Intraperitoneal Bortezomib and Carboplatin in Treating Patients With Persistent or Recurrent Ovarian Epithelial Cancer, Fallopian Tube Cancer, or Primary Peritoneal Cancer

A Phase I Pharmacokinetic Study of Intraperitoneal CTEP-Supplied Agent Bortezomib (PS-341, NSC 681239) and Carboplatin (NSC# 241240) in Patients With Persistent or Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

This phase I trial studies the side effects and best dose of intraperitoneal bortezomib when given together with intraperitoneal carboplatin in treating patients with ovarian epithelial cancer, fallopian tube cancer, or primary peritoneal cancer that is persistent or has come back. Bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as carboplatin, 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. Bortezomib may help carboplatin work better by making tumor cells more sensitive to the drug. Infusing bortezomib and carboplatin directly into the abdomen (intraperitoneal) may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Seromucinous Carcinoma; Ovarian Serous Cystadenocarcinoma; Ovarian Clear Cell Adenocarcinoma; Ovarian Mucinous Adenocarcinoma; Fallopian Tube Transitional Cell Carcinoma; Ovarian Transitional Cell Carcinoma; Fallopian Tube Clear Cell Adenocarcinoma; Fallopian Tube Endometrioid Adenocarcinoma; Fallopian Tube Mucinous Adenocarcinoma; Fallopian Tube Serous Adenocarcinoma; Ovarian Serous Adenocarcinoma; Ovarian Brenner Tumor; Ovarian Mucinous Cystadenocarcinoma; Undifferentiated Ovarian Carcinoma; Undifferentiated Fallopian Tube Carcinoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Carboplatin; Drug: Bortezomib

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of intraperitoneal (IP) bortezomib (BTZ) when administered with intraperitoneal carboplatin in women with epithelial ovarian, fallopian tube, or primary peritoneal cancer that is persistent or recurrent and who have failed primary therapy and at least one second-line therapy.

II. To examine the safety of administering BTZ in combination with carboplatin by the IP route.

SECONDARY OBJECTIVES:

I. To estimate objective tumor response rate as determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria.

II. To determine the pharmacokinetic profile of BTZ and carboplatin when administered intraperitoneally once every 21 days.

III. To characterize the frequency of carboplatin hypersensitivity reactions (HSR) when administered as an intraperitoneal infusion in the context of recurrent ovarian cancer.

OUTLINE: This is a dose-escalation study of bortezomib.

Patients receive bortezomib intraperitoneally (IP) and carboplatin IP on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 1 year.

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Hartford Hospital
    • New Britain, Connecticut, United States, 06050
      • The Hospital of Central Connecticut
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • University of Iowa/Holden Comprehensive Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Hospital University Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Reserve University
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic Foundation
    • Cleveland, Ohio, United States, 44111
      • Cleveland Clinic Cancer Center/Fairview Hospital
    • Mayfield Heights, Ohio, United States, 44124
      • Hillcrest Hospital Cancer Center
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
    • Tulsa, Oklahoma, United States, 74146
      • Oklahoma Cancer Specialists and Research Institute-Tulsa
  • Rhode Island
    • Providence, Rhode Island, United States, 02905
      • Women and Infants Hospital
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center
    • Richmond, Virginia, United States, 23298
      • Virginia Commonwealth University/Massey Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal cancer; histologic documentation of the original primary tumor is required via the pathology report

  • Patients with the following histologic epithelial cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's tumor, or adenocarcinoma not otherwise specified (N.O.S)

• Patients must have either measurable disease or detectable disease:

  • Measurable disease will be defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1; measureable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded); each lesion must be >= 10 mm when measured by computed tomography (CT), magnetic resonance imaging (MRI) or caliper measurement by clinical exam; or >= 20 mm when measured by chest x-ray; lymph nodes must be >= 15 mm in short axis when measured by CT or MRI

  • Detectable disease is defined in a patient as one who does not have measurable disease but has at least one of the following conditions:

    • Baseline values of cancer antigen (CA)-125 at least twice the upper limit of normal
    • Ascites and/or pleural effusion attributed to tumor
    • Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions
  • In addition, patients are allowed to undergo surgical cytoreduction of relapsed disease as proof of detectable disease at the discretion of their treating physician; if performed to allow participation in this protocol, the operative and pathology reports will be required for submission
• Patients must have a Gynecologic Oncology Group (GOG) performance status 0, 1, or 2

• Recovery from effects of recent surgery, radiotherapy, or chemotherapy

  • Patients should be free of active infection requiring antibiotics (with the exception of uncomplicated urinary tract infection [UTI])
  • Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration; continuation of hormone replacement therapy is permitted
  • Any other prior therapy directed at the malignant tumor, including biological and immunologic agents, must be discontinued at least three weeks prior to registration

• Patients must have had one prior platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin, or another organoplatinum compound; this initial treatment may have included non-cytotoxic therapy, intraperitoneal therapy, consolidation, or extended therapy administered after surgical or non-surgical assessment

  • Patients are required to receive, one additional cytotoxic regimen for management of recurrent or persistent disease
  • Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease (maximum number of prior cytotoxic regimens including primary therapy is 4); patients are allowed to receive, but are not required to receive, biologic (non-cytotoxic) therapy either alone or as part of the cytotoxic regimens for management of recurrent or persistent disease
• Absolute neutrophil count (ANC) greater than or equal to 1,500/mcl, equivalent to the National Cancer Institute (NCI) Common Terminology Criteria (CTCAE) version 4 grade 1
• Platelets greater than or equal to 100,000/mcl
• Creatinine less than or equal to institutional upper limit of normal (ULN)
• Bilirubin less than or equal to 1.5 x ULN (per the NCI CTCAE version 4 grade 1)
• Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) less than or equal to 3 x ULN (per the active version of the NCI CTCAE grade 1)
• Alkaline phosphatase less than or equal to 2.5 x ULN (per the NCI CTCAE version 4 grade 1)
• Neuropathy (sensory and motor) less than or equal to the NCI CTCAE version 4 grade 1
• Prothrombin time (PT) such that international normalized ratio (INR) is =< 1.5 x ULN (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin)
• Partial thromboplastin time (PTT) =< 1.5 x ULN (heparin, low molecular weight heparin, or alternative anticoagulants are acceptable)
• Patients who have met the pre-entry requirements
• An approved informed consent and authorization permitting release of personal health information must be signed by the patient or guardian
• Patients of childbearing potential must have a negative serum pregnancy test prior to the study entry and be practicing an effective form of contraception
• Patients in this trial may receive ovarian estrogen +/- progestin replacement therapy as indicated at the lowest effective dose(s) for control of menopausal symptoms at any time, but not progestins for management of anorexia while on protocol directed therapy or prior to disease progression

Exclusion Criteria:

• Patients who have had prior therapy with bortezomib
• Patient with a history of other invasive malignancies, with the exceptions of non-melanoma skin cancer and localized breast cancer, are excluded if there is any evidence of other malignancy being present within the last five years; patients are also excluded if their previous cancer treatment contraindicates this protocol therapy
• Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of ovarian cancer are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than three years prior to registration, and the patient remains free of recurrent or metastatic disease

• Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian cancer are excluded

  • Patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than three years prior to registration, and that the patient remains free of recurrent or metastatic disease
• Patients with known brain metastases are excluded
• History of allergic reactions attributed to carboplatin or compounds of similar chemical or biologic composition to bortezomib including boron or mannitol
• Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, are excluded, unless all of the following conditions are met: stage not greater than I-B; no more than superficial myometrial invasion, without vascular or lymphatic invasion; no poorly differentiated subtypes, including papillary serous, clear cell or other International Federation of Gynecology and Obstetrics (FIGO) grade 3 lesions
• Patients with a history of prior myocardial infarction in the last 12 months or patients with new electrocardiographic evidence of acute ischemia or new conduction abnormalities are ineligible
• Uncontrolled concurrent illness including but not limited to ongoing or active infection that requires parenteral antibiotics, acute hepatitis, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Patients with insulin-dependent diabetes will be excluded
• Concomitant medications known to inhibit or induce cytochrome P450, family 3, subfamily A, polypeptide 4 (3A4) are to be avoided

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Treatment (bortezomib, carboplatin); Patients receive bortezomib IP and carboplatin IP on day 1. Treatment repeats every 21 days for 6 courses in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; Correlative studies; Drug: Carboplatin; Given IP; Other Names: Blastocarb; Carboplat; Carboplatin Hexal; Carboplatino; Carbosin; Carbosol; Carbotec; CBDCA; Displata; Ercar; JM-8; Nealorin; Novoplatinum; Paraplatin; Paraplatin AQ; Paraplatine; Platinwas; Ribocarbo; Drug: Bortezomib; Given IP; Other Names: Velcade; MLN341; PS-341; LDP 341; [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid; PS341

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Dose-limiting toxicities defined by drug-related adverse events which occur in association with the first course of treatment as evaluated by the NCI CTCAE version 4 unless clearly unrelated to study drugs (e.g., disease progression)	21 days
Frequency and severity of toxicities as assessed by NCI CTCAE version 4	Up to 1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Objective tumor response (complete and partial response)	Objective tumor response will be tabulated by regimen.	Up to 1 year
Progression free survival	Will be summarized using Kaplan-Meier plots.	Time from study entry to time of progression or death, whichever occurs first, assessed up to 1 year
Pharmacokinetic parameters	Descriptive analysis will be given for the pharmacokinetic parameters of bortezomib and carboplatin.	10 minutes prior to infusion; immediately following infusion; 15, 30 and 60 minutes after infusion; immediately following carboplatin; 90 minutes after infusion; and 2, 4, and 6 hours after infusion

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Collaborators: NRG Oncology

Publications and helpful links

General Publications

• Jandial DA, Brady WE, Howell SB, Lankes HA, Schilder RJ, Beumer JH, Christner SM, Strychor S, Powell MA, Hagemann AR, Moore KN, Walker JL, DiSilvestro PA, Duska LR, Fracasso PM, Dizon DS. A phase I pharmacokinetic study of intraperitoneal bortezomib and carboplatin in patients with persistent or recurrent ovarian cancer: An NRG Oncology/Gynecologic Oncology Group study. Gynecol Oncol. 2017 May;145(2):236-242. doi: 10.1016/j.ygyno.2017.03.013. Epub 2017 Mar 22.

Study record dates

Study Major Dates

• Study Start (ACTUAL): April 5, 2010
• Primary Completion (ACTUAL): April 4, 2014
• Study Completion (ACTUAL): January 27, 2018

Study Registration Dates

• First Submitted: February 23, 2010
• First Submitted That Met QC Criteria: February 23, 2010
• First Posted (ESTIMATE): February 24, 2010

Study Record Updates

• Last Update Posted (ACTUAL): August 9, 2019
• Last Update Submitted That Met QC Criteria: August 8, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Endocrine System Diseases; Disease Attributes; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Endocrine Gland Neoplasms; Fallopian Tube Diseases; Neoplasms, Connective Tissue; Neoplasms, Cystic, Mucinous, and Serous; Endometrial Neoplasms; Neoplasms, Fibrous Tissue; Neoplasms, Fibroepithelial; Carcinoma; Recurrence; Adenocarcinoma; Ovarian Neoplasms; Fallopian Tube Neoplasms; Carcinoma, Ovarian Epithelial; Cystadenocarcinoma, Serous; Carcinoma, Endometrioid; Cystadenocarcinoma; Adenocarcinoma, Clear Cell; Carcinoma, Transitional Cell; Adenocarcinoma, Mucinous; Cystadenocarcinoma, Mucinous; Brenner Tumor; Antineoplastic Agents; Carboplatin; Bortezomib
• Other Study ID Numbers: NCI-2011-02014 (REGISTRY: CTRP (Clinical Trial Reporting Program)); U10CA180868 (U.S. NIH Grant/Contract); U10CA027469 (U.S. NIH Grant/Contract); CDR0000665312; GOG-9924 (OTHER: CTEP)