Clinical trial NCT02861872: Intra-peritoneal Chemotherapy in Ovarian Cancer
Official title: Predictive Factors and Pharmacokinetics of Intra-peritoneal Chemotherapy
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: Ovarian Neoplasms
Immune Tolerance
Neoplasms
Effects of Chemotherapy
Keywords: Ovarian
Ovarian cancer
Chemotherapy
Intraperitoneal chemotherapy
pharmacokinetics
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
First posted: 2016-08-10
Enrollment: 15
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Women, aged younger than 70 years, who will receive standard IP chemotherapy for advanced epithelial ovarian cancer, who are in an adequate physical and biochemical state to receive chemotherapy.

Brief summary: Ovarian cancer is the third most common gynecological malignancy worldwide. Because of late, aspecific symptoms, the disease is usually diagnosed at an advanced stage. Most patients experience recurrence and die as a result of the disease within 5 years. Treatment is a combination of surgical debulking and systemic administered chemotherapy. Intra-peritoneal (IP) chemotherapy with is currently considered the most effective treatment. In patients with at least an optimal surgical debulking, this leads to an improvement in life expectancy from 50 to 66 months. IP administration of chemotherapeutic agents is still not common practice. Furthermore recent studies revealed that cancer cells express a variety of tumor antigens, which can be targeted by the immune system. Also ovarian cancer shows evidence of a role for the immune system in clinical outcome. Novel insights into the mechanism of action of chemotherapy indicate that the efficacy of chemotherapeutic interventions are dependent on the modulation of the immune system. The impression exists that since IP chemotherapy is used, relatively more recurrences outside the abdominal cavity are observed. As of yet, no studies have described pharmacokinetics and pharmacodynamics of IP administered cisplatin and paclitaxel in the blood circulation. The investigators propose to study the use of this aspiration fluid from the IP cavity as a biomarker for the efficacy of chemotherapy intervention, monitor the effect of chemotherapy on IP tumor cells in the peritoneal cavity and monitor the effect of chemotherapy on immune cells present in the IP cavity. As well the investigators propose to correlate the presence and amount of tumor cells in peritoneal fluid with the debulking efficacy and CA 125 levels. Secondary to this the investigators intend to determine the pharmacokinetics of cisplatin and paclitaxel when administered in the IP cavity in the central circulation (plasma) as well as in the peritoneal fluid. In this observational explorative study women, aged younger than 70 years, who will receive standard IP chemotherapy for advanced epithelial ovarian cancer, who are in an adequate physical and biochemical state to receive chemotherapy are included. Immunological cell counts, tumor marker, immunological cell pathway activation and plasma concentrations of cisplatinum and paclitaxel in venous blood and in fluid aspirated from the abdominal cavity will be measured.


Eligibility criteria: Inclusion Criteria:

Patients receiving IP chemotherapy and therefore meeting the following criteria:

* Primary epithelial ovarian carcinoma FIGO stage III;
* Optimal or complete primary debulking (tumor rests ≤ 1cm;
* WHO 0 - 2;
* Adequate hematological function: WBC ≥ 3. 106/L en Platelets ≥ 100. 106/L,
* Adequate renal function (Creatinine clearance \>60 ml/min (Cockcroft))
* Adequate liver function tests (bilirubin and/or transaminases \<1.25 UNL)

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study (according to the standard IP chemotherapy):

* Intestinal stoma proximal to the flexura lienalis;
* Postoperative sepsis after primary debulking;
* Haemoglobin \< 6.0 mMol/L
* Extended intraperitoneal adhesions;
* Neurotoxicity grade\>1;
* Previous chemotherapy for ovarian carcinoma;
* Symptomatic hearing loss;
* Age \>70 years.

Primary outcomes:
measure: Primary immunological endpoint: study the use of aspiration fluid from the IP cavity as a biomarker for the efficacy of chemotherapy intervention, measured by decrease in tumor cell count in IP fluid.
timeFrame: Change in tumor cell counts between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Primary pharmacokinetic endpoint: study pharmacokinetics of cisplatin (platinum unbound fraction) when administered in the IP cavity in plasma and in the peritoneal fluid.
timeFrame: Change in platinum unbound fraction of cisplatin during the first course (first three weeks) of chemotherapy.
measure: Primary pharmacokinetic endpoint: study pharmacokinetics of paclitaxel (plasma concentrations) when administered in the IP cavity in plasma and in the peritoneal fluid.
timeFrame: Change in plasma concentration of paclitaxel during the first course (first three weeks) of chemotherapy.
Secondary outcomes:
measure: Secondary immunological endpoint: rise in dendritic cells
timeFrame: Change in dendritic cell counts between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Secondary immunological endpoint: rise in tumor infiltrating lymphocytes
timeFrame: Change in lymphocyte cell counts between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Secondary immunological endpoint: rise in natural killer cells
timeFrame: Change in natural killer cell counts between samples 15 min before and after administration of chemotherapy through completion of chemotherpy during 18 weeks
measure: Secondary immunological endpoint: decrease in macrophages M1 type
timeFrame: Change in macrophages M1 type cell counts between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Secondary immunological endpoint: decrease in macrophages M2 type
timeFrame: Change in macrophages M2 type cell counts between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Secondary immunological endpoint: change in cytokine level (IL-6) measured by ELISA
timeFrame: Change in IL-6 cytokine levels between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Secondary immunological endpoint: change in cytokine level (IL-10) measured by ELISA
timeFrame: Change in IL-10 cytokine levels between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Secondary immunological endpoint: change in cytokine level (IFNg) measured by ELISA
timeFrame: Change in IFNg cytokine levels between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Secondary immunological endpoint: change in cytokine level (TNFa) measured by ELISA
timeFrame: Change in TNFa cytokine levels between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Secondary immunological endpoint: change in cytokine level (CCL2) measured by ELISA
timeFrame: Change in CCL2 cytokine levels between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
measure: Primary immunological endpoint: study the use of aspiration fluid from the IP cavity as a biomarker for the efficacy of chemotherapy intervention, measured by decrease in pSTAT in IP fluid.
timeFrame: Change in pSTAT between samples 15 min before and after administration of chemotherapy through completion of chemotherapy during 18 weeks
Other outcomes:
Locations:
city: Nijmegen
country: Netherlands
facility: Radboudumc
Study officials:
affiliation: Internist-oncologist and principal investigator
name: Nelleke Ottevanger, M.D. PhD.
role: STUDY_CHAIR
References:
citation: Armstrong DK, Bundy B, Wenzel L, Huang HQ, Baergen R, Lele S, Copeland LJ, Walker JL, Burger RA; Gynecologic Oncology Group. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006 Jan 5;354(1):34-43. doi: 10.1056/NEJMoa052985.
citation: Tewari D, Java JJ, Salani R, Armstrong DK, Markman M, Herzog T, Monk BJ, Chan JK. Long-term survival advantage and prognostic factors associated with intraperitoneal chemotherapy treatment in advanced ovarian cancer: a gynecologic oncology group study. J Clin Oncol. 2015 May 1;33(13):1460-6. doi: 10.1200/JCO.2014.55.9898. Epub 2015 Mar 23.
citation: Schlappe BA, Mueller JJ, Zivanovic O, Gardner GJ, Long Roche K, Sonoda Y, Chi DS, O'Cearbhaill RE. Cited rationale for variance in the use of primary intraperitoneal chemotherapy following optimal cytoreduction for stage III ovarian carcinoma at a high intraperitoneal chemotherapy utilization center. Gynecol Oncol. 2016 Jul;142(1):13-18. doi: 10.1016/j.ygyno.2016.05.015. Epub 2016 May 21.
citation: Wright JD, Hou JY, Burke WM, Tergas AI, Chen L, Hu JC, Ananth CV, Neugut AI, Hershman DL. Utilization and Toxicity of Alternative Delivery Methods of Adjuvant Chemotherapy for Ovarian Cancer. Obstet Gynecol. 2016 Jun;127(6):985-991. doi: 10.1097/AOG.0000000000001436.