic therapy (paclitaxel, ramucirumab), as assessed by: Ia. Response Evaluation Criteria in Solid Tumors (RECIST), if available, version 1.1 via computed tomography (CT) scan at baseline and every 8 weeks until disease progression; Ib. Peritoneal Regression Grading Score (PRGS) via biopsy at each PIPAC cycle (both pre-PIPAC and post-PIPAC peritoneal samples will be obtained); Ic. Peritoneal Carcinomatosis Index (PCI) at the time of laparoscopy; and Id. Overall survival (OS) and progression-free survival (PFS) estimates at 6-months, 1-year and 2-years. II. To estimate the PIPAC technical failure rate. III. To characterize and evaluate peritoneal tumor associated complications. IV. To characterize and evaluate post-operative surgical complications by Clavien-Dindo classification evaluated at 30 days after each PIPAC technical failure rate. V. To evaluate patient-reported health state/quality of life and symptoms before treatment and at 6, 12, 18, and 24 weeks/off study, as measured by the European Quality of Life Five Dimension Five Level Scale (EQ-5D-5L) and MD Anderson Symptom Inventory (MDASI). EXPLORATORY OBJECTIVES: I. Characterize the peritoneal tumor and immune tumor microenvironment changes in response to therapy. II. Evaluate the pharmacokinetics of nab-paclitaxel PIPAC. III. Evaluate patients' quality of life during nab-paclitaxel PIPAC plus systemic therapy. OUTLINE: This is a dose-escalation study of nab-paclitaxel PIPAC in combination with paclitaxel and ramucirumab followed by a dose-expansion study. Patients receive nab-paclitaxel PIPAC intraperitoneally (IP) over 40 minutes on day 1 and standard of care (SOC) paclitaxel intravenously (IV) over 60 minutes on days 15, 22, 29, 43, and 50 and ramucirumab IV over 30-60 minutes on days 15, 29 and 43 of each cycle. Cycles repeat every 8 weeks (56 days) for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients may then continue SOC paclitaxel IV on days 1, 8, and 15 and ramucirumab IV on days 1 and 15 of each cycle per physician as deemed appropriate. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Additionally, patients undergo blood sample collection, tumor biopsy, and CT or magnetic resonance imaging (MRI) throughout the study. After completion of study treatment, patients are followed up at 4 weeks, then every 3 months for year 1 followed by every 6 months until progression or initiation of a new systemic anti-cancer therapy or death, whichever occurs first.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
30
Undergo tumor biopsy
Undergo blood sample collection
Undergo CT
Undergo MRI
Given PIPAC
Given IP
Given IV
Ancillary studies
Given IV
City of Hope Medical Center
Duarte, California, United States
RECRUITINGDose-limiting toxicity (DLT)
Will be evaluated and graded based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v) 5.0. Toxicities 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. Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.
Time frame: Up to 6 weeks after the first pressurized intraperitoneal aerosolized chemotherapy (PIPAC) treatment
Incidence of treatment-related adverse events (AEs)
Will be evaluated and graded based on NCI CTCAE v 5.0. The number and percent of patients with AEs will be tabulated by system organ class and preferred term using the Medical Dictionary for Regulatory Activities preferred term dictionary. The tabulations will be generated so that the number and percent of patients with events in each severity, relatedness, and serious category can be obtained for each preferred term. Listings and narratives will be provided for deaths on study, serious AEs, DLTs, and events leading to discontinuation of treatment.
Time frame: Up to 4 weeks after last dose of nab-paclitaxel
Incidence of post-operative surgical complications
Will be evaluated using Clavien-Dindo classification. Results will be strictly descriptive in nature.
Time frame: At 4 weeks post-PIPAC procedure
Objective response rate (ORR)
Will be evaluated according to Response Evaluation Criteria in Solid Tumors v 1.1. ORR will be defined as the percentage of evaluable patients who have achieved complete response (CR), partial response (PR), or stable disease (SD). Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.
Time frame: Up to 2 years
Peritoneal Carcinomatosis Index (PCI)
PCI will be defined as the percentage of evaluable patients who have achieved CR, PR, or SD. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson
Time frame: At time of laparoscopy
Peritoneal Regression Grading Score (PRGS)
PRGS will be defined as the percentage of evaluable patients who have achieved a decrease in the PRGS over successive biopsies. Confidence intervals for the true success proportion will be calculated according to the approach of Clopper and Pearson
Time frame: At baseline and post-PIPAC, assessed up to 2 years
Progression-free survival (PFS)
PFS will be estimated using the Kaplan-Meier estimator and 95% confidence intervals will be calculated using the logit transformation and the Greenwood variance estimate.
Time frame: From first PIPAC to progression of disease, assessed up to 2 years
Overall survival (OS)
OS will be estimated using the Kaplan-Meier estimator and 95% confidence intervals will be calculated using the logit transformation and the Greenwood variance estimate.
Time frame: From initiation of treatment to death or last contact, whichever occurs first up to 2 years
PIPAC technical failure rate
The technical failure rate will be calculated. The device malfunction rate will also be calculated. Rates and associated 95% Clopper and Pearson binomial confidence limits will be estimated.
Time frame: Up to 2 years
Patient-reported health status and quality of life
Will be measured using the European Quality of Life Five Dimension Five Level Scale and will be summarized with descriptive statistics.
Time frame: At baseline and at 6, 12, 18 and 24 weeks off study
Patient-reported symptoms
Will be measured using the MD Anderson Symptom Inventory and will be summarized with descriptive statistics.
Time frame: At baseline and at 6, 12, 18 and 24 weeks off study
Time to peritoneal tumor associated complications
Will be estimated using the Kaplan-Meier estimator and 95% confidence intervals will be calculated using the logit transformation and the Greenwood variance estimate.
Time frame: Up to 2 years
Functional status
Will be measured by the number of daily steps before and after treatments.
Time frame: Up to 1 year
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