VTX-2337 and Liposomal Doxorubicin Hydrochloride in Treating Patients With Recurrent or Persistent Ovarian Epithelial, Fallopian Tube, or Peritoneal Cavity Cancer

OBJECTIVES:

Primary

- To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities (DLTs) of
VTX-2337 when administered in combination with pegylated liposomal doxorubicin (Doxil®)
40 mg/m^2 and the associated DLTs based on adverse events that occur in cycle 1 for
this combination in women with recurrent or persistent, epithelial ovarian, fallopian
tube, or primary peritoneal cancer.

- To examine the tolerability of the combination at the MTD of VTX-2337 (assessed in
combination with Doxil 40 mg/m^2) with Doxil 50 mg/m^2.

- To determine recommended phase II dose (RP2D) of VTX-2337 in combination with Doxil.

Secondary

- To assess the biological effects (immune activation) of VTX-2337 in combination with
Doxil. (Translational research)

- To assess the pharmacokinetics of Doxil and VTX-2337 in patients receiving VTX-2337 in
combination with Doxil. (Translational research)

Tertiary

- To assess the anti-tumor activity of VTX-2337 when administered concomitantly with
Doxil in patients with recurrent or persistent epithelial ovarian, fallopian tube, or
primary peritoneal cancer. (Exploratory)

- To assess the effect of TLR8 polymorphisms on the biological (immune) and clinical
effects of VTX-2337 in combination with Doxil. (Exploratory)

OUTLINE: This is a multicenter, dose-escalation study.

Patients receive TLR8 agonist VTX-2337 subcutaneously on days 3, 10, and 17 and pegylated
liposomal doxorubicin hydrochloride IV over 60 minutes on day 1. 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.

DISEASE CHARACTERISTICS:

- Patients must have recurrent or persistent epithelial ovarian, fallopian tube, or
primary peritoneal carcinoma

- Histologic documentation of the original primary tumor is required via the
pathology report

- 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 tumor

- Adenocarcinoma not otherwise specified (N.O.S.)

- Patient must have measurable disease or detectable (non-measurable) disease:

- Measurable disease will be defined by RECIST 1.1

- Measurable disease is defined as at least one lesion that can be accurately
measured in at least one dimension (longest diameter to be recorded)

- Each lesion must be ≥ 10 mm when measured by CT, 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 (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

- Patients whose CA-125 is < 100 U/mL must undergo a second confirmatory
value within a period of ≤ 4 weeks

- Patients with a level ≥ 100 U/mL may be entered without confirmatory
measurement

- The CA-125 assessment for eligibility must be done at least 4 weeks
after paracentesis or other surgical procedures

- 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

- Tumors within a previously irradiated field will be designated as
"non-target" lesions unless progression is documented or a biopsy is
obtained to confirm persistence at least 90 days following completion of
radiation therapy

- 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

- 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

PATIENT CHARACTERISTICS:

- See Disease Characteristics

- 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 ≤ 1.2 x ULN

- SGOT (AST) ≤ 3.0 x ULN

- Alkaline phosphatase ≤ 2.5 x ULN

- Not pregnant or nursing

- Negative pregnancy test

- Patients of childbearing potential must be practicing an effective form of
contraception during and for up to four months after taking study drug

- Neuropathy (sensory and motor) less than or equal to grade 1

- Patients should be free of active infection requiring parenteral antibiotics

- No 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

- 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:

- Uncontrolled hypertension, defined as systolic > 140 mm Hg or diastolic > 90 mm
Hg

- Myocardial infarction or unstable angina within 6 months of the first date of
treatment on this study

- History of serious ventricular arrhythmia (i.e., ventricular tachycardia or
ventricular fibrillation) or cardiac arrhythmias requiring anti-arrhythmic
medications (except for atrial fibrillation that is well controlled with
anti-arrhythmic medication)

- QTc interval ≥ 450 ms on baseline ECG

- Baseline ejection fraction ≤ 50% as assessed by echocardiogram or MUGA

- New York Heart Association (NYHA) class II or higher congestive heart failure

- Grade 2 or higher peripheral ischemia (brief [< 24 hours] episode of ischemia
managed non-surgically and without permanent deficit)

- No patients with clinical symptoms or signs of gastrointestinal obstruction and who
require parenteral hydration or nutrition

PRIOR CONCURRENT THERAPY:

- See Disease Characteristics

- 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

- 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, fallopian tube or primary peritoneal cancer within
the last three years 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

- No patients who have received an investigational agent within 30 days of study entry

- 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

- 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

- 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