Clinical trial NCT01666444: VTX-2337 and Pegylated Liposomal Doxorubicin (PLD) in Patients With Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Official title: A Randomized, Double-Blind, Placebo-Controlled Phase II Study of VTX-2337 in Combination With Pegylated Liposomal Doxorubicin (PLD) in Patients With Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Epithelial Ovarian Cancer
Fallopian Tube Cancer
Primary Peritoneal Cancer
Keywords: recurrent epithelial ovarian cancer
recurrent fallopian tube cancer
recurrent primary peritoneal cavity cancer
ovarian serous cystadenocarcinoma
ovarian endometrioid adenocarcinoma
ovarian mucinous cystadenocarcinoma
ovarian undifferentiated adenocarcinoma
ovarian clear cell cystadenocarcinoma
ovarian mixed epithelial carcinoma
Brenner tumor
Lead sponsor: Celgene
Sponsor class: INDUSTRY
Collaborators: name: Gynecologic Oncology Group
First posted: 2012-08-16
Enrollment: 297
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: The purpose of this study is to compare the overall survival of patients treated with VTX-2337 + pegylated liposomal doxorubicin (PLD) versus those treated with PLD alone in women with recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer.

VTX-2337, a small molecule agonist of Toll-like Receptor 8 (TLR8), activates multiple components of the innate immune system and is being developed as a novel therapeutic agent for use in oncology. Experimental data obtained in an animal model of ovarian cancer supports the combination of VTX-2337 with PLD. In this model, the combination of VTX-2337 and PLD resulted in a significant reduction in tumor growth compared to either agent alone and an increase in the number of T lymphocytes infiltrating the tumor. The combination of PLD and VTX-2337 has been tested in a small number of women with ovarian cancer in a Phase 1b study and appears to be generally well-tolerated.

Detailed description: OBJECTIVES

Primary Objectives:

* To compare the overall survival (OS) of patients treated with VTX-2337 + PLD versus those treated with PLD alone in women with recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer.
* To compare the progression-free survival (PFS) between the two treatment groups using Immune-Related Response Evaluation Criteria in Solid Tumors (irRECIST).

Secondary Objectives:

* To compare the progression-free survival (PFS) between the two treatment groups using Response Evaluation Criteria In Solid Tumors (RECIST 1.1).
* To compare the nature, frequency and severity of drug-related adverse events (AEs) between the two treatment groups.

Exploratory Objectives:

* To compare the best overall response rate (ORR) and duration of response (based on the probability of being in response function \[PBRF\]) between the two treatment groups using irRECIST and RECIST 1.1.
* To compare the disease control rate (DCR) between the two treatment groups using irRECIST and RECIST 1.1.
* To assess the impact of immune status and response on the clinical effects (OS, PFS, DCR, ORR, PBRF, AEs) of study treatment.
* To assess the effect of TLR8 polymorphisms and BRCA1/BRCA2 mutations on the clinical effects (OS, PFS, DCR, ORR, PBRF, AEs) of study treatment.
* To assess the effect of immune cell subsets, as measured by immunohistochemistry and micro RNA in primary tumor tissue (e.g. immune score), on the clinical effects (OS, PFS, DCR, ORR, PBRF, AEs) of study treatment.
* To assess whether the presence of autoantibodies to tumor-derived proteins are predictive of the clinical effects (OS, PFS, DCR, ORR, PBRF, AEs) of study treatment.

OUTLINE:

This is Phase 2 multicenter clinical study to evaluate the efficacy and safety of the combination of VTX-2337 + PLD compared to PLD + Placebo.

The dosing schedule will be the same for both treatment arms, and will be based on a 28-day cycle. The starting dose schedule is PLD on Day 1 plus VTX-2337 or placebo on Day 3, Day 10, and Day 17 for the first 4 cycles. Starting with cycle 5, the dose regimen will be PLD on Day 1 plus VTX-2337 or placebo on Day 3.

Blood samples are collected periodically during cycle 1 for pharmacodynamics, pharmacogenomics, and other research studies.

Patients will receive therapy until disease progression based on Immune-Related RECIST or until adverse effects prohibit further therapy. Following treatment completion, all patients will be followed with physical exams and histories every three months for the first two years, and then every six months for the next three years, and then

Eligibility criteria: Inclusion Criteria:

1. Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma.
2. Patients with the following histologic cell types are eligible: serous adenocarcinoma, endometrioid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial adenocarcinoma, transitional cell carcinoma, malignant Brenner's tumor or adenocarcinoma not otherwise specified.
3. Patient must have measurable disease as defined by RECIST 1.1.
4. Patients must have received treatment with a platinum-based chemotherapeutic regimen for management of primary disease containing carboplatin, cisplatin or another organoplatinum compound. This initial treatment may have included intraperitoneal therapy, consolidation, non-cytotoxic agents or extended therapy administered after surgical or non-surgical assessment.

   Patients are allowed to receive, but are not required to receive, one additional cytotoxic regimen for management of recurrent or persistent disease.

   Patients are allowed to have received, but are not required to have received, biologic/targeted therapy (e.g., bevacizumab and/or PARP inhibitor) as part of their primary treatment regimen or for management of recurrent or persistent disease.
5. Patients must have platinum-resistant disease, defined as having a platinum-free interval (PFI) of \< 12 months after first- or second-line platinum-based chemotherapy, or having disease progression while receiving second-line platinum-based chemotherapy.
6. Patients must have adequate bone marrow, renal, hepatic, and neurologic functions as defined by the following:

   * Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3. This ANC cannot have been induced or supported by granulocyte colony stimulating factors. Platelets ≥ 100,000/mm3. Hemoglobin ≥ 9 g/dL.
   * Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN).
   * Hepatic function: bilirubin \< 1.2 mg/dL, SGOT (AST) and SGPT (ALT) ≤ 3.0 x ULN and alkaline phosphatase ≤ 2.5 x ULN.
7. Patients must have recovered from effects of recent surgery, radiotherapy or chemotherapy:

   * Patients should be free of active infection requiring parenteral antibiotics.
   * 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 chemotherapy, biologic/targeted agents and immunologic agents, must be discontinued at least three weeks prior to registration.
   * Any prior radiation therapy must be completed at least four weeks prior to registration.
8. Patients must have a GOG performance status of 0 or 1.
9. Patients of childbearing potential must have a negative pregnancy test prior to the study entry and be practicing an effective form of contraception. If applicable, patients must discontinue breastfeeding prior to study entry.
10. Patients must meet the entry requirements and undergo the baseline procedures.
11. Patients must have signed an IRB-approved informed consent form and authorization permitting release of personal health information.

Exclusion Criteria:

1. Patients who have had treatment with VTX-2337, doxorubicin, PLD, or any other anthracycline.
2. Patients who have received an investigational agent \< 30 days prior to registration.
3. Patients who have received oral or parenteral corticosteroids \< 2 weeks prior to registration or who require ongoing systemic immunosuppressive therapy for any reason.
4. Patients with active autoimmune disease. "Active" refers to any condition currently requiring therapy. Examples of autoimmune disease include systemic lupus erythematosus, multiple sclerosis, inflammatory bowel disease and rheumatoid arthritis.
5. Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer, are excluded if there is any evidence of the other malignancy being present within the last three years.
6. Patients who have received prior radiotherapy OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded.
7. Patients who have received prior chemotherapy OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded.
8. Patients with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases, or history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA) or subarachnoid hemorrhage within six months of the first date of treatment on this study.
9. Patients with clinically significant cardiovascular disease.
10. Patients who are pregnant or nursing.
11. Patients under the age of 18.
12. Patients with clinical symptoms or signs of gastrointestinal obstruction and/or who require parenteral hydration or nutrition.

Primary outcomes:
measure: Overall Survival
timeFrame: Survival is measured from date of enrollment and randomization on the study until death from any cause, or if alive at last contact, date of last contact.
Secondary outcomes:
measure: Progression-free Survival (PFS)
timeFrame: Progression-free survival is measured from enrollment and randomization on the study until first indication of progression based on irRECIST criteria or death from any cause, or if progression-free at last contact, the date of last disease assessment.
measure: Frequency and Severity of Adverse Events (AEs)
timeFrame: Assessed during each cycle of therapy and within 30 days after the last cycle of therapy
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: St. Joseph's Hospital and Medical Center
state: Arizona
city: Little Rock
country: United States
facility: Winthrop P. Rockefeller Cancer Institute - University of Arkansas
state: Arkansas
city: Burbank
country: United States
facility: Providence Saint Joseph Medical Center
state: California
city: Hayward
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: Long Beach
country: United States
facility: Long Beach Memorial Medical Center
state: California
city: Oakland
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: Roseville
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: Sacramento
country: United States
facility: Sutter Cancer Center
state: California
city: Sacramento
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: San Francisco
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: San Jose
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: Santa Clara
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: South San Francisco
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: Stanford
country: United States
facility: Stanford University School of Medicine
state: California
city: Vallejo
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: Walnut Creek
country: United States
facility: Kaiser Permanente Medical Center
state: California
city: Aurora
country: United States
facility: University of Colorado Cancer Center
state: Colorado
city: Hartford
country: United States
facility: Hartford Hospital
state: Connecticut
city: Hartford
country: United States
facility: St. Francis Hospital and Medical Center
state: Connecticut
city: New Britain
country: United States
facility: The Hospital of Central Connecticut
state: Connecticut
city: New Haven
country: United States
facility: Yale - New Haven Hospital
state: Connecticut
city: Orlando
country: United States
facility: MD Anderson Cancer Center - Orlando
state: Florida
city: Saint Petersburg
country: United States
facility: Women's Cancer Associates
state: Florida
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Augusta
country: United States
facility: Georgia Regents University
state: Georgia
city: Gainesville
country: United States
facility: Northeast Georgia Medical Center
state: Georgia
city: Macon
country: United States
facility: Central Georgia Gynecologic Oncology
state: Georgia
city: Savannah
country: United States
facility: Memorial Health University Medical Center
state: Georgia
city: Savannah
country: United States
facility: St. Joseph's - Candler Gynecologic Oncology
state: Georgia
city: Honolulu
country: United States
facility: Kapiolani Medical Center for Women and Children
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University - Robert H. Lurie Comprehensive Cancer Center
state: Illinois
city: Chicago
country: United States
facility: Rush University Medical Center
state: Illinois
city: Hinsdale
country: United States
facility: Sudarshan K. Sharma, MD, LTD
state: Illinois
city: Urbana
country: United States
facility: Carle Cancer Center
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University Medical Center
state: Indiana
city: Indianapolis
country: United States
facility: St. Vincent Gynecologic Oncology
state: Indiana
city: Ames
country: United States
facility: McFarland Clinic
state: Iowa
city: Iowa City
country: United States
facility: University of Iowa Hospitals and Clinics
state: Iowa
city: Westwood
country: United States
facility: University of Kansas Medical Center
state: Kansas
city: Scarborough
country: United States
facility: Maine Medical Partners Women's Health
state: Maine
city: Baltimore
country: United States
facility: University of Maryland Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Greater Baltimore Medical Center
state: Maryland
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Baltimore
country: United States
facility: Johns Hopkins Medical Institution
state: Maryland
city: Burlington
country: United States
facility: Lahey Hospital & Medical Center
state: Massachusetts
city: Worcester
country: United States
facility: University of Massachusetts Memorial Healthcare
state: Massachusetts
city: Ann Arbor
country: United States
facility: St. Joseph Mercy Hospital
state: Michigan
city: Battle Creek
country: United States
facility: Bronson Battle Creek
state: Michigan
city: Detroit
country: United States
facility: Karmanos Cancer Institute - Wayne State University
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System
state: Michigan
city: Grand Rapids
country: United States
facility: Grand Rapids Clinical Oncology
state: Michigan
city: Grand Rapids
country: United States
facility: Saint Mary's Health Care
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health at Butterworth Campus
state: Michigan
city: Grand Rapids
country: United States
facility: Gynecologic Oncology of West Michigan
state: Michigan
city: Kalamazoo
country: United States
facility: West Michigan Cancer Center
state: Michigan
city: Muskegon
country: United States
facility: Mercy Health Partners - Mercy Campus
state: Michigan
city: Reed City
country: United States
facility: Reed City Hospital - Spectrum Health
state: Michigan
city: Traverse City
country: United States
facility: Munson Medical Center
state: Michigan
city: Coon Rapids
country: United States
facility: Minnesota Oncology Coon Rapids Clinic
state: Minnesota
city: Edina
country: United States
facility: Fairview Southdale Hospital
state: Minnesota
city: Minneapolis
country: United States
facility: Abbott Northwestern Hospital
state: Minnesota
city: Saint Louis Park
country: United States
facility: Metro Minnesota Clinical Oncology Program
state: Minnesota
city: Saint Louis Park
country: United States
facility: Park Nicollet Frauenshuh Cancer Center
state: Minnesota
city: Saint Paul
country: United States
facility: Minnesota Oncology Hematology - St. Paul Cancer Center
state: Minnesota
city: Woodbury
country: United States
facility: Woodbury Clinic - CornerStone Medical Specialty Centre
state: Minnesota
city: Jackson
country: United States
facility: St. Dominic-Jackson Memorial Hospital
state: Mississippi
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Columbia
country: United States
facility: Ellis Fischel Cancer Center - University of Missouri
state: Missouri
city: Las Vegas
country: United States
facility: Women's Cancer Care Center of Nevada
state: Nevada
city: Lebanon
country: United States
facility: Dartmouth-Hitchcock Medical Center
state: New Hampshire
city: Camden
country: United States
facility: Cooper University Hospital
state: New Jersey
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: Southwest Gynecologic Oncology Associates
state: New Mexico
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Las Cruces
country: United States
facility: Memorial Medical Center
state: New Mexico
city: Albany
country: United States
facility: Women's Cancer Care Associates
state: New York
city: Brooklyn
country: United States
facility: SUNY Downstate Medical Center
state: New York
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: Lake Success
country: United States
facility: Monter Cancer Center
state: New York
city: Manhasset
country: United States
facility: North Shore University Hospital
state: New York
city: New Hyde Park
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: New York
country: United States
facility: NYU Langone Medical Center - Cancer Institute
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Syracuse
country: United States
facility: Gynecologic Oncology of Central New York - SUNY Upstate
state: New York
city: Asheville
country: United States
facility: Hope Women's Cancer Center
state: North Carolina
city: Burlington
country: United States
facility: Alamance Regional Cancer Center
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center / Levine Cancer Institute
state: North Carolina
city: Concord
country: United States
facility: Carolinas Medical Center - Northeast
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Health Science
state: North Carolina
city: Akron
country: United States
facility: Summa Health System
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Cleveland
country: United States
facility: University Hospitals of Cleveland
state: Ohio
city: Cleveland
country: United States
facility: Fairview Hospital Moll Pavilion Cancer Center
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic Foundation
state: Ohio
city: Columbus
country: United States
facility: Ohio State University Medical Center
state: Ohio
city: Kettering
country: United States
facility: Women's Cancer Center at Kettering Medical Center
state: Ohio
city: Mayfield Heights
country: United States
facility: Hillcrest Hospital - Cleveland Clinic
state: Ohio
city: Mentor
country: United States
facility: Lake University Seidman Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: Peggy and Charles Stephenson Cancer Center
state: Oklahoma
city: Tulsa
country: United States
facility: Tulsa Cancer Institute
state: Oklahoma
city: Abington
country: United States
facility: Abington Memorial Hospital; Hanjani Institute for Gynecologic Oncology
state: Pennsylvania
city: Danville
country: United States
facility: Geisinger Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: University of Pennsylvania Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Fox Chase Cancer Center
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Hillman Cancer Center - University of Pittsburgh
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Western Pennsylvania Hospital
state: Pennsylvania
city: West Reading
country: United States
facility: Reading Hospital (McGlinn Family Regional Cancer Center)
state: Pennsylvania
city: Providence
country: United States
facility: Women and Infants Hospital of Rhode Island
state: Rhode Island
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Greenville
country: United States
facility: Bon Secours St. Francis Hospital
state: South Carolina
city: Spartanburg
country: United States
facility: Gibbs Cancer Center
state: South Carolina
city: Sioux Falls
country: United States
facility: Avera Cancer Institute
state: South Dakota
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch
state: Texas
city: Houston
country: United States
facility: MD Anderson Cancer Center
state: Texas
city: Houston
country: United States
facility: The Methodist Hospital
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute, University of Utah
state: Utah
city: Annandale
country: United States
facility: Mid Atlantic Pelvic Surgery Associates
state: Virginia
city: Richmond
country: United States
facility: Virginia Gynecology Oncology
state: Virginia
city: Roanoke
country: United States
facility: Carilion Clinic Gynecological Oncology
state: Virginia
city: Seattle
country: United States
facility: Pacific Gynecology Specialists
state: Washington
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
city: Seattle
country: United States
facility: Northwest Hospital - UW Medicine
state: Washington
city: Seattle
country: United States
facility: Women's Cancer Care of Seattle
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Green Bay
country: United States
facility: Green Bay Oncology at St. Vincent's Hospital
state: Wisconsin
city: Green Bay
country: United States
facility: St Vincent Hospital
state: Wisconsin
city: Green Bay
country: United States
facility: Green Bay Oncology at St. Mary's Hospital
state: Wisconsin
city: Madison
country: United States
facility: University of Wisconsin-Madison
state: Wisconsin
city: Manitowoc
country: United States
facility: Holy Family Memorial Medical Center
state: Wisconsin
city: Marinette
country: United States
facility: Bay Area Medical Center
state: Wisconsin
city: Marshfield
country: United States
facility: Marshfield Clinic
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora St. Luke's Medical Center Gynecologic Oncology
state: Wisconsin
city: Milwaukee
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: Wausau
country: United States
facility: Aspirus Regional Cancer Center
state: Wisconsin
Study officials:
affiliation: St. Joseph's Hospital and Medical Center, Phoenix AZ
name: Bradley J. Monk, MD
role: STUDY_CHAIR
affiliation: Celgene
name: Amar Patel, MD
role: STUDY_DIRECTOR
References:
citation: Monk BJ, Brady MF, Aghajanian C, Lankes HA, Rizack T, Leach J, Fowler JM, Higgins R, Hanjani P, Morgan M, Edwards R, Bradley W, Kolevska T, Foukas P, Swisher EM, Anderson KS, Gottardo R, Bryan JK, Newkirk M, Manjarrez KL, Mannel RS, Hershberg RM, Coukos G. A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study. Ann Oncol. 2017 May 1;28(5):996-1004. doi: 10.1093/annonc/mdx049.