Intraperitoneal vs Intravenous Chemotherapy Following Neoadjuvant Chemotherapy in Ovarian Cancer

A Phase II Study of Intraperitoneal (IP) Plus Intravenous (IV) Chemotherapy Versus IV Carboplatin Plus Paclitaxel in Patients With Epithelial Ovarian Cancer Optimally Debulked at Surgery Following Neoadjuvant Intravenous Chemotherapy

RATIONALE: Drugs used in chemotherapy, such as paclitaxel, carboplatin, and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) and giving them in different ways may kill more tumor cells. It is not yet known which combination chemotherapy regimen is more effective in treating patients with ovarian epithelial cancer, primary peritoneal cancer, and fallopian tube cancer.

PURPOSE: This randomized phase II trial is comparing the side effects of three combination chemotherapy regimens and to see how well they work in treating patients with stage IIB, stage IIC, stage III, or stage IV ovarian epithelial cancer, primary peritoneal cancer, or fallopian tube cancer.

Study Overview

• Status: Completed
• Conditions: Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cavity Cancer; Metastatic Cancer
• Intervention / Treatment: Drug: carboplatin; Drug: paclitaxel; Drug: cisplatin

Detailed Description

OBJECTIVES:

Primary

• To compare the efficacy of the selected IP chemotherapy regimen (Arm 3: IV paclitaxel and IP carboplatin plus day 8 IP paclitaxel) versus IV carboplatin plus paclitaxel (Arm 1) in patients with epithelial ovarian cancer optimally debulked at surgery following neoadjuvant intravenous chemotherapy. Nine month progressive rate post randomization is the primary endpoint for assessment of efficacy.

Secondary

• To compare IP plus IV chemotherapy versus IV carboplatin plus paclitaxel with respect to progression free survival and overall survival.

OUTLINE: This is a multicenter study. Patients are stratified according to cooperative group, residual disease (observable [e.g., macroscopic] disease that is evident at end of delayed primary debulking surgery vs no evidence of observable disease at end of delayed primary debulking surgery), reason for delayed primary debulking surgery at initial diagnosis (nonresectable disease vs other reasons), and timing of intraperitoneal catheter insertion (intra-operative catheter insertion vs post-operative insertion).

• Phase II: Patients are randomized to 1 of 3 treatment groups.

  • ARM 1: Paclitaxel 135 mg/m2 intravenous day 1 plus Carboplatin AUC 5 if measured GFR or AUC6 if estimated GFR intravenous day 1; Paclitaxel 60 mg/m2 intravenous day 8. Cycles given Q 21 days x 3 cycles
  • ARM 2: Paclitaxel 135 mg/m2 intravenous day 1 plus Cisplatin 75 mg/m2 intraperitoneal day 1; Paclitaxel 60 mg/m2 intraperitoneal day 8. Cycles given Q 21 days x 3 cycles (Phase II cisplatin arm closed to accrual on 2014-Feb-03)
  • ARM 3: Paclitaxel 135 mg/m2 intravenous day 1 plus Carboplatin AUC 5 if measured GFR or AUC6 if estimated GFR intraperitoneal day 1; Paclitaxel 60 mg/m2 intraperitoneal day 8. Cycles given Q 21 days x 3 cycles.

Patients also receive carboplatin IP on day 1. Treatment repeats every 21 days for 3 courses in the absence of disease progression or unacceptable toxicity.

• Expanded Phase II: Patients are randomized to 1 of 2 treatment groups.

  • Arm I: Patients receive paclitaxel and carboplatin as in phase II, arm I.
  • Arm III: Patients receive paclitaxel and cisplatin as in phase II, arm II or paclitaxel and carboplatin as in phase II, arm III.

Patients complete quality of life questionnaires EORTC QLQ-C30, ovarian cancer module (EORTC QLQ-OV28), and FACT/GOG-Ntx at baseline, on day 1 of courses 2 and 3, at 3, 6 and 12 months after completion of study treatment, and then annually until disease progression, death, or initiation of second-line therapy.

After completion of study treatment, patients are followed at 6 weeks, every 3 months for 2 years, every 6 months for 2 years, and then annually until progression, death, or initiation of second-line therapy.

• Study Type: Interventional
• Enrollment (Actual): 275
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2N 4N2
      • Tom Baker Cancer Centre
    • Edmonton, Alberta, Canada, T6G 1Z2
      • Cross Cancer Institute
  • British Columbia
    • Kelowna, British Columbia, Canada, V1Y 5L3
      • BCCA - Cancer Centre for the Southern Interior
    • Surrey, British Columbia, Canada, V3V 1Z2
      • BCCA - Fraser Valley Cancer Centre
    • Vancouver, British Columbia, Canada, V5Z 4E6
      • BCCA - Vancouver Cancer Centre
  • Manitoba
    • Winnipeg, Manitoba, Canada, R3E 0V9
      • CancerCare Manitoba
  • New Brunswick
    • Saint John, New Brunswick, Canada, E2L 4L2
      • Regional Health Authority B, Zone 2
  • Newfoundland and Labrador
    • St. John's, Newfoundland and Labrador, Canada, A1B 3V6
      • Dr. H. Bliss Murphy Cancer Centre
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 1V7
      • QEII Health Sciences Centre
  • Ontario
    • Kingston, Ontario, Canada, K7L 5P9
      • Cancer Centre of Southeastern Ontario at Kingston
    • London, Ontario, Canada, N6A 4L6
      • London Regional Cancer Program
    • Ottawa, Ontario, Canada, K1H 8L6
      • Ottawa Hospital Research Institute
    • Thunder Bay, Ontario, Canada, P7B 6V4
      • Thunder Bay Regional Health Science Centre
    • Toronto, Ontario, Canada, M5G 2M9
      • Univ. Health Network-Princess Margaret Hospital
  • Quebec
    • Montreal, Quebec, Canada, H2L 4M1
      • CHUM - Hopital Notre-Dame
    • Montreal, Quebec, Canada, H2W 1S6
      • McGill University - Dept. Oncology
    • Montreal, Quebec, Canada, H1T 2M4
      • Hôpital Maisonneuve-Rosemont
    • Quebec City, Quebec, Canada, G1R 2J6
      • CHUQ-Pavillon Hotel-Dieu de Quebec
    • Sherbrooke, Quebec, Canada, J1H 5N4
      • Centre Hospitalier Universitaire de Sherbrooke
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Barcelona, Spain, 08041
    • Hospital de la Santa Creu i Sant Pau
  • Barcelona, Spain, 08036
    • Corporacio Sanitaria Clinic
  • Madrid, Spain, 28009
    • Hospital Gregorio Marañón
  • Madrid, Spain, 28040
    • Hospital Clinico San Carlos
  • Madrid, Spain, 28033
    • Centro Oncologico MD Anderson - Madrid
  • Valencia, Spain, 46009
    • Fundación Instituto Valenciano de Oncología
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
  • Barcelona
    • Hospitalet de Llobregat, Barcelona, Spain, 08908
      • Instituto Catalan de Oncologia - L'Hospitalet
  • Madrid
    • Alcorcon, Madrid, Spain, 28922
      • Hospital Fundación Alcorcón
• United Kingdom
  • Edinburgh, United Kingdom, EH4 2XU
    • The Western General Hospital - Edinburgh
  • Leeds, United Kingdom, LS9 7TF
    • St. James University Hospital - Leeds
  • Liverpool, United Kingdom, L8 755
    • Liverpool Women's Hospital - Liverpool
  • London, United Kingdom, SW3 6JJ
    • The Royal Marsden Hospital - London
  • London, United Kingdom, EC1M 6BQ
    • St. Bartholomew's Hospital - London
  • London, United Kingdom, W12 0HS
    • The Hammersmith Hospital - London
  • London, United Kingdom, W1T 4TJ
    • University College London Hospital - London
  • Manchester, United Kingdom, M13 0JH
    • St Marys Hospital - Manchester
  • Oxford, United Kingdom, OX3 7LJ
    • The Churchill Hospital - Oxford
  • Plymouth, United Kingdom, PL6 8DH
    • The Derriford Hospital - Plymouth
  • Bebington
    • Wirral, Bebington, United Kingdom, CH63 4JY
      • The Clatterbridge Center for Oncology - Liverpool
  • Northwood
    • Middlesex, Northwood, United Kingdom, HA6 2RN
      • Mount Vernon Hospital - Middlesex
  • Tooting
    • London, Tooting, United Kingdom, SW17 0QT
      • St. George's Hospital - London
  • Wexham
    • Slough, Wexham, United Kingdom, SL2 4HL
      • Wexham Park Hospital
  • Withington
    • Manchester, Withington, United Kingdom, M20 4BX
      • The Christie Hospital - Manchester
• United States
  • Missouri
    • Springfield, Missouri, United States, 65804
      • Mercy-Springfield
    • Springfield, Missouri, United States, 65807
      • CoxHealth
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73190-0001
      • University of Oklahoma Health Sciences Center
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women and Infants Hospital of Rhode Island
  • Utah
    • Salt Lake City, Utah, United States, 84132
      • Univ of Utah (Huntsman Cancer Institute)
  • Washington
    • Tacoma, Washington, United States, 98415
      • Northwest CCOP - Multicare Health System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Histologically confirmed ovarian epithelial, primary serous type peritoneal, or fallopian tube carcinoma

  • Patients with ovarian cancer of the clear cell histology are eligible. Histologic confirmation is preferably by biopsy or limited excision prior to neo-adjuvant treatment. If the diagnosis prior to neo-adjuvant chemotherapy is based on cytology, histologic confirmation is required prior to randomization. Histologic confirmation can be obtained at the time of debulking surgery by intra-operative frozen section, thus permitting intra-operative randomization, or by final pathologic review of the resected specimen if randomization is to be performed following debulking surgery.

  • Initial FIGO stage IIB-III disease

    • Stage IV disease allowed provided the only criterion for stage IV disease is the presence of a pleural effusion confirmed to be associated with positive cytology for ovarian cancer
• Completed ≥ 3 but no more than 4 courses of platinum-based neoadjuvant chemotherapy prior to the first debulking surgery

• Meets the following criteria for surgical treatment prior to randomization:

  • Initial Diagnosis: No debulking surgery was attempted or completed.
  • The patient's first cytoreductive (debulking) surgery must be after neoadjuvant chemotherapy (Delayed Primary Debulking). The delayed primary debulking surgery must be completed no more than 4 weeks after commencing administering of the last cycle of neoadjuvant chemotherapy and must be completed no more than 6 weeks prior to randomization.

  • Surgery will include total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy and any additional procedures required to achieve maximal cytoreduction with residual disease of 1 cm or less as assessed by the surgeon at the end of surgery.

    • Delayed primary debulking surgery must be completed no more than 4 weeks after the last course of neoadjuvant chemotherapy and must be completed no more than 6 weeks prior to randomization
  • Surgery will include total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and any additional procedures required to achieve maximal cytoreduction with residual disease of ≤ 1 cm as assessed by the surgeon at the end of surgery
• No borderline ovarian tumors (i.e., tumors of low malignant potential) alone
• No mucinous tumor

PATIENT CHARACTERISTICS:

• ECOG performance status 0-2
• Life expectancy ≥ 12 weeks
• Granulocyte count ≥ 1.5 x 10^9/L
• Platelet count ≥ 100 x 10^9/L
• Serum creatinine ≤ upper limit of normal (ULN) OR > ULN to ≤ 1.25 ULN provided measured creatinine clearance is > 60 mL/min
• Serum bilirubin normal
• AST/ALT ≤ 2.5 times ULN
• Fertile patients must use effective contraception
• Able (i.e., sufficiently fluent) and willing to complete the quality of life questionnaires
• Accessible for treatment and follow-up
• No history of other malignancy, except adequately treated nonmelanoma skin cancer, curatively treated carcinoma in situ of the cervix, or other solid tumors curatively treated with no evidence of disease for ≥ 5 years

• No uncontrolled atrial or ventricular arrhythmias including second or third degree heart block unless managed with implanted pacemaker

  • Patients with a history of first degree heart block are eligible
• No documented myocardial infarction within the past 6 months preceding randomization (pretreatment ECG evidence only of infarct will not exclude patients)
• No diagnosis of bowel obstruction

• No serious illness or medical condition which would not permit the patient to be managed according to protocol including, but not limited to, any of the following:

  • Prior allergic reactions to drugs containing cremophor or to compounds chemically related to cisplatin, paclitaxel, or carboplatin
  • Symptomatic congestive heart failure within the past 6 months or other conditions which would lead to a contraindication of a high-volume saline diuresis
  • History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent
  • Active uncontrolled infection
  • Persistent peripheral neuropathy or hearing loss ≥ grade 2 resulting from prior therapy
  • Extensive intraperitoneal adhesion intra- or post-operatively which would impede intraperitoneal treatment delivery

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No prior therapy for ovarian cancer, except for neoadjuvant platinum-based chemotherapy and surgery
• No concurrent intraperitoneal adhesion barriers
• No other concurrent anticancer treatment, including cytotoxic agents, biological response modifiers, immunotherapy, anticancer hormone therapy, or investigational drug therapy
• No other concurrent experimental drugs or anticancer therapy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: IV carboplatin + IV paclitaxel; ARM 1: Paclitaxel 135 mg/m2 intravenous day 1 plus Carboplatin AUC 5 if measured GFR or AUC6 if estimated GFR intravenous day 1; Paclitaxel 60 mg/m2 intravenous day 8. Cycles given Q 21 days x 3 cycles	Drug: carboplatin; Carboplatin AUC 5 if measured GFR or AUC6 if calculated GFR intravenous or intraperitoneal.; Drug: paclitaxel; Paclitaxel 135 mg/m2 intravenous day 1 plus Paclitaxel 60 mg/m2 intraperitoneal or intravenously day 8. Cycles given Q 21 days x 3 cycles
Active Comparator: IP cisplatin + IV/IP paclitaxel; ARM 2: Paclitaxel 135 mg/m2 intravenous day 1 plus Cisplatin 75 mg/m2 intraperitoneal day 1; Paclitaxel 60 mg/m2 intraperitoneal day 8. Cycles given Q 21 days x 3 cycles (Phase II cisplatin arm closed to accrual on 2014-FEB-03)	Drug: paclitaxel; Paclitaxel 135 mg/m2 intravenous day 1 plus Paclitaxel 60 mg/m2 intraperitoneal or intravenously day 8. Cycles given Q 21 days x 3 cycles; Drug: cisplatin; Cisplatin 75 mg/m2 intraperitoneal day 1
Active Comparator: IP carboplatin + IV/IP paclitaxel; ARM 3: Paclitaxel 135 mg/m2 intravenous day 1 plus Carboplatin AUC 5 if measured GFR or AUC6 if estimated GFR intraperitoneal day 1; Paclitaxel 60 mg/m2 intraperitoneal day 8. Cycles given Q 21 days x 3 cycles	Drug: carboplatin; Carboplatin AUC 5 if measured GFR or AUC6 if calculated GFR intravenous or intraperitoneal.; Drug: paclitaxel; Paclitaxel 135 mg/m2 intravenous day 1 plus Paclitaxel 60 mg/m2 intraperitoneal or intravenously day 8. Cycles given Q 21 days x 3 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
9-month Progression Rate Post-randomization	It is defined as proportion of patients who had progressed at or before 9 months after randomization, i.e., the time from the randomization to the date when the first observation of disease progression (earliest of the date when the first CA 125 meets progression definition and the date of first objective relapse or progression, defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, recorded) has been documented or when death due to any cause has been observed was less than or equal to 9 months.	9 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival	Time from the day of randomization until the time when first observation of disease progression (earliest of the dates of first CA125 which meets progression definition and first objective relapse or progression defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions, has been documented or when death due to any cause has been observed.	During the study with median follow-up of 33 months
Overall Survival	Time from the day of randomization to death from any cause.	During the study with median follow-up of 33 months

Collaborators and Investigators

• Sponsor: Canadian Cancer Trials Group
• Collaborators: National Cancer Institute (NCI); Cancer Research UK; Grupo Español de Investigación en Cáncer de Ovario; SWOG Cancer Research Network
• Investigators: Study Chair: Helen J. Mackay, MD, Princess Margaret Hospital, Canada; Study Chair: Diane M. Provencher, MD, FRCS, FACOG, Hopital Notre-Dame du CHUM

Publications and helpful links

General Publications

• Provencher DM, Gallagher CJ, Parulekar WR, Ledermann JA, Armstrong DK, Brundage M, Gourley C, Romero I, Gonzalez-Martin A, Feeney M, Bessette P, Hall M, Weberpals JI, Hall G, Lau SK, Gauthier P, Fung-Kee-Fung M, Eisenhauer EA, Winch C, Tu D, MacKay HJ. OV21/PETROC: a randomized Gynecologic Cancer Intergroup phase II study of intraperitoneal versus intravenous chemotherapy following neoadjuvant chemotherapy and optimal debulking surgery in epithelial ovarian cancer. Ann Oncol. 2018 Feb 1;29(2):431-438. doi: 10.1093/annonc/mdx754.

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2010
• Primary Completion (Actual): March 10, 2016
• Study Completion (Actual): July 11, 2016

Study Registration Dates

• First Submitted: October 9, 2009
• First Submitted That Met QC Criteria: October 9, 2009
• First Posted (Estimated): October 12, 2009

Study Record Updates

• Last Update Posted (Actual): August 28, 2023
• Last Update Submitted That Met QC Criteria: August 3, 2023
• Last Verified: March 1, 2020

More Information

Terms related to this study

• Keywords: stage III ovarian epithelial cancer; stage IV ovarian epithelial cancer; fallopian tube cancer; ovarian clear cell cystadenocarcinoma; stage II ovarian epithelial cancer; peritoneal cavity cancer; ovarian clear cell tumor with proliferating activity; malignant pleural effusion
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Genital Neoplasms, Female; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Carboplatin; Paclitaxel
• Other Study ID Numbers: OV21; CAN-NCIC-OV21 (Registry Identifier: PDQ (NCI US Physician Data Query)); UCL08/0379 (Other Identifier: NCI); GEICO-0902 (Other Identifier: GEICO); SWOG OV.21 (Other Identifier: South West Oncology Group); CDR0000655241 (Other Identifier: PDQ)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No