Clinical trial NCT00993655: Intraperitoneal vs Intravenous Chemotherapy Following Neoadjuvant Chemotherapy in Ovarian Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fallopian Tube Cancer
Metastatic Cancer
Ovarian Cancer
Peritoneal Cavity Cancer
Keywords: peritoneal cavity cancer
fallopian tube cancer
stage II ovarian epithelial cancer
stage III ovarian epithelial cancer
stage IV ovarian epithelial cancer
malignant pleural effusion
ovarian clear cell cystadenocarcinoma
ovarian clear cell tumor with proliferating activity
Lead sponsor: Canadian Cancer Trials Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
name: Grupo Español de Investigación en Cáncer de Ovario
name: Cancer Research UK
name: SWOG Cancer Research Network
First posted: 2009-10-12
Enrollment: 275
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

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.

Eligibility criteria: 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

Primary outcomes:
measure: 9-month Progression Rate Post-randomization
timeFrame: 9 months
Secondary outcomes:
measure: Progression Free Survival
timeFrame: During the study with median follow-up of 33 months
measure: Overall Survival
timeFrame: During the study with median follow-up of 33 months
Other outcomes:
Locations:
city: Springfield
country: United States
facility: Mercy-Springfield
state: Missouri
city: Springfield
country: United States
facility: CoxHealth
state: Missouri
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Providence
country: United States
facility: Women and Infants Hospital of Rhode Island
state: Rhode Island
city: Salt Lake City
country: United States
facility: Univ of Utah (Huntsman Cancer Institute)
state: Utah
city: Tacoma
country: United States
facility: Northwest CCOP - Multicare Health System
state: Washington
city: Calgary
country: Canada
facility: Tom Baker Cancer Centre
state: Alberta
city: Edmonton
country: Canada
facility: Cross Cancer Institute
state: Alberta
city: Kelowna
country: Canada
facility: BCCA - Cancer Centre for the Southern Interior
state: British Columbia
city: Surrey
country: Canada
facility: BCCA - Fraser Valley Cancer Centre
state: British Columbia
city: Vancouver
country: Canada
facility: BCCA - Vancouver Cancer Centre
state: British Columbia
city: Winnipeg
country: Canada
facility: CancerCare Manitoba
state: Manitoba
city: Saint John
country: Canada
facility: Regional Health Authority B, Zone 2
state: New Brunswick
city: St. John's
country: Canada
facility: Dr. H. Bliss Murphy Cancer Centre
state: Newfoundland and Labrador
city: Halifax
country: Canada
facility: QEII Health Sciences Centre
state: Nova Scotia
city: Kingston
country: Canada
facility: Cancer Centre of Southeastern Ontario at Kingston
state: Ontario
city: London
country: Canada
facility: London Regional Cancer Program
state: Ontario
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Thunder Bay
country: Canada
facility: Thunder Bay Regional Health Science Centre
state: Ontario
city: Toronto
country: Canada
facility: Univ. Health Network-Princess Margaret Hospital
state: Ontario
city: Montreal
country: Canada
facility: Hopital Maisonneuve-Rosemont
state: Quebec
city: Montreal
country: Canada
facility: CHUM - Hopital Notre-Dame
state: Quebec
city: Montreal
country: Canada
facility: McGill University - Dept. Oncology
state: Quebec
city: Quebec City
country: Canada
facility: CHUQ-Pavillon Hotel-Dieu de Quebec
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre hospitalier universitaire de Sherbrooke
state: Quebec
city: Hospitalet de Llobregat
country: Spain
facility: Instituto Catalan de Oncologia - L'Hospitalet
state: Barcelona
city: Alcorcon
country: Spain
facility: Hospital Fundacion Alcorcon
state: Madrid
city: Barcelona
country: Spain
facility: Hospital Vall d'Hebron
city: Barcelona
country: Spain
facility: Corporacio Sanitaria Clinic
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Gregorio Maranon
city: Madrid
country: Spain
facility: Centro Oncologico MD Anderson - Madrid
city: Madrid
country: Spain
facility: Hospital Clinico San Carlos
city: Valencia
country: Spain
facility: Fundacion Instituto Valenciano de Oncologia
city: Valencia
country: Spain
facility: Hospital Clinico Universitario de Valencia
city: Wirral
country: United Kingdom
facility: The Clatterbridge Center for Oncology - Liverpool
state: Bebington
city: Middlesex
country: United Kingdom
facility: Mount Vernon Hospital - Middlesex
state: Northwood
city: London
country: United Kingdom
facility: St. George's Hospital - London
state: Tooting
city: Slough
country: United Kingdom
facility: Wexham Park Hospital
state: Wexham
city: Manchester
country: United Kingdom
facility: The Christie Hospital - Manchester
state: Withington
city: Edinburgh
country: United Kingdom
facility: The Western General Hospital - Edinburgh
city: Leeds
country: United Kingdom
facility: St. James University Hospital - Leeds
city: Liverpool
country: United Kingdom
facility: Liverpool Women's Hospital - Liverpool
city: London
country: United Kingdom
facility: St. Bartholomew's Hospital - London
city: London
country: United Kingdom
facility: The Royal Marsden Hospital - London
city: London
country: United Kingdom
facility: The Hammersmith Hospital - London
city: London
country: United Kingdom
facility: University College London Hospital - London
city: Manchester
country: United Kingdom
facility: St Marys Hospital - Manchester
city: Oxford
country: United Kingdom
facility: The Churchill Hospital - Oxford
city: Plymouth
country: United Kingdom
facility: The Derriford Hospital - Plymouth
Study officials:
affiliation: Princess Margaret Hospital, Canada
name: Helen J. Mackay, MD
role: STUDY_CHAIR
affiliation: Hopital Notre-Dame du CHUM
name: Diane M. Provencher, MD, FRCS, FACOG
role: STUDY_CHAIR
References:
citation: 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.