Neoplasms

All Conditions

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Rare Diseases

Carcinoma

Adenocarcinoma

Recurrence

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Adenocarcinoma, Clear Cell

Adenomyoepithelioma

Fallopian Tube Neoplasms

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Fallopian Tube Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Renal Cell Carcinoma

Clear Cell Renal Cell Carcinoma

Fallopian Tube Cancer

Epithelial-myoepithelial Carcinoma

Antineoplastic Agents

All Drugs and Chemicals

Nivolumab

Ipilimumab

Antineoplastic Agents, Immunological

Immune Checkpoint Inhibitors

Nivolumab 240 mg every 2 weeks Ipilimumab 1mg/kg day 1 Cycle=6 weeks

Don Dizon, MD

Preclinical and early-phase clinical data suggest that immune modulation represents a treatment strategy that is worthy of further investigation in relapsed epithelial ovarian cancer. One method by which tumor cells may evade immune surveillance is by activation of the programmed cell death (PD-1) pathway, mediated by expression of PD-1 on the surface of T lymphocytes, which conveys an inhibitory signal after binding to its ligand PD-L1 on the surface of tumor cells. Nivolumab and Ipilimumab have shown activity as monotherapies in solid tumors and very early data suggest that nivolumab may be particularly active for ovarian clear cell carcinoma.(Hamanishi et al., 2015). Given the uniformly poor prognosis for patients with clear cell carcinoma in general, we are interested in formally evaluating this agent in all extra-renal clear cell carcinomas.

BrUOG 354 Nivolumab +/- Ipilimumab for Ovarian and Extra-renal Clear Cell Carcinomas

BrUOG 354: A Phase II Randomized Trial of Nivolumab +/- Ipilimumab for Ovarian and Extra-renal Clear Cell Carcinomas

RECIST 1.1 and immune mediated RECIST. Confirmatory scans are required. Patients may remain on study post initial progression, but are required to be removed from treatment if they progress an additional 10%.

Bristol-Myers Squibb

Rhode Island Hospital

The Miriam Hospital

Women and Infants Hospital of Rhode Island

Brown University

Immune System Diseases

Skin and Connective Tissue Diseases

Carcinoma, Transitional Cell

Neoplasm Metastasis

Hypersensitivity

Cystadenocarcinoma, Serous

Adenocarcinoma, Mucinous

Cystadenocarcinoma

Brenner Tumor

Carcinoma, Endometrioid

Disease Attributes

Ovarian Diseases

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Cystic, Mucinous, and Serous

Endometrial Neoplasms

Uterine Neoplasms

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Transitional Cell Carcinoma

Adenocarcinoma of the Appendix

Brenner Tumor of Ovary

Gemcitabine

Paclitaxel

Docetaxel

Albumin-Bound Paclitaxel

Bevacizumab

Carboplatin

Antibodies

Antibodies, Monoclonal

Immunoglobulins

Immunoglobulin G

Endothelial Growth Factors

Mitogens

Immunoglobulins, Intravenous

Tubulin Modulators

Antimitotic Agents

Angiogenesis Inhibitors

Growth Inhibitors

Immunologic Factors

Antimetabolites

Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days.

Patients receive chemotherapy as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days.

Patients receive gemcitabine hydrochloride IV over 60 minutes on days 1 and 8 and carboplatin as in Arm I.

Patients receive gemcitabine hydrochloride IV as in Arm III, bevacizumab IV and carboplatin IV as in Arm II.

Gemcitabine Hydrochloride

Laboratory Biomarker Analysis

Quality-of-Life Assessment

Robert L Coleman

This randomized phase III trial studies carboplatin, paclitaxel and gemcitabine hydrochloride when given together with or without bevacizumab after surgery to see how well it works in treating patients with ovarian, epithelial, primary peritoneal, or fallopian tube cancer that has come back. Drugs used in chemotherapy, such as carboplatin, paclitaxel and gemcitabine hydrochloride work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as bevacizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. It is not yet known whether combination chemotherapy is more effective when given with or without bevacizumab after surgery in treating patients with ovarian, epithelial, primary peritoneal, or fallopian tube cancer.

PRIMARY OBJECTIVES:

I. To determine if surgical secondary cytoreduction in addition to adjuvant chemotherapy increases the duration of overall survival in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer.

II. To determine if the addition of bevacizumab to the second-line and maintenance phases of treatment increases the duration of overall survival relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer.

SECONDARY OBJECTIVES:

I. To determine if the addition of bevacizumab to the second-line and maintenance phase of treatment increases the duration of progression-free survival relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer.

II. To prospectively determine the incidence of carboplatin and paclitaxel hypersensitivity in these patients undergoing retreatment with both agents as first recurrence therapy.

III. To determine if surgical secondary cytoreduction in addition to adjuvant chemotherapy increases quality of life (QOL) in patients with recurrent platinum-sensitive epithelial ovarian cancer, peritoneal primary or fallopian tube cancer, as measured by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) trial outcome index and Rand Short Form (SF)-36 physical functioning scale.

IV. To determine if the addition of bevacizumab to the second-line and maintenance phases of treatment increases QOL relative to second-line paclitaxel and carboplatin alone in patients with recurrent platinum-sensitive epithelial ovarian, peritoneal primary or fallopian tube cancer.

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To define molecular and biochemical profiles associated with the duration of progression-free survival in platinum-sensitive recurrent ovarian, peritoneal primary or fallopian tube carcinoma treated with combination chemotherapy with or without bevacizumab followed with or without maintenance bevacizumab therapy in the presence or absence of secondary surgical cytoreduction.

II. To identify molecular determinants that predict sensitivity or resistance to carboplatin and paclitaxel with or without bevacizumab followed with or without maintenance bevacizumab therapy.

III. To bank deoxyribonucleic acid (DNA) from whole blood for research and evaluate the association between single nucleotide polymorphisms (SNPs) and measures of clinical outcome including overall survival, progression-free survival and adverse events.

OUTLINE: Patients are assigned to 1 of 4 treatment groups. Patients who are not candidates for surgical cytoreduction (i.e., those for whom complete cytoreduction in the estimation of the investigator is impossible or a medical infirmity precludes exploration and debulking) are eligible to receive chemotherapy after randomization.

Patients who are eligible for surgery undergo abdominal exploration with cytoreduction. Patients are then randomized to 1 of 4 treatment arms.

ARM I: Patients receive paclitaxel intravenously (IV) over 3 hours or docetaxel IV over 1 hour and carboplatin IV over 60 minutes on day 1.

ARM II: Patients receive chemotherapy as in Arm I and bevacizumab IV over 30-90 minutes on day 1.

ARM III: Patients receive gemcitabine hydrochloride IV over 60 minutes on days 1 and 8 and carboplatin as in Arm I.

ARM IV: Patients receive gemcitabine hydrochloride IV as in Arm III, bevacizumab IV and carboplatin IV as in Arm II.

In all arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Patients with measurable disease achieving a clinical response (CR) receive 6-8 courses of therapy. Patients with stable disease or partial regression receive a maximum of 8 courses.

Patients without measurable lesions as determined by a computed tomography (CT) scan prior to initiating study treatment continue therapy for 6 courses or, if cancer antigen (CA)-125 normalizes, for 2 courses beyond CA-125 normalization, whichever is greater. Patients in Arm II then receive a maintenance regimen comprising bevacizumab IV over 30-90 minutes. Treatment with bevacizumab alone repeats every 3 weeks in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then yearly for 5 years.

Carboplatin, Paclitaxel and Gemcitabine Hydrochloride With or Without Bevacizumab After Surgery in Treating Patients With Recurrent Ovarian, Epithelial, Primary Peritoneal, or Fallopian Tube Cancer

A Phase III Randomized Controlled Clinical Trial of Carboplatin and Paclitaxel (or Gemcitabine) Alone or in Combination With Bevacizumab (NSC #704865) Followed by Bevacizumab and Secondary Cytoreductive Surgery in Platinum-Sensitive, Recurrent Ovarian, Peritoneal Primary and Fallopian Tube Cancer. NCI-Supplied Agents: Bevacizumab (NSC #704865)

The treatment regimens will be compared with a logrank procedure which includes all of the patients categorized by their randomly assigned treatment. The logrank test will be stratified by the secondary surgical debulking status (randomized to undergo cytoreduction, vs randomized to not undergo secondary cytoreduction vs not a candidate or did not consent to secondary surgical cytoreduction) and the duration of treatment free-interval prior to enrolling onto this study (6-12 months vs \> 12 months). The median duration of follow-up is calculated by the reverse Kaplan-Meier method.

Progression-free survival was defined as the time from randomization to cancer progression as shown on radiography, according to the RECIST version 1.0 criteria, an increase in the CA125 level according to Gynecologic Cancer InterGroup (GCIG) criteria, global deterioration of health, or death from any cause.

Number of treated patients with at least one adverse event reported (assessed by Common Terminology Criteria for Adverse Events (version 4.0))

Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). Each item in the FACT-O TOI was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). The FACT-O TOI score ranges 0-100 with a large score suggests better QOL.

Patient reported physical functioning was measured with physical functioning subscale of the RAND SF-36. The Physical Functioning Subscale consists of 10 items concerning activities of daily living: walking, climbing stairs, bathing, dressing, and performance of physical activities. Each item is rated on a three-point scale of limitation of activity due to the patients' health from 1=limited a lot to 3=not limited. The total PF score is the summation of item scores and then rescaled to 0-100. A larger score suggests better physical functioning.

Patient reported physical functioning was measured with physical functioning subscale of the RAND SF-36. The Physical Functioning subscale consists of 10 items concerning activities of daily living: walking, climbing stairs, bathing, dressing, and performance of physical activities. Each item is rated on a three-point scale of limitation of activity due to the patients' health from 1=limited a lot to 3=not limited. The total PF score is the summation of item scores and then rescaled to 0-100. A larger score suggests better physical functioning. This measure was completed by US patients only.

NRG Oncology

National Cancer Institute (NCI)

Eligible and treated participants were affected if they experienced grade 1 - 5 adverse event. Adverse events were not collected in a manner that allow them to be attributed to an intervention (i.e. surgery or chemotherapy).

Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. Patients are not in secondary cytoreductive surgery portion of study.

Arm I (no Surgery; Carboplatin and Paclitaxel)

Patients receive chemotherapy as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days. Patients are not in secondary cytoreductive surgery portion of study.

Arm II (no Surgery; Carboplatin, Paclitaxel and Bevacizumab)

Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery.

Arm III (Surgery; Carboplatin and Paclitaxel)

Arm IV (Surgery; Carboplatin, Paclitaxel and Bevacizumab)

Patients receive carboplatin as in arm I. Patients receive gemcitabine. Treatment repeats every 21 days. Patients do not receive secondary cytoreductive surgery.

Arm V (no Surgery; Carboplatin and Gemcitabine)

Patients receive carboplatin as in arm I and bevacizumab IV over 30-90 minutes on day 1. Patients receive gemcitabine. Treatment repeats every 21 days. Patients do not receive secondary cytoreductive surgery.

Arm VI (no Surgery; Carboplatin, Gemcitabine and Bevacizumab)

Patients receive carboplatin as in arm I. Patients receive gemcitabine. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery.

Arm VII (Surgery; Carboplatin and Gemcitabine)

Patients receive carboplatin as in arm I and bevacizumab IV over 30-90 minutes on day 1. Patients receive gemcitabine. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery.

Arm VIII (Surgery; Carboplatin, Gemcitabine and Bevacizumab)

Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. Patients are not in secondary cytoreductive surgery portion of study.

Carboplatin: Given IV

Docetaxel: Given IV

Laboratory Biomarker Analysis: Correlative studies

Paclitaxel: Given IV

Quality-of-Life Assessment: Ancillary studies

Patients receive chemotherapy as in arm I and bevacizumab IV over 30-90 minutes on day 1. Treatment repeats every 21 days. Patients are not in secondary cytoreductive surgery portion of study.

Bevacizumab: Given IV

Carboplatin: Given IV

Docetaxel: Given IV

Laboratory Biomarker Analysis: Correlative studies

Paclitaxel: Given IV

Quality-of-Life Assessment: Ancillary studies

Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery.

Carboplatin: Given IV

Laboratory Biomarker Analysis: Correlative studies

Paclitaxel: Given IV

Quality-of-Life Assessment: Ancillary studies

Patients receive paclitaxel IV over 3 hours or docetaxel IV over 1 hour and carboplatin over 30 minutes on day 1. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery.

Bevacizumab: Given IV

Carboplatin: Given IV

Docetaxel: Given IV

Laboratory Biomarker Analysis: Correlative studies

Paclitaxel: Given IV

Quality-of-Life Assessment: Ancillary studies

Patients receive carboplatin as in arm I. Patients receive gemcitabine. Treatment repeats every 21 days. Patients do not receive secondary cytoreductive surgery.

Carboplatin: Given IV

Gemcitabine Hydrochloride: Given IV

Laboratory Biomarker Analysis: Correlative studies

Quality-of-Life Assessment: Ancillary studies

Patients receive carboplatin as in arm I and bevacizumab IV over 30-90 minutes on day 1. Patients receive gemcitabine. Treatment repeats every 21 days. Patients do not receive secondary cytoreductive surgery.

Bevacizumab: Given IV

Carboplatin: Given IV

Gemcitabine Hydrochloride: Given IV

Laboratory Biomarker Analysis: Correlative studies

Quality-of-Life Assessment: Ancillary studies

Arm VI (no Surgery; Carboplatin, Gemcitabine and Bevacizumab))

Patients receive carboplatin as in arm I. Patients receive gemcitabine. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery.

Carboplatin: Given IV

Gemcitabine Hydrochloride: Given IV

Laboratory Biomarker Analysis: Correlative studies

Quality-of-Life Assessment: Ancillary studies

Patients receive carboplatin as in arm I and bevacizumab IV over 30-90 minutes on day 1. Patients receive gemcitabine. Treatment repeats every 21 days. Patients receive secondary cytoreductive surgery.

Bevacizumab: Given IV

Carboplatin: Given IV

Gemcitabine Hydrochloride: Given IV

Laboratory Biomarker Analysis: Correlative studies

Quality-of-Life Assessment: Ancillary studies

Arm VIII (Surgery; Carboplatin, Gemcitabine and Bevacizumab))

Total

Age, Continuous

< 40 years

40 - 49 years

50 - 59 years

60 - 69 years

70 - 79 years

≥ 80 years

Age, Customized

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

South Korea

United States

Japan

Russia

Region of Enrollment

Serous

Endometrioid

Clear Cell

Mucinous

Other

Histology

Christopher Purdy on behalf of Austin Miller PhD

All patients enrolled in the study who did not receive cytoreductive surgery and included in the surgery analysis

No Cytoreductive Surgery

All patients enrolled in the study who received secondary cytoreductive surgery and were included in the surgery analysis

Cytoreductive Surgery

All patients who were eligible for the surgery analysis (data were combined and analyzed according to randomized surgical assignment, regardless of chemotherapy regimen, as pre-specified in the study protocol)

To Determine if Surgical Secondary Cytoreduction in Addition to Adjuvant Chemotherapy Increases the Duration of Overall Survival in Patients With Recurrent Platinum Sensitive Epithelial Ovarian Cancer, Peritoneal Primary or Fallopian Tube Cancer

All patients who received paclitaxel and carboplatin chemotherapy and were included in the chemotherapy analysis

Paclitaxel and Carboplatin Chemotherapy

All patients who received paclitaxel and carboplatin chemotherapy with bevacizumab followed by bevacizumab maintenance therapy and were included in the chemotherapy analysis

Paclitaxel and Carboplatin Chemotherapy With Bevacizumab

All patients who were enrolled between December 10, 2007 and August 26, 2011 and received paclitaxel and carboplatin (with or without bevacizumab) (data were combined and analyzed according to randomized chemotherapy regimen, regardless of surgical assignment, as pre-specified in the study protocol).

To Determine if the Addition of Bevacizumab Increases the Duration of Overall Survival Relative to Second-line Paclitaxel and Carboplatin Alone in Patients With Recurrent Platinum Sensitive Epithelial Ovarian, Peritoneal Primary or Fallopian Tube Cancer

All patients who were enrolled and eligible for the chemotherapy analysis (data were combined and analyzed according to randomized chemotherapy regimen, regardless of surgical assignment, as pre-specified in the study protocol).

Progression-free Survival (Chemotherapy Analysis)

All randomized patients who were eligible for the surgery analysis (data were combined and analyzed according to randomized surgical assignment, regardless of chemotherapy regimen, as pre-specified in the study protocol).

Progression Free Survival (Surgery Analysis)

Summary of Adverse Events (CTCAE Version 4.0)

Prior to cycle 1 (baseline)

Prior to cycle 3

Prior to cycle 6

6 months post cycle 1

12 months post cycle 1

Provided baseline and at least one follow-up assessment (data were combined and analyzed according to randomized chemotherapy regimen, regardless of surgical assignment, as pre-specified in the study protocol).

Patient Reported Quality of Life (Chemotherapy Analysis)

Provided baseline and at least one follow-up assessments (data were combined and analyzed according to randomized chemotherapy regimen, regardless of surgical assignment, as pre-specified in the study protocol).

Patient Reported Physical Function (Chemotherapy Analysis)

Prior to surgery

6 weeks post-surgery

15 weeks post-surgery

6 months post-surgery

12 months post-surgery

Provided baseline and at least one follow-up assessment (data were combined and analyzed according to randomized surgical assignment, regardless of chemotherapy regimen, as pre-specified in the study protocol).

Patient Reported Quality of Life (Surgery Analysis)

Prior to surgery (baseline)

US patients who provided baseline and ≥ 1 follow-up assessments (data were combined and analyzed according to randomized surgical assignment, regardless of chemotherapy regimen, as pre-specified in the study protocol).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
BrUOG 354 Nivolumab +/- Ipilimumab for Ovarian and Extra-renal Clear Cell Carcinomas	NCT03355976	Ovarian Cancer Fallopian Tube ... Primary Periton... Extra Renal Ori... Clear Cell Aden...	Nivolumab Ipilimumab	18 Years -	Brown University
Carboplatin, Paclitaxel and Gemcitabine Hydrochloride With or Without Bevacizumab After Surgery in Treating Patients With Recurrent Ovarian, Epithelial, Primary Peritoneal, or Fallopian Tube Cancer	NCT00565851	Clear Cell Aden... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... Fallopian Tube ... Mucinous Adenoc... Ovarian Brenner... Ovarian Clear C... Ovarian Clear C... Ovarian Endomet... Ovarian Seromuc... Ovarian Serous ... Ovarian Transit... Ovarian Undiffe... Primary Periton... Primary Periton... Primary Periton... Primary Periton... Primary Periton... Recurrent Fallo... Recurrent Ovari... Recurrent Prima... Undifferentiate...	Bevacizumab Carboplatin Docetaxel Gemcitabine Hyd... Laboratory Biom... Paclitaxel Quality-of-Life...	18 Years -	National Cancer Institute (NCI)

Spots Global Cancer Trial Database for clear cell adenocarcinoma