Brief Title
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
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
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Overall Survival
Secondary Outcome
Progression-free Survival (PFS)
Condition
Epithelial Ovarian Cancer
Intervention
pegylated liposomal doxorubicin (PLD)
Study Arms / Comparison Groups
PLD 40 mg/m2 plus VTX-2337
Description: The dosing schedule will be be based on a 28-day cycle. The starting dose schedule is PLD on Day 1 plus VTX-2337 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 on Day 3 only, without additional doses of VTX-2337 on Days 10 and Day 17.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
297
Start Date
October 31, 2012
Completion Date
July 31, 2016
Primary Completion Date
July 31, 2016
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.
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Bradley J. Monk, MD, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01666444
Organization ID
GOG-3003
Responsible Party
Sponsor
Study Sponsor
Celgene
Collaborators
Gynecologic Oncology Group
Study Sponsor
Bradley J. Monk, MD, Study Chair, St. Joseph's Hospital and Medical Center, Phoenix AZ
Verification Date
September 2019