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About
This phase I trial is studying the side effects and best dose of TLR8 agonist VTX-2337 and pegylated liposomal doxorubicin hydrochloride in treating patients with recurrent or persistent ovarian epithelial, fallopian tube, or peritoneal cavity cancer. Biological therapies, such as TLR8 agonist VTX-2337, may stimulate the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as pegylated liposomal doxorubicin hydrochloride and paclitaxel, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving TLR8 agonist VTX-2337 together with pegylated liposomal doxorubicin hydrochloride or paclitaxel may kill more tumor cells.
Full description
PRIMARY OBJECTIVES:
I. To determine the maximum tolerated doses (MTD) and dose limiting toxicities (DLTs) of VTX-2337 when administered in combination with pegylated liposomal doxorubicin (PLD; Doxil, Lipodox™) 40 mg/m2 in Regimen 1 and when administered in combination with weekly paclitaxel 80 mg/m2 in Regimen 2, and the associated DLTs based on adverse events that occur in cycle 1 for each of these combinations in women with recurrent or persistent, epithelial ovarian, fallopian tube or primary peritoneal cancer.
II. To examine the tolerability of the combination at the MTD of VTX-2337 assessed in combination with PLD 40 mg/m2 and with PLD 50 mg/m2 in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.
III. To determine recommended phase II doses (RP2D) of VTX-2337 in combination with PLD in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.
SECONDARY OBJECTIVES:
I. To assess the biological effects (immune activation) of VTX-2337 in combination with PLD in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.
II. To assess the pharmacokinetics in patients receiving VTX-2337 in combination with PLD in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.
III. To assess the tolerability (including CTCAE v4 Grade 3/4 allergic reaction) of weekly paclitaxel 80 mg/m2 when administered without corticosteroid premedication (Regimen 2 only).
TERTIARY OBJECTIVES:
I. To assess the anti-tumor activity of VTX-2337 when administered concomitantly with PLD in Regimen 1 and when administered concomitantly with weekly paclitaxel in Regimen 2 in patients with recurrent or persistent epithelial ovarian fallopian tube or primary peritoneal cancer.
II. To assess the effect of TLR8 polymorphisms on the biological (immune) and clinical effects of VTX-2337 in combination with PLD in Regimen 1 and in combination with weekly paclitaxel in Regimen 2.
OUTLINE: This is a multicenter, dose-escalation study.
Patients receive TLR8 agonist VTX-2337 subcutaneously (SC) on days 3, 10, and 17 and pegylated liposomal doxorubicin hydrochloride IV over 60 minutes on day 1 or TLR8 agonist VTX-2337 subcutaneously on days 1, 8, and 15 and paclitaxel IV over 60 minutes on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Blood samples are collected periodically during courses 1 and 2 for pharmacokinetic, pharmacogenomic, and other research studies. After completion of study treatment, patients are followed up every 3 months for 1 year.
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Inclusion and exclusion criteria
Inclusion Criteria:
Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or primary peritoneal carcinoma
Patients with the following histologic cell types are eligible:
Patient must have measurable disease or detectable (non-measurable) disease:
Measurable disease will be defined by RECIST 1.1
Detectable (non-measurable) disease is defined as not having measurable disease but has at least one of the following conditions:
Baseline values of CA-125 ≥ 2 x ULN
Solid and/or cystic abnormalities on radiographic imaging that do not meet RECIST 1.1 definitions for target lesions
Patient with measurable disease must have at least one "target lesion" to be used to assess response on this protocol as defined by RECIST 1.1
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 intraperitoneal therapy, consolidation, non-cytotoxic agents or extended therapy administered after surgical or non-surgical assessment
For patients enrolled in Regimen 2, weekly paclitaxel, treatment for their primary disease must have included paclitaxel; this can have been given weekly or every 3 weeks; patients who experienced severe hypersensitivity to paclitaxel are excluded
Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen
Patients are allowed to receive, but are not required to receive, non-cytotoxic therapy (such as bevacizumab) as part of their primary treatment regimen; patients are allowed to receive, but are not required to receive, non-cytotoxic therapy for management of recurrent or persistent disease
Patients who have received only one prior cytotoxic regimen (platinum-based regimen for management of primary disease), must have a platinum-free interval of less than 12 months, or have progressed during platinum-based therapy, or have persistent disease after a platinum-based therapy
No 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
No patients who have received oral or parenteral corticosteroids within 2 weeks of study entry or who require ongoing systemic immunosuppressive therapy for any reason
Patients must have a GOG performance status of 0 or 1
Absolute neutrophil count (ANC) ≥ 1,500/mm^3; this ANC cannot have been induced or supported by granulocyte colony-stimulating factors
Platelets ≥ 100,000/mm^3
Hemoglobin ≥ 9 g/dL
Creatinine ≤ 1.5 x institutional upper limit normal (ULN)
Bilirubin ≤ 1.5 x ULN
SGOT (AST) ≤ 3.0 x ULN
Alkaline phosphatase ≤ 2.5 x ULN
Neuropathy (sensory and motor) less than or equal to grade 1
Not pregnant or nursing
Negative pregnancy test
Patients of childbearing potential must be practicing an effective form of contraception
Patients should be free of active infection requiring parenteral antibiotics
No patients with active autoimmune disease
Patients with a history of other invasive malignancies, with the exception of non-melanoma skin cancer or localized cancer of the breast, head and neck, or skin, are excluded if there is any evidence of other malignancy being present within the last three years
No patients with known chronic or active hepatitis
No patients with clinically significant cardiovascular disease, this includes:
No patients with clinical symptoms or signs of gastrointestinal obstruction and who require parenteral hydration or nutrition
Any hormonal therapy directed at the malignant tumor must be discontinued at least one week prior to registration
No patients who have had previous treatment with VTX-2337, pegylated liposomal doxorubicin, doxorubicin, or any other anthracycline
Patients are excluded if their previous cancer treatment contraindicates this protocol therapy
Patients are allowed to receive, but are not required to receive, two additional cytotoxic regimens for management of recurrent or persistent disease, with no more than 1 non-platinum, non-taxane regimen (prior treatment with pegylated liposomal doxorubicin is NOT allowed)
Patients are allowed to receive, but are not required to receive, non-cytotoxic therapy (such as bevacizumab) as part of their primary treatment regimen
Patients are allowed to receive, but are not required to receive, non-cytotoxic therapy for management of recurrent or persistent disease
Patients must have recovered from effects of recent surgery, radiotherapy, or chemotherapy
Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis OTHER THAN for the treatment of ovarian, fallopian tube, or primary peritoneal cancer within the last three years are excluded
Patients who have received prior chemotherapy for any abdominal or pelvic tumor OTHER THAN for the treatment of ovarian, fallopian tube or primary peritoneal cancer within the last three years are excluded
No patients who have received an investigational agent within 30 days of study entry
Any other prior therapy directed at the malignant tumor, including biological and immunologic agents, must be discontinued at least three weeks prior to registration
Primary purpose
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20 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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