Peritoneal CarcinomatosisPhase 1PIPACNCT03172416
Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) With Oxaliplatin In Patients With Peritoneal Carcinomatosis
A Phase 1 study testing Oxaliplatin and Oxaliplatin & Nivolumab in people with Peritoneal Carcinomatosis, run by National University Hospital, Singapore at 3 sites in 2 countries.
Trial summary
PIPAC is a procedure that involves the administration of intraperitoneal chemotherapy using an innovative concept that enhances the efficacy by taking advantage of the physical properties of gas and pressure. The chemotherapy drugs will be delivered in aerosolised form. Read more about this study
- Who is it for?
- Ages 21 years and older
- Conditions the study is for
- Peritoneal Carcinomatosis
- What is being tested?
- Oxaliplatin and Oxaliplatin & Nivolumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 21 participants
- Where
- 3 sitesin 2 countries
- Study dates
- 12 Apr 2017to 31 Dec 2024
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 21 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Gastric cancer patients with peritoneal metastasis on peritoneal cytology/histology.
- Patients who refuse, are unable to tolerate, or have completed at least 1st line systemic chemotherapy.
- Patients who have completed chemotherapy/targeted therapy > 21 days or at least 5 half-lives (or whichever is longer) prior to PIPAC.
- Age >21 years.
- Eastern Cooperative Oncology Group performance status 0-1.
- Adequate bone marrow function (neutrophil count >1500/mm3, hemoglobin >8.0 g/dl and platelet count >100 000/mm3).
Show all 21Show fewer
- Adequate liver function (bilirubin, AST/ALT within upper limit of normal)
- Adequate renal function (serum creatinine within the upper limit of normal)
- Expected survival >3 months
- Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation.
- Gastric cancer patients with peritoneal metastasis on peritoneal cytology/histology, for whom oxaliplatin is considered standard of care for the peritoneal carcinoma of origin.
- Patients who refuse, are unable to tolerate, or have completed at least 1st line systemic chemotherapy
- Patients who have completed chemotherapy/targeted therapy > 21 days or at least 5 half-lives (or whichever is longer) prior to PIPAC
- Patients must have recovered (≤ grade 1) from all reversible treatment toxicity from prior chemotherapy, radiotherapy or surgery.
- Age ≥21 years
- Eastern Cooperative Oncology Group performance status 0-1
- Adequate bone marrow function (neutrophil count ≥1500/mm3, hemoglobin ≥8.0 g/dl and platelet count ≥100 000/mm3)
- Adequate liver function (bilirubin ≤ 1.5x ULN(upper limit normal) and AST/ALT ≤3x ULN or ≤5x ULN in the presence of liver metastases)
- Adequate renal function (serum creatinine ≤1.5x ULN)
- Expected survival >3 months
- Women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation.
Who cannot join
- Predominant extra-peritoneal metastases at the discretion of the study team after discussion at the multidisciplinary tumour board
- Good response to systemic chemotherapy based on RECIST guidelines VI.I with complete or partial response to systemic chemotherapy.
- Known allergy to oxaliplatin
- Previous malignancy unrelated to current peritoneal carcinomatosis diagnosed in the last 5 years
- Patients with treated skin cancer besides melanoma may be included.
- Patients with reproductive potential who refuse to use an adequate means of contraception (including male patients)
Show all 24Show fewer
- Significant disease or conditions which, in the investigator's opinion, would exclude patient from the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant or lactating female
- Predominant extra-peritoneal metastases at the discretion of the study team after discussion at the multidisciplinary tumour board
- Patients who have previously received prior nivolumab or PD-/L1 blockade therapy
- Patients with clinical or radiological evidence of hollow viscera perforation or impending perforation, including but not limited to gastric, small bowel, colon, gallbladder. Decision will be made at the discretion of the study team in consultation with multidisciplinary tumour board or with necessary specialists
- Good response to systemic chemotherapy based on RECIST guidelines VI.I with complete or partial response to systemic chemotherapy.
- Active autoimmune disease requiring disease-modifying therapy.
- Concurrent systemic steroid therapy higher than physiologic dose (equivalent of prednisolone 10mg daily), except for short courses (< 2 weeks) required to treat acute medical conditions (e.g. asthma exacerbation, or for CT scans)
- Any form of active primary or secondary immunodeficiency.
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, uncontrolled hypertension (systolic >160 mmHg and/or diastolic >100 mmHg), symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction/cerebrovascular event (≤ 6 months prior to study entry), cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements, long term systemic immunosuppressant or corticosteroid, and active viral hepatitis.
- Known allergy to oxaliplatin
- Previous malignancy unrelated to current peritoneal carcinomatosis diagnosed in the last 2 years
- Patients with treated skin cancer besides melanoma may be included.
- Patients with reproductive potential who refuse to use an adequate means of contraception (including male patients)
- Significant disease or conditions which, in the investigator's opinion, would exclude patient from the study
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
- Pregnant or lactating female
Trial locations and contacts
3 sites in 2 countries.
3 sites in 2 countries
Singapore2 sites
National University Hospital
Singapore, 119228
National Cancer Centre Singapore
Singapore
About this study
Official title: Phase 1 Study of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) With Oxaliplatin. Phase 1 Study of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) With Oxaliplatin and in Combination With Nivolumab in Patients With Peritoneal Carcinomatosis (PIANO)
PIPAC is a procedure that involves the administration of intraperitoneal chemotherapy using an innovative concept that enhances the efficacy by taking advantage of the physical properties of gas and pressure. The chemotherapy drugs will be delivered in aerosolised form. This results in a superior distribution and depth of penetration of the drug.
This research study serves to determine the safety profile and tolerability of PIPAC with oxaliplatin. It may offer a novel and effective option of treatment for patients with peritoneal carcinomatosis, who, at present have limited options involving the use of systemic chemotherapy and who suffer from poor life expectancy and poor quality of life.
Read more
To date, most trials have used PIPAC cisplatin with doxorubicin, or oxaliplatin alone, and more studies are on-going globally.
Intravenous (IV) nivolumab has been approved for the treatment of progressive gastric cancer after conventional chemotherapy. PIPAC in combination with nivolumab may have the potential to improve immune activation and response to immune checkpoint inhibition for patients with peritoneal disease.
Hence we propose an amendment to our trial protocol for the addition of a second cohort (Cohort 2) to investigate the safety and tolerability of the combination of PIPAC oxaliplatin and IV nivolumab.
Read the detailed description
Gastric cancer is the 5th most common cancer (1 million incidences per year) and the third leading cause of cancer-related mortality worldwide (740,000 deaths per year). Unresectable gastric cancer is associated with a poor 5-year survival rate (< 30%) because of its late presentation with approximately 50% of the patients diagnosed at advanced stage with a median survival of about 12 months. The treatment for advanced gastric cancer patients relies mainly on doublet or triplet chemotherapy, but results are often limited by severe side effects of the aggressive regimens. Novel efficacious treatments with reduced adverse effects are highly desirable to improve the clinical outcome.
Peritoneal disease is notoriously difficult to treat. In patients with histologically proven unresectable or recurrent gastric cancer limited to the peritoneum and/or cancer cells in peritoneal cytology, the combination of intraperitoneal (IP) paclitaxel with systemic chemotherapy seems promising. However, a phase III trial (PHOENIX-GC trial) comparing IP regimen with systemic chemotherapy versus systemic therapy alone in Japan did not show any superiority of the IP regimen.
PIPAC is an innovative intraperitoneal chemotherapy concept that enhances the efficacy by taking advantage of the physical properties of gas and pressure. This results in a superior distribution and depth of penetration of the drug. A recent systematic review of 45 clinical studies on 1810 PIPAC procedures showed response rates of 50-91% for gastric cancer (median survival of 8 to 15 months), 71-86% for colorectal cancer (median survival of 16 months).
To date, most phase II trials utilising PIPAC involve the use of cisplatin and doxorubicin or oxaliplatin. Oxaliplatin is an approved drug for systemic chemotherapy, with well documented use intraperitoneally via hyperthermic intraperitoneal chemotherapy (HIPEC) as well. This makes is a favourable agent for PIPAC in early phase studies. The dose of oxaliplatin utilised for PIPAC in the literature has thus far been arbitrarily set at 92 mg/m2, which is approximately 80% of the drug concentration used in HIPEC. Furthermore, these studies were performed on patients with a recent or concurrent administration of systemic chemotherapy, which may make interpretation of the side effects and safety profile difficult to interpret.
In Cohort 1 of this study, we intend to determine the safety profile and tolerability of PIPAC with oxaliplatin by assessment of dose limiting toxicities and the adverse event profile.
Cancer immunotherapy with checkpoint inhibitor has demonstrated clinical activities and survival benefits as a monotherapy and in combination with other immunotherapies or conventional chemotherapies in multiple cancer types. Nivolumab has been showed to have overall survival benefit over placebo in the third line treatment of metastatic gastric cancer with a response rate of 11%. In the CheckMate032 trial, nivolumab, with or without ipilumumab, demonstrated durable responses and long-term survival. Nivolumab alone, dosed at 3mg/kg, had a response rate of 12%.
It is hypothesized that the delivery of PIPAC deep into the peritoneal tissue is likely to affect the tumor microenvironment and potentially release neoantigens which would improve clinical outcomes with immune checkpoint inhibition. Hence we propose an amendment to our trial protocol for the addition of a second cohort (Cohort 2) to combine this Phase I proof-of-concept study with nivolumab.
The aim is to determine the determine the safety profile and tolerability of PIPAC oxaliplatin by assessment of dose limiting toxicities and the adverse event profile. With Cohort 2, the co-primary endpoints are the safety and efficacy of the combination of PIPAC oxaliplatin and IV nivolumab. Safety will be evaluated in terms of adverse events, serious adverse events, discontinuation of treatment due to toxicity. Efficacy will be evaluated in terms of the percentage of patients with 6 months of time-to-treatment failure (TTF). TTF is defined as the interval from treatment initiation to treatment discontinuation for disease progression, treatment toxicity, and death. The secondary objective is to evaluate the clinical and pathological response of PIPAC oxaliplatin as well as to identify the pharmacokinetic profile of oxaliplatin administered via PIPAC. The clinical and pathological response to combination treatment will also be determined. Quality of life will be evaluated.
- Conditions
- Peritoneal Carcinomatosis
- Being tested
- Oxaliplatin, Oxaliplatin & Nivolumab
- Keywords
- Gastric Cancer, Unresectable Peritoneal Carcinomatosis, Oxaliplatin, Pressurized intraperitoneal aerosol chemotherapy, Nivolumab
- Medical subject headings
- Peritoneal Neoplasms, Stomach Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OxaliplatinDrug
This study started as a prospective, single arm phase I trial in a 3 + 3 dose escalation evaluating the safety and tolerability of PIPAC using oxaliplatin in patients with peritoneal carcinomatosis.
Oxaliplatin & NivolumabDrug
PIPAC oxaliplatin 90mg/m2 has been well tolerated in our Cohort 1 study. Hence, we added a second cohort (Cohort 2) which combines PIPAC oxaliplatin at 90mg/m2 every 6 weeks with IV nivolumab at 240mg every 2 weeks to evaluate the safety and tolerability of combination therapy.
| Study group | Role | What they receive |
|---|---|---|
| Oxaliplatin | Other | 3+3 dose escalation of oxaliplatin
This is a single arm phase I trial in a 3 + 3 dose escalation and cohort expansion design evaluating the safety and tolerability of PIPAC using oxaliplatin.
The pre-planned dose levels of oxaliplatin are 45mg/m2 (Cohort 1), 60mg/m2 (Cohort 2), 90mg/m2 (Cohort 3),120mg/m2 (Cohort 4) and 150mg/m2 (Cohort 5) administered as PIPAC. Successive cohorts of patients (3 participants/cohort) will be enrolled and started on a fixed dose of oxaliplatin. The protocol specifies oxaliplatin 45mg/m2 once every 6 weeks for Cohort 1. Dose escalation continues until dose-limiting toxicities (DLT) are observed in one-third of participants. If no DLT occurs, the next cohort will be enrolled at the next planned dose level. If 1 DLT occurs in a cohort, another 3 patients will be treated with the same dose level.
Oxaliplatin every 6 weeks with IV nivolumab every 2 weeks
PIPAC oxaliplatin at 90mg/m2 every 6 weeks with IV nivolumab at 240mg every 2 weeks Receives: Drug: Oxaliplatin; Drug: Oxaliplatin & Nivolumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Safety Profile of PIPAC with oxaliplatin by monitoring adverse event profile of patient undergo PIPAC
Measured: 1 to 2 years
Tolerability of PIPAC with oxaliplatin by monitoring dose limiting toxicities
Measured: 1-2 years
Safety Profile of PIPAC with oxaliplatin in combination with IV nivolumab by monitoring adverse event profile of patient undergo PIPAC
Measured: 1-2 years
Tolerability of PIPAC with oxaliplatin in combination with IV nivolumab by monitoring dose limiting toxicities
Measured: 1-2 years
Secondary outcomes (10)
Clinical response of PIPAC with oxaliplatin according to Peritoneal Cancer Index (PCI)
Measured: 1-2 years
Pathological response of PIPAC with oxaliplatin according to Peritoneal Regression Grade Scoring (PRGS) System
Measured: 1-2 years
Maximum concentration (Cmax) of oxaliplatin administered via PIPAC using blood drawn from patient.
Maximum concentration (Cmax) of oxaliplatin, for patients with peritoneal carcinomatosis after PIPAC administration.
Measured: Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24 and 30 hours
Half-life (t1/2) of oxaliplatin administered via PIPAC using blood drawn from patient.
Half-life (t1/2) of oxaliplatin for patients with peritoneal carcinomatosis after PIPAC administration.
Measured: Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24 and 30 hours
Area under the curve (AUC) of oxaliplatin administered via PIPAC using blood drawn from patient.
Area under the curve (AUC) of oxaliplatin for patients with peritoneal carcinomatosis after PIPAC administration
Measured: Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24 and 30 hours
Clinical response of PIPAC with oxaliplatin in combination with IV nivolumab according to Peritoneal Cancer Index (PCI)
Measured: 1-2 years
Pathological response of PIPAC with oxaliplatin in combination with IV nivolumab according to Peritoneal Regression Grade Scoring (PRGS) System
Measured: 1-2 years
Maximum concentration (Cmax) of oxaliplatin and in combination with IV nivolumab administered via PIPAC using blood drawn from patient.
Maximum concentration (Cmax) of oxaliplatin and in combination with IV nivolumab for patients with peritoneal carcinomatosis after PIPAC administration.
Measured: Pre-dose, 30 minutes, 1 and 30 hours
Half-life (t1/2) of oxaliplatin and in combination with IV nivolumab administered via PIPAC using blood drawn from patient.
Half-life (t1/2) of oxaliplatin and in combination with IV nivolumab for patients with peritoneal carcinomatosis after PIPAC administration.
Measured: Pre-dose, 30 minutes, 1 and 30 hours
Area under the curve (AUC) of oxaliplatin and in combination with IV nivolumab administered via PIPAC using blood drawn from patient.
Area under the curve (AUC) of oxaliplatin and in combination with IV nivolumab for patients with peritoneal carcinomatosis after PIPAC administration
Measured: Pre-dose, 30 minutes, 1 and 30 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jun 2017
- Study start12 Apr 2017
- Primary completion31 Dec 2024 (estimated)
- Study completion31 Dec 2024 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (8)Papers the sponsor has linked to this study.
- Other trials for Peritoneal CarcinomatosisStudies of the same condition, open and under way.
- More trials run by National University Hospital, SingaporeThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 21 participants (estimated)
Sponsor and investigators
- Lead sponsor
- National University Hospital, Singapore
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Jimmy So, MBChB, Principal investigator, National University Hospital, Singapore
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03172416
- Sponsor's protocol ID
- DSRB 2016/01088
- Acronym
- PIPAC
- Status last verified
- May 2024
- First submitted
- 23 Jan 2017
- Last updated
- 29 May 2024
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ishigami H, Kitayama J, Kaisaki S, Hidemura A, Kato M, Otani K, Kamei T, Soma D, Miyato H, Yamashita H, Nagawa H. Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol. 2010 Jan;21(1):67-70. doi: 10.1093/annonc/mdp260. Epub 2009 Jul 15.
PubMed 19605503Solass W, Hetzel A, Nadiradze G, Sagynaliev E, Reymond MA. Description of a novel approach for intraperitoneal drug delivery and the related device. Surg Endosc. 2012 Jul;26(7):1849-55. doi: 10.1007/s00464-012-2148-0. Epub 2012 May 12.
PubMed 22580869Solass W, Herbette A, Schwarz T, Hetzel A, Sun JS, Dutreix M, Reymond MA. Therapeutic approach of human peritoneal carcinomatosis with Dbait in combination with capnoperitoneum: proof of concept. Surg Endosc. 2012 Mar;26(3):847-52. doi: 10.1007/s00464-011-1964-y. Epub 2011 Nov 1.
PubMed 22042585Robella M, Vaira M, De Simone M. Safety and feasibility of pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic chemotherapy: an innovative approach to treat peritoneal carcinomatosis. World J Surg Oncol. 2016 Apr 29;14:128. doi: 10.1186/s12957-016-0892-7.
PubMed 27125996Solass W, Kerb R, Murdter T, Giger-Pabst U, Strumberg D, Tempfer C, Zieren J, Schwab M, Reymond MA. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy. Ann Surg Oncol. 2014 Feb;21(2):553-9. doi: 10.1245/s10434-013-3213-1. Epub 2013 Sep 5.
PubMed 24006094Demtroder C, Solass W, Zieren J, Strumberg D, Giger-Pabst U, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin in colorectal peritoneal metastasis. Colorectal Dis. 2016 Apr;18(4):364-71. doi: 10.1111/codi.13130.
PubMed 26400556Sundar R, Chia DKA, Zhao JJ, Lee ARYB, Kim G, Tan HL, Pang A, Shabbir A, Willaert W, Ma H, Huang KK, Hagihara T, Tan ALK, Ong CJ, Wong JSM, Seo CJ, Walsh R, Chan G, Cheo SW, Soh CCC, Callebout E, Geboes K, Ng MCH, Lum JHY, Leow WQ, Selvarajan S, Hoorens A, Ang WH, Pang H, Tan P, Yong WP, Chia CSL, Ceelen W, So JBY. Phase I PIANO trial-PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes. ESMO Open. 2024 Sep;9(9):103681. doi: 10.1016/j.esmoop.2024.103681. Epub 2024 Sep 16.
PubMed 39288528Kim G, Tan HL, Chen E, Teo SC, Jang CJM, Ho J, Ang Y, Ngoi NYL, Chee CE, Lieske B, Shabbir A, Wang LZ, So JBY, Yong WP. Study protocol: phase 1 dose escalating study of Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) with oxaliplatin in peritoneal metastasis. Pleura Peritoneum. 2018 Aug 29;3(3):20180118. doi: 10.1515/pp-2018-0118. eCollection 2018 Sep 1.
PubMed 30911663
Study at a glance
From the registry record, last updated by the sponsor on 29 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 1 Study of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) With Oxaliplatin. Phase 1 Study of Pressurized Intraperitoneal Aerosol Chemotherapy (PIPAC) With Oxaliplatin and in Combination With Nivolumab in Patients With Peritoneal Carcinomatosis (PIANO)
- ClinicalTrials.gov ID
- NCT03172416
- Acronym / sponsor ID
- PIPAC / DSRB 2016/01088
- Conditions
- Peritoneal Carcinomatosis
- Keywords
- Gastric Cancer, Unresectable Peritoneal Carcinomatosis, Oxaliplatin, Pressurized intraperitoneal aerosol chemotherapy, Nivolumab
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 21 participants (estimated)
- Lead sponsor
- National University Hospital, SingaporeUniversity, hospital or other
- Study start
- 12 Apr 2017 (actual)
- Primary completion
- 31 Dec 2024 (estimated)
- Study completion
- 31 Dec 2024 (estimated)
- First posted
- 1 Jun 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
PIPAC is a procedure that involves the administration of intraperitoneal chemotherapy using an innovative concept that enhances the efficacy by taking advantage of the physical properties of gas and pressure. The chemotherapy drugs will be delivered in aerosolised form. This results in a superior distribution and depth of penetration of the drug.
This research study serves to determine the safety profile and tolerability of PIPAC with oxaliplatin. It may offer a novel and effective option of treatment for patients with peritoneal carcinomatosis, who, at present have limited options involving the use of systemic chemotherapy and who suffer from poor life expectancy and poor quality of life.
To date, most trials have used PIPAC cisplatin with doxorubicin, or oxaliplatin alone, and more studies are on-going globally.
Intravenous (IV) nivolumab has been approved for the treatment of progressive gastric cancer after conventional chemotherapy. PIPAC in combination with nivolumab may have the potential to improve immune activation and response to immune checkpoint inhibition for patients with peritoneal disease.
Hence we propose an amendment to our trial protocol for the addition of a second cohort (Cohort 2) to investigate the safety and tolerability of the combination of PIPAC oxaliplatin and IV nivolumab.
Detailed description
Gastric cancer is the 5th most common cancer (1 million incidences per year) and the third leading cause of cancer-related mortality worldwide (740,000 deaths per year). Unresectable gastric cancer is associated with a poor 5-year survival rate (< 30%) because of its late presentation with approximately 50% of the patients diagnosed at advanced stage with a median survival of about 12 months. The treatment for advanced gastric cancer patients relies mainly on doublet or triplet chemotherapy, but results are often limited by severe side effects of the aggressive regimens. Novel efficacious treatments with reduced adverse effects are highly desirable to improve the clinical outcome.
Peritoneal disease is notoriously difficult to treat. In patients with histologically proven unresectable or recurrent gastric cancer limited to the peritoneum and/or cancer cells in peritoneal cytology, the combination of intraperitoneal (IP) paclitaxel with systemic chemotherapy seems promising. However, a phase III trial (PHOENIX-GC trial) comparing IP regimen with systemic chemotherapy versus systemic therapy alone in Japan did not show any superiority of the IP regimen.
PIPAC is an innovative intraperitoneal chemotherapy concept that enhances the efficacy by taking advantage of the physical properties of gas and pressure. This results in a superior distribution and depth of penetration of the drug. A recent systematic review of 45 clinical studies on 1810 PIPAC procedures showed response rates of 50-91% for gastric cancer (median survival of 8 to 15 months), 71-86% for colorectal cancer (median survival of 16 months).
To date, most phase II trials utilising PIPAC involve the use of cisplatin and doxorubicin or oxaliplatin. Oxaliplatin is an approved drug for systemic chemotherapy, with well documented use intraperitoneally via hyperthermic intraperitoneal chemotherapy (HIPEC) as well. This makes is a favourable agent for PIPAC in early phase studies. The dose of oxaliplatin utilised for PIPAC in the literature has thus far been arbitrarily set at 92 mg/m2, which is approximately 80% of the drug concentration used in HIPEC. Furthermore, these studies were performed on patients with a recent or concurrent administration of systemic chemotherapy, which may make interpretation of the side effects and safety profile difficult to interpret.
In Cohort 1 of this study, we intend to determine the safety profile and tolerability of PIPAC with oxaliplatin by assessment of dose limiting toxicities and the adverse event profile.
Cancer immunotherapy with checkpoint inhibitor has demonstrated clinical activities and survival benefits as a monotherapy and in combination with other immunotherapies or conventional chemotherapies in multiple cancer types. Nivolumab has been showed to have overall survival benefit over placebo in the third line treatment of metastatic gastric cancer with a response rate of 11%. In the CheckMate032 trial, nivolumab, with or without ipilumumab, demonstrated durable responses and long-term survival. Nivolumab alone, dosed at 3mg/kg, had a response rate of 12%.
It is hypothesized that the delivery of PIPAC deep into the peritoneal tissue is likely to affect the tumor microenvironment and potentially release neoantigens which would improve clinical outcomes with immune checkpoint inhibition. Hence we propose an amendment to our trial protocol for the addition of a second cohort (Cohort 2) to combine this Phase I proof-of-concept study with nivolumab.
The aim is to determine the determine the safety profile and tolerability of PIPAC oxaliplatin by assessment of dose limiting toxicities and the adverse event profile. With Cohort 2, the co-primary endpoints are the safety and efficacy of the combination of PIPAC oxaliplatin and IV nivolumab. Safety will be evaluated in terms of adverse events, serious adverse events, discontinuation of treatment due to toxicity. Efficacy will be evaluated in terms of the percentage of patients with 6 months of time-to-treatment failure (TTF). TTF is defined as the interval from treatment initiation to treatment discontinuation for disease progression, treatment toxicity, and death. The secondary objective is to evaluate the clinical and pathological response of PIPAC oxaliplatin as well as to identify the pharmacokinetic profile of oxaliplatin administered via PIPAC. The clinical and pathological response to combination treatment will also be determined. Quality of life will be evaluated.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Oxaliplatin | Other | Drug: Oxaliplatin, Drug: Oxaliplatin & Nivolumab3+3 dose escalation of oxaliplatin This is a single arm phase I trial in a 3 + 3 dose escalation and cohort expansion design evaluating the safety and tolerability of PIPAC using oxaliplatin. The pre-planned dose levels of oxaliplatin are 45mg/m2 (Cohort 1), 60mg/m2 (Cohort 2), 90mg/m2 (Cohort 3),120mg/m2 (Cohort 4) and 150mg/m2 (Cohort 5) administered as PIPAC. Successive cohorts of patients (3 participants/cohort) will be enrolled and started on a fixed dose of oxaliplatin. The protocol specifies oxaliplatin 45mg/m2 once every 6 weeks for Cohort 1. Dose escalation continues until dose-limiting toxicities (DLT) are observed in one-third of participants. If no DLT occurs, the next cohort will be enrolled at the next planned dose level. If 1 DLT occurs in a cohort, another 3 patients will be treated with the same dose level. Oxaliplatin every 6 weeks with IV nivolumab every 2 weeks PIPAC oxaliplatin at 90mg/m2 every 6 weeks with IV nivolumab at 240mg every 2 weeks |
Who may qualify
- Ages
- 21 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- Gastric cancer patients with peritoneal metastasis on peritoneal cytology/histology.
- Patients who refuse, are unable to tolerate, or have completed at least 1st line systemic chemotherapy.
- Patients who have completed chemotherapy/targeted therapy > 21 days or at least 5 half-lives (or whichever is longer) prior to PIPAC.
- Age >21 years.
- Eastern Cooperative Oncology Group performance status 0-1.
Key exclusion criteria (24 listed)
- Predominant extra-peritoneal metastases at the discretion of the study team after discussion at the multidisciplinary tumour board
- Good response to systemic chemotherapy based on RECIST guidelines VI.I with complete or partial response to systemic chemotherapy.
- Known allergy to oxaliplatin
- Previous malignancy unrelated to current peritoneal carcinomatosis diagnosed in the last 5 years
- Patients with treated skin cancer besides melanoma may be included.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OxaliplatinThis study started as a prospective, single arm phase I trial in a 3 + 3 dose escalation evaluating the safety and tolerability of PIPAC using oxaliplatin in patients with peritoneal carcinomatosis. | Drug | Oxaliplatin |
| Oxaliplatin & NivolumabPIPAC oxaliplatin 90mg/m2 has been well tolerated in our Cohort 1 study. Hence, we added a second cohort (Cohort 2) which combines PIPAC oxaliplatin at 90mg/m2 every 6 weeks with IV nivolumab at 240mg every 2 weeks to evaluate the safety and tolerability of combination therapy. | Drug | Oxaliplatin |
Primary outcome
Safety Profile of PIPAC with oxaliplatin by monitoring adverse event profile of patient undergo PIPAC
Time frame: 1 to 2 years
Tolerability of PIPAC with oxaliplatin by monitoring dose limiting toxicities
Time frame: 1-2 years
Safety Profile of PIPAC with oxaliplatin in combination with IV nivolumab by monitoring adverse event profile of patient undergo PIPAC
Time frame: 1-2 years
Tolerability of PIPAC with oxaliplatin in combination with IV nivolumab by monitoring dose limiting toxicities
Time frame: 1-2 years
10 secondary outcomes
Clinical response of PIPAC with oxaliplatin according to Peritoneal Cancer Index (PCI)
Time frame: 1-2 years
Pathological response of PIPAC with oxaliplatin according to Peritoneal Regression Grade Scoring (PRGS) System
Time frame: 1-2 years
Maximum concentration (Cmax) of oxaliplatin administered via PIPAC using blood drawn from patient.
Time frame: Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24 and 30 hours
Half-life (t1/2) of oxaliplatin administered via PIPAC using blood drawn from patient.
Time frame: Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24 and 30 hours
Area under the curve (AUC) of oxaliplatin administered via PIPAC using blood drawn from patient.
Time frame: Pre-dose; 30 and 45 minutes; and 1, 2, 4, 8, 24 and 30 hours
Clinical response of PIPAC with oxaliplatin in combination with IV nivolumab according to Peritoneal Cancer Index (PCI)
Time frame: 1-2 years
Pathological response of PIPAC with oxaliplatin in combination with IV nivolumab according to Peritoneal Regression Grade Scoring (PRGS) System
Time frame: 1-2 years
Maximum concentration (Cmax) of oxaliplatin and in combination with IV nivolumab administered via PIPAC using blood drawn from patient.
Time frame: Pre-dose, 30 minutes, 1 and 30 hours
Half-life (t1/2) of oxaliplatin and in combination with IV nivolumab administered via PIPAC using blood drawn from patient.
Time frame: Pre-dose, 30 minutes, 1 and 30 hours
Area under the curve (AUC) of oxaliplatin and in combination with IV nivolumab administered via PIPAC using blood drawn from patient.
Time frame: Pre-dose, 30 minutes, 1 and 30 hours
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 May 2024.
- Background: PubMed 19605503Ishigami H, Kitayama J, Kaisaki S, Hidemura A, Kato M, Otani K, Kamei T, Soma D, Miyato H, Yamashita H, Nagawa H. Phase II study of weekly intravenous and intraperitoneal paclitaxel combined with S-1 for advanced gastric cancer with peritoneal metastasis. Ann Oncol. 2010 Jan;21(1):67-70. doi: 10.1093/annonc/mdp260. Epub 2009 Jul 15.
- Background: PubMed 22580869Solass W, Hetzel A, Nadiradze G, Sagynaliev E, Reymond MA. Description of a novel approach for intraperitoneal drug delivery and the related device. Surg Endosc. 2012 Jul;26(7):1849-55. doi: 10.1007/s00464-012-2148-0. Epub 2012 May 12.
- Background: PubMed 22042585Solass W, Herbette A, Schwarz T, Hetzel A, Sun JS, Dutreix M, Reymond MA. Therapeutic approach of human peritoneal carcinomatosis with Dbait in combination with capnoperitoneum: proof of concept. Surg Endosc. 2012 Mar;26(3):847-52. doi: 10.1007/s00464-011-1964-y. Epub 2011 Nov 1.
- Background: PubMed 27125996Robella M, Vaira M, De Simone M. Safety and feasibility of pressurized intraperitoneal aerosol chemotherapy (PIPAC) associated with systemic chemotherapy: an innovative approach to treat peritoneal carcinomatosis. World J Surg Oncol. 2016 Apr 29;14:128. doi: 10.1186/s12957-016-0892-7.
- Background: PubMed 24006094Solass W, Kerb R, Murdter T, Giger-Pabst U, Strumberg D, Tempfer C, Zieren J, Schwab M, Reymond MA. Intraperitoneal chemotherapy of peritoneal carcinomatosis using pressurized aerosol as an alternative to liquid solution: first evidence for efficacy. Ann Surg Oncol. 2014 Feb;21(2):553-9. doi: 10.1245/s10434-013-3213-1. Epub 2013 Sep 5.
- Background: PubMed 26400556Demtroder C, Solass W, Zieren J, Strumberg D, Giger-Pabst U, Reymond MA. Pressurized intraperitoneal aerosol chemotherapy with oxaliplatin in colorectal peritoneal metastasis. Colorectal Dis. 2016 Apr;18(4):364-71. doi: 10.1111/codi.13130.
- Derived from this study: PubMed 39288528Sundar R, Chia DKA, Zhao JJ, Lee ARYB, Kim G, Tan HL, Pang A, Shabbir A, Willaert W, Ma H, Huang KK, Hagihara T, Tan ALK, Ong CJ, Wong JSM, Seo CJ, Walsh R, Chan G, Cheo SW, Soh CCC, Callebout E, Geboes K, Ng MCH, Lum JHY, Leow WQ, Selvarajan S, Hoorens A, Ang WH, Pang H, Tan P, Yong WP, Chia CSL, Ceelen W, So JBY. Phase I PIANO trial-PIPAC-oxaliplatin and systemic nivolumab combination for gastric cancer peritoneal metastases: clinical and translational outcomes. ESMO Open. 2024 Sep;9(9):103681. doi: 10.1016/j.esmoop.2024.103681. Epub 2024 Sep 16.
- Derived from this study: PubMed 30911663Kim G, Tan HL, Chen E, Teo SC, Jang CJM, Ho J, Ang Y, Ngoi NYL, Chee CE, Lieske B, Shabbir A, Wang LZ, So JBY, Yong WP. Study protocol: phase 1 dose escalating study of Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) with oxaliplatin in peritoneal metastasis. Pleura Peritoneum. 2018 Aug 29;3(3):20180118. doi: 10.1515/pp-2018-0118. eCollection 2018 Sep 1.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Jimmy So, MBChB principal investigator
National University Hospital, Singapore
3 sites in 2 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Oxaliplatin and Oxaliplatin & Nivolumab in people with Peritoneal Carcinomatosis, run by National University Hospital, Singapore at 3 sites in 2 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 29 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 3 sites in Singapore, Belgium. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Safety Profile of PIPAC with oxaliplatin by monitoring adverse event profile of patient undergo PIPAC (time frame: 1 to 2 years). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03172416, which also lists 8 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 May 2024; AzTrials last refreshed its copy on 7 Nov 2026.