JCOG0602 ver.1.3
Japan Clinical Oncology Group(JCOG)-
Gynecologic Cancer Study Group(GCSG)
Japan Clinical Oncology Group Study JCOG0602
Phase III Study of
Upfront Debulking Surgery versus NeoadjuvantChemotherapy
for Stage III/IV Ovarian, Tubal and PeritonealCancers.
Version 1.3
Short title: OV-NACTC-P3
Group Representative: Nobuo Yaegashi(Tohoku University)
Principal Investigator: Hiroyuki Yoshikawa(University of Tsukuba)
Study coordinator: Takashi Onda (Kitasato University School of Medicine)
Protocol concept was accepted by the JCOG Executive Committee
on February 26, 2005
Protocol was accepted by the JCOG Protocol Review Committee
on October 18, 2006
Revision 1 was accepted by the JCOG Data and Safety Monitoring Committee
on January 8, 2010(Version 1.1)
Revision 2was accepted by the JCOG Data and Safety Monitoring Committee
on November 14, 2011(Version 1.2)
Revision 3 was accepted by the JCOG Data and Safety Monitoring Committee
on May7, 2014 (Version 1.3)
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0.Outline
0.1.Schema
0.2.Objectives of the study
The purposes are to prove the efficacyof treatment starting with 4 cycles of NAC with paclitaxel plus carboplatin(TC) followed by IDS and additional 4 cycles of chemotherapywith TC compared with standard treatment starting with PDS followed by 8 cycles of chemotherapy with TC for stage III/IV ovarian, tubal or peritoneal carcinomas.
Primary endpoint：Overall survival (OS)
Secondary endpoints：
1)Proportion of clinical complete remission (%cCR) among all eligible patients
2)Progression-free survival among all eligible patients
3)Response rate to NAC among patients assigned to the NAC arm.
4)Adverse events
5)Surgical invasiveness of the treatment(number of times of surgery, total duration of the surgery, total amount of blood loss, amount of blood transfusion during protocol treatment, amount of blood plasma, plasma expander and albumin infusion during protocol treatment, among all treated patients)
6)Positive predictive value of clinical stage and detection rate of tumors in several parts of abdomen or lymph nodes by imaging study among patients assigned to PDS arm.
0.3.Patients selection criteria
The study subjects should fulfill all following criteria:
1)Patients diagnosed with stage III or IV ovarian, tubal or peritoneal carcinoma.The diagnosis isbased onboth imaging studies (CT or MRI, and chest radiography) and cytology/histology of ascites, pleural effusion, or fluid/tissue obtained by tumor centesis.
a)Malignancies of other origins, such as breast and digestive tract, should be excluded by endoscopy, opaque enema, or ultrasonography when these malignancies are suspected from symptoms, physical examination or imaging diagnosis.
b)Among the epithelial stromal tumor of ovarian cancer, carcinosarcoma, stromal sarcoma and adenosarcoma are excluded from subjects of the study.
c)Patients with stage III disease only with retroperitoneal lymphnode metastases are allowed to be subjects of the study when the lymphnodes are no less than 2cm in diameter by imaging study.
2)To rule out malignancies of digestive tract origin, the criteria for tumor markers are set to be CA125>200U/ml and CEA<20ng/ml.
3)Clinically deemed to be a candidate for debulking surgery without evidence of brain, bone or bone marrow metastases
4)Previously untreated for these malignancies and have no history of treatment with chemotherapy or radiotherapy for other diseases
5)Age 20 to 75 years
6)Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3
7)Adequate bone marrow, hepatic, renal, cardiac and respiratory functionsby the newest evaluations within 14days before enrollment except for electrocardiographic findings
a)ANC(absolute neutrophil count)≥1.5 x 109/L
b)Platelet ≥100 x 109/L
c)AST(aspartate aminotransferase)≤ 100 IU/L
d)ALT(alanine aminotransferase)≤ 100 IU/L
e)Serum total bilirubin≤1.5mg/dL
f)Serum creatinine≤1.5mg/dL
g)No abnormal electrocardiographic findings which require treatment within 28days before enrollment
h)PaO2(partial pressure of oxygen in arterial blood) ≥70 mmHg in room air (allowed to measure after drainage of pleural effusion)
8)With written informed consent
0.4.Treatment methods
I.ArmA: Upfront surgery arm
Upfrontprimary debulking surgery (PDS) followed by 8 cycles of combination chemotherapy consisted of Carboplatin (CBDCA) and Paclitaxel (PTX) (TC regimen).
II.Arm B: Neoadjuvant chemotherapy arm
Neoadjuvant chemotherapy with 4cycles of combination chemotherapy consisted of CBDCA and PTX followed by interval debulking surgery (IDS) and additional 4 cycles of same combination chemotherapy.
In both treatment arms, a combination of paclitaxel and carboplatin, namely the TC regimen, are started with following doses and administered every 3 weeks, 8 cycles in total.
Drug / Dosage / Rout / DatePTX / 175 mg/m2 / div / day 1
CBDCA / AUC 6 / div / day 1
0.5.Planned accrual number and study period
・Planned accrual number: 300 patients
Accrual time: 4.5 years*, Follow-up time: 5 years after last accrual, Total study period: 9.5 years*
*Accrual time and total study period were extended by 1.5 years at revision 1.
・Protocol revision is not necessary to extend accrual time not exceed 6 months.
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0.Outline
0.1.Schema
0.2.Objectives of the study
0.3.Patients selection criteria
0.4.Treatment methods
0.5.Planned accrual number and study period
1.Objectives of the study
2.Background and basis for protocol design (omitted)
3.Criteria and definitions used in this study
3.1.Clinical staging
3.2.Classification of epithelial stromal tumor of ovarian cancer
3.3.Definition for surgical debulking
3.4.Calvert formula
3.5.Cockcroft-Gault formula
4.Patients selection criteria
4.1.Eligibility criteria
4.2.Exclusion criteria
5.Registration and assignment (omitted)
6.Protocol treatment and criteria for treatment modification
6.1.Protocol treatment
6.2.Criteria for discontinuation or completion of protocol treatment
6.3.Criteria for modification of protocol treatment
6.4.Simultaneous or supportive therapy
6.5.Post- protocol treatment
7.Drug information and expected adverse reactions (omitted)
8.Evaluation item, Clinical laboratory test and Evaluation schedule
8.1.Evaluation item before enrollment
8.2.Tests and evaluations during protocol treatment
8.3.Test and evaluation after protocol treatment
8.4.Added data by the 2ndprotocol revision
8.5.Study calendar (arm A, i.e. upfront surgery arm)
8.6.Study calendar (arm B, i.e. neoadjuvant chemotherapy arm)
9.Collection of the data(omitted)
10.Report of adverse events(omitted)
11.Response evaluation and endpoint definition (RECISTv1.0)
11.1.Response evaluation
11.2.Definition of analysis subjects
11.3.Endpoint definition
12.Statistical consideration
12.1.Primary analysis and decision criteria
12.2.Planned sample size, accrual period and follow-up period
12.3.Interim analysis and early termination of the trial
12.4.Analyses for the secondary endpoints
12.5.Final analysis
13.Ethical matter (omitted)
14.Monitoring and audit (omitted)
15.Special notes (omitted)
16.Research organization (omitted)
17.Publication of the study results (omitted)
18.Reference
19.Appendix(omitted)
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1.Objectives of the study
The purposes are to prove the efficacyof treatment starting with 4 cycles of NAC with paclitaxel plus carboplatin(TC) followed by IDS and additional 4 cycles of chemotherapy with TC compared with standard treatment starting with PDS followed by 8 cycles of chemotherapy with TC for stage III/IV ovarian, tubal or peritoneal carcinomas.
Primary endpoint：Overall survival (OS)
Secondary endpoints：
1)Proportion of clinical complete remission (%cCR) among all eligible patients
2)Progression-free survival among all eligible patients
3)Response rate to NAC among patients assigned to the NAC arm.
4)Adverse events
5)Surgical invasiveness of the treatment(number of times of surgery, total duration of the surgery, total amount of blood loss, amount of blood transfusion during protocol treatment, amount of blood plasma, plasma expander and albumin infusion during protocol treatment, among all treated patients)
6)Positive predictive value of clinical stage and detection rate of tumors in several parts of abdomen or lymph nodes by imaging study among patients assigned to PDS arm.
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2.Background and basis for protocol design (omitted)
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3.Criteria and definitionsused in this study
3.1.Clinical staging
Staging before enrollment should be performed according to the staging classification of 1992 version of JSOG (Japan Society of Obstetrics and Gynecology), 1988 version of Federation of Gynecology and Obstetrics (FIGO) and 2002version of American Joint Committee on Cancer (AJCC).Although staging of ovarian cancer is originally surgical staging, following classification will be applied taking account of clinical information such as imaging study, physical examination, and cytological diagnosis.Stage should be classified as lower category when it wavers in judgement.
3.1.1.Ovarian cancer
Stage ITumor limited to the ovaries.
Stage IITumor involving one or both ovaries with pelvic extension.
Stage IIITumor involving one or both ovaries with intraperitoneal metastases outside the pelvis and/or positive retroperitoneal lymph nodes.
IIIaMicroscopic disease in the upper abdomen.
IIIbMetastases smaller than 2 cm in the upper abdomen.
IIIcMetastases larger than 2 cm in the upper abdomen.
Stage IVTumor involving one or both ovaries with distant metastases outside the upper abdomen or intrahepatic metastases.
3.1.2.Tubal cancer
Staging of tubal cancer should be performed according to the classification of 1991 version of FIGO.The definitions of stage III/IV disease are same as above described definition for ovarian cancer.
3.1.3.Peritoneal cancer
Staging of stage III/IV peritoneal cancer is performed according to the classification for ovarian cancer, thereforedefinition of extra-pelvic metastases and distant metastases in each stage are same as those for ovarian cancer.
3.2.Classification of epithelial stromal tumor of ovarian cancer
Histological classification of 1990 version of Japan Society of Obstetrics and Gynecology and The Japanese Society of Pathology is applied for the histological classification of ovarian cancer.Subjects of this study are following tumors other than underlinedtumors.
1)Serous tumors
- Adenocarcinoma
- Surface papillary adenocarcinoma
- Adenocarcinofibroma
2)Mucinous tumors、endocervical、intestinal and mixed types
- Adenocarcinoma
- Adenocarcinofibroma
3)Endometrioid tumors
- Adenocarcinoma
- Adenocarcinofibroma
- Adenosarcoma
- Mesodermal mixed tumor、Carcinosarcoma
- Stromal sarcoma
4)Clear cell tumors
- Adenocarcinoma
- Adenocarcinofibroma
5)Brenner tumors
6)Transitional cell carcinoma
7)Mixed epithelial tumors
8)Undifferentiated carcinoma
9)Unclassified
For the histological classification of tubal cancer or peritoneal cancer, above histological classification for ovarian cancer is also applied.
3.3.Definition for surgical debulking
Optimal surgery in PDS (primary debulking surgery) and IDS (interval debulking surgery): Regardless of removed tumor volume or range of surgery, debulking surgery leaving residual tumors less than 1cm in diameter of maximum residual tumor at the completion of debulking surgery is classified as optimal surgery and no less than 1cm classified as suboptimal surgery.
3.4.Calvertformula
Dose of Carboplatin (CBDCA) should be calculated using following Calvert formula
Dose (mg) = Planned AUC (mg/ml･min) x (GFR(ml/min) + 25)
3.5.Cockcroft-Gault formula
Creatinine clearance should be calculated using following Cockcroft-Gault formula
Ccr(ml/min) =0.85 x / (140-Age) x Body Weight(Kg)72 x Serum Cr(mg/dl)
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4.Patients selection criteria
4.1.Eligibility criteria
The study subjects should fulfill all following criteria:
1)Patients diagnosed with stage III or IV ovarian, tubal or peritoneal carcinoma.The diagnosis isbased onboth imaging studies (CT or MRI, and chest radiography) and cytology/histology of ascites, pleural effusion, or fluid/tissue obtained by tumor centesis.
a)Malignancies of other origins, such as breast and digestive tract, should be excluded by endoscopy, opaque enema, or ultrasonography when these malignancies are suspected from symptoms, physical examination or imaging diagnosis.
b)Among the epithelial stromal tumor of ovarian cancer, carcinosarcoma, stromal sarcoma and adenosarcoma are excluded from subjects of the study.
c)Patients with stage III disease only with retroperitoneal lymphnode metastases are allowed to be subjects of the study when the lymphnodes are no less than 2cm in diameter by imaging study.
2)To rule out malignancies of digestive tract origin, the criteria for tumor markers are set to be CA125>200U/ml and CEA<20ng/ml.
3)Clinically deemed to be a candidate for debulking surgery without evidence of brain, bone or bone marrow metastases
4)Previously untreated for these malignancies and have no history of treatment with chemotherapy or radiotherapy for other diseases
5)Age 20 to 75 years
6)Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 3
7)Adequate bone marrow, hepatic, renal, cardiac and respiratory functionsby the newest evaluations within 14days before enrollment except for electrocardiographic findings
a)ANC(absolute neutrophil count: stab and segmented cells)≥1.5 x 109/L
b)Platelet ≥100 x 109/L
c)AST(aspartate aminotransferase)≤ 100 IU/L
d)ALT(alanine aminotransferase)≤ 100 IU/L
e)Serum total bilirubin≤1.5mg/dL
f)Serum creatinine ≤1.5mg/dL
g)No abnormal electrocardiographic findings which require treatment within 28days before enrollment
h)PaO2 (partial pressure of oxygen in arterial blood) ≥ 70 mmHg in room air (allowed to measure after drainage of pleural effusion)
8)With written informed consent
4.2.Exclusion criteria
The study subjects should not have any of the following conditions:
1)Synchronous or metachronous (within 5 years) malignancy other than carcinoma in situ
2)Pregnant or nursing
3)Severe mental disorder
4)Systemic and continuous use of steroidal drugs
5)Positive for serum hepatitis B surface antigen
6)Active infections
7)Uncontrolled hypertension
8)Diabetes mellitus, uncontrolled or controlled with insulin
9)History of cardiac failure, unstable angina, myocardial infarction within 6 months prior to registration
10)Intestinal occlusion requiring surgical treatment
11)Hypersensitivity to polyoxyethylated castor oil
12)Hypersensitivity to alcohol.
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5.Registration and assignment(omitted)
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6.Protocol treatment and criteria for treatment modification
Treatment and modification of treatment should be performed according to the description of this section, as far as safety of the patients is not threatened.
Treatment should be modified according to the judgment by physicians in charge when it is medically danger to follow the protocol.Though, in that case the modification may be “protocol deviation”, it should be considered as “clinically appropriate protocol deviation” when it is judged as medically appropriate (refer section “14.1.3. “).It should not be considered as “clinically appropriate protocol deviation” when the deviation is performed with the intension of improving the efficacy.
6.1.Protocol treatment
6.1.1.Treatment plan
Treatment for arm A and Bareset to upfront surgery arm and neoadjuvant chemotherapy arm, respectively.Thoughpatients should be hospitalized for each chemotherapy cycle as a rule, chemotherapy in outpatients’ clinic is allowed in both treatment arms.
“6.3.1. Criteria for starting a cycle of chemotherapy” is not applied for a first cycle of chemotherapy in arm B.
I.Arm A (Upfront surgery arm)
Patients are treated with PDS followed by 4cycles of post-operative chemotherapy, IDS if eligible (refer “6.1.3.II.) and additional 4 cycles of post-operative chemotherapy.
1)PDS should be performed within 28 days after enrollment.Reasons should be recorded in the “Case report form for courses of treatment” when PDS is postponed until29th day or later after enrollment.“Case report form for end of treatment” should be recorded as discontinuation of protocol treatment when PDS cannot be performed.To start protocol treatment or not is depend on the judge of physicians in charge when clinical laboratory data and so on become worse not to satisfy eligibility criteria after enrollment.
2)Post-operative (PDS) chemotherapy should be started within 21 days after PDS when only uterus, adnexa, omentum and peritoneum are removed during PDS.Chemotherapy should be started within 35 days after PDS when any other organs are removed during PDS.Before the initiation of chemotherapy, it should be confirmed that criteria for starting a cycle of chemotherapy is fulfilled.
3)IDS should be performed from 28thday to 49th day after 4th cycle of post-operative chemotherapy when eligibility criteria for IDS are fulfilled during 21st day to 49th day.Even if PDS resulted in suboptimal surgery, the 5th cycle of post-operative chemotherapy can be started from 21st day or later after 4th cycle of chemotherapy when physicians in charge decide it is not necessary to perform IDS.
4)Post-operative (IDS) chemotherapy should be started within 21 days after IDS when only uterus, adnexa, omentum and peritoneum are removed during IDS.Chemotherapy should be started within 35 days after IDS when any other organs are removed during IDS.In either case, number of chemotherapy is 4 cycles after IDS and 8 cycles in total.Before the initiation of chemotherapy, it should be confirmed that criteria for starting a cycle of chemotherapy is fulfilled.
II.Arm B (Neoadjuvant chemotherapy arm)
Patients are treated with 4 cycles of neoadjuvant chemotherapy, followed by IDS and 4cycles of post-operative chemotherapy.
1)NAC should be started within 14 days after enrollment.Reasons should be recorded in the “Case report form for courses of treatment” when NAC is postponed until 15th day or later after enrollment.“Case report form for end of treatment” should be recorded as discontinuation of protocol treatment when NAC cannot be started.To start protocol treatment or not is depend on the judge of physicians in charge when laboratory data and so on become worse not to satisfy eligibility criteria after enrollment.
2)IDS should be performed from 28th day to 49th day after 4th cycle of NAC when eligibility criteria for IDS are fulfilled during 21st day to 49th day.
3)Post-operative (IDS) chemotherapy should be started within 21 days after IDS when only uterus, adnexa, omentum and peritoneum are removed during IDS.Chemotherapy should be started within 35 days after IDS when any other organs are removed during IDS.In either case, number of chemotherapy is 4 cycles after IDS and 8 cycles in total.Before the initiation of chemotherapy, it should be confirmed that criteria for starting a cycle of chemotherapy is fulfilled.
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6.1.2.Chemotherapy
TC regimen will be administered 8cycles intotal every 3 weeks in both A and B arms.It should be confirmed that criteria for starting a cycle of chemotherapy is fulfilled except for first cycle in arm B.Paclitaxel is intravenously administered in 3 hours followed by intravenous administration of Carboplatin.
Drug / Dose / Rout / DatePaclitaxel / 175 mg/m2 / div(3 hr) / day 1
Carboplatin / AUC 6 / div(1 hr) / day 1
I.Paclitaxel(PTX)
1)Body surface area to calculate dose of PTX is based on body weight (BW) at entry for 1st to 4th cycles of chemotherapy or BW before 5th cycle of chemotherapy for 5th to 8th cycles of chemotherapy.Dose is determined by discarding fractions less than 5mg. (c.f. 124mg is rounded off to 120mg.)
2)Dose modification due to a change of BW should not be performed at startingany other cycles of chemotherapy.
3)It is recommended to administerdexamethasone, diphenhydramine and ranitidine as premedication before administration of `PTX to protect anaphylactic reactions.
4)Dexamethasone is administered once at 30 min before administration of PTX for practical convenience.