PRIMARY OBJECTIVE:
I. Compare clinical efficacy of Arm A (MV-NIS therapy) and Arm B (standard cytotoxic
chemotherapy), as measured by overall survival (OS).
SECONDARY OBJECTIVES:
I. Compare progression-free survival (PFS), overall survival at 12 months (OS12),
progression-free survival at six months (PFS6), and objective response rate (ORR) between
MV-NIS therapy and standard chemotherapy.
II. Assess safety and tolerability of MV-NIS, and compare with standard chemotherapy.
III. Compare quality of life as assessed by Functional Assessment of Cancer Therapy-Ovarian
(FACT-O) between MV-NIS and standard chemotherapy.
TRANSLATIONAL OBJECTIVES:
I. Assess the time course of viral gene expression and virus elimination and biodistribution
of virally infected cells at various time points after infection with MV-NIS using
single-photon emission computerized tomography (SPECT)/computed tomography (CT) imaging
within the MV-NIS treatment arm.
II. Assess viremia, viral replication, and viral shedding/persistence following
intraperitoneal administration within the NV-NIS treatment arm.
III. Measure humoral and cellular immune responses to MV-NIS within the NV-NIS treatment arm.
IV. Measure changes in anti-ovarian cancer (OC) immune responses in both treatment arms.
V. Perform transcriptomic analysis on tumor biopsy specimens to determine a gene expression
profile predictive of therapeutic response to MV-NIS.
OUTLINE: Patients are randomized to 1 of 2 treatment arms.
ARM A: Patients receive oncolytic measles virus encoding thyroidal sodium iodide symporter
intraperitoneally (IP) over 30 minutes on day 1. Cycles repeat every 28 days in the absence
of disease progression or unacceptable toxicity.
ARM B: Patients receive pegylated liposomal doxorubicin hydrochloride intravenously (IV) over
1 hour on day 1, or gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15, or
topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15, or paclitaxel IV over 1 hour
on days 1, 8, and 15. Patients may also receive bevacizumab IV over 30-90 minutes on days 1
and 15 with pegylated liposomal doxorubicin hydrochloride, topotecan hydrochloride, or
paclitaxel. Cycles repeat every 28 days in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 3 months until disease
progression and then every 6 months for 5 years.
Inclusion Criteria:
- PRE-REGISTRATION INCLUSION CRITERIA:
- Ability to understand and the willingness to sign a written informed consent document
- The effects of the candidate chemoprevention agents on the developing human fetus
remain incompletely defined; however, study participants will be women who have gone
through a bi-lateral oophorectomy procedure
- Willingness to be evaluated for surgical placement of an intraperitoneal port and
undergo biopsy if feasible for a research sample
- REGISTRATION/RANDOMIZATION INCLUSION CRITERIA:
- Recurrent, persistent, or progressive epithelial ovarian, fallopian tube, or primary
peritoneal cancer after treatment with bilateral oophorectomy and either cisplatin or
carboplatin and either paclitaxel, albumin-bound paclitaxel, or docetaxel; histologic
confirmation of the primary tumor is required; eligible histologies include serous,
endometrioid, clear cell, mucinous, transitional cell, undifferentiated, or mixed
carcinoma
- Platinum-resistant or platinum-refractory disease, defined as either 1) less than a
complete response to the most recent carboplatin- or cisplatin-containing chemotherapy
regimen, 2) serum cancer antigen (CA)-125 >= 2 x upper limit of normal (ULN) within
180 days of last dose of carboplatin- or cisplatin-containing chemotherapy, confirmed
by a second CA-125 (the second CA-125 does not have to be within 180 days of
chemotherapy), or 3) CT or positron emission tomography (PET)/CT evidence of cancer
recurrence within 180 days of last dose of carboplatin- or cisplatin-containing
chemotherapy
- Absolute neutrophil count (ANC) >= 1500/uL (obtained =< 7 days prior to registration)
- Platelet (PLT) >= 100,000/uL (obtained =< 7 days prior to registration)
- Total bilirubin =< ULN (obtained =< 7 days prior to registration)
- Aspartate aminotransferase (AST) =< 2 x ULN (obtained =< 7 days prior to registration)
- Creatinine =< 1.5 x ULN (obtained =< 7 days prior to registration)
- Hemoglobin (Hgb) >= 9.0 g/dL (obtained =< 7 days prior to registration)
- Willingness to return to Mayo Clinic Rochester or another participating institution
for follow-up; patients who are randomized to Arm B (cytotoxic chemotherapy) may
receive chemotherapy at any oncology clinic able to provide the protocol-directed
therapy and willing to send laboratory data to the participating institution; however,
patients must be willing to return to the participating institution every two months
for evaluation; patients who are randomized to Arm A must be willing to receive all
treatment and follow-up at a participating institution
- Life expectancy >= 12 weeks
- Willingness to provide all biologic specimens as required by the protocol
- Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) criteria,
or evaluable disease by CA-125; (NOTE: CA-125-evaluable disease is defined as serum
CA-125 >= 2 x ULN that is determined by the treating clinician to be due to recurrent
ovarian, fallopian tube, or primary peritoneal cancer)
- Normal cardiac function, as determined by left ventricular ejection fraction (LVEF) >=
institutional lower limit of normal on echocardiogram or multi-gated acquisition scan
(MUGA) =< 1 month prior to registration
- If liposomal doxorubicin hydrochloride (DOXIL) is selected as the investigator's
choice chemotherapy:
- Lifetime exposure to doxorubicin =< 240 mg/m^2 (or equivalent biologic dose if
prior exposure to a different anthracycline)
- Candidate for surgical placement of an intraperitoneal port, as determined by a
gynecologic oncology surgeon
- Must have anti-measles immunity as demonstrated by serum immunoglobulin (Ig)G
anti-measles antibody levels of >= 1.1 EU/ml as determined by BioPlex Measles IgG
multiplex flow immunoassay
Exclusion Criteria:
- REGISTRATION/RANDOMIZATION EXCLUSION CRITERIA:
- Epithelial tumors of low malignant potential, stromal tumors, and germ cell tumors of
the ovary
- Evidence of measurable disease (per Response Evaluation Criteria in Solid Tumors
version 1.1 [RECIST 1.1]) outside of the peritoneal cavity (ex: mediastinal
lymphadenopathy, parenchymal liver metastasis, or symptomatic pleural effusion proven
or suspected to be due to cancer)
- Note: Asymptomatic pleural effusion with or without minimal pleural involvement
as long as there is no measurable disease outside the peritoneum/retroperitoneum
is allowed
- Bulky metastases, defined as any tumor nodule or lymph nodes > 5 cm in greatest
dimension on axial images on pre-treatment CT, PET/CT, or magnetic resonance imaging
(MRI)
- Note: patients with bulky (> 5 cm) disease for whom gross total cytoreduction is
deemed feasible by a surgeon (with confirmation by a second surgeon after
radiologic review) are eligible for participation in the context of cytoreductive
surgery
- Resistant to all of the following: DOXIL, gemcitabine hydrochloride (GEM), topotecan
hydrochloride (TOPA), and weekly paclitaxel (TAXOL); (NOTE: resistance is defined as
either 1) less than a complete response to any chemotherapy regimen containing the
agent in question [consider weekly TAXOL as a separate agent from every-three-week
TAXOL], 2) serum CA-125 >= 2 x ULN within 180 days of last dose of chemotherapy
containing the agent in question, confirmed by a second CA-125 [the second CA-125 does
not have to be within 180 days of chemotherapy], or 3) CT or PET/CT evidence of cancer
recurrence/progression within 180 days of last dose of chemotherapy containing the
agent in question; [for example, if a patient previously received carboplatin and GEM,
had a complete response, and had initial evidence of relapse > 180 days after the last
dose of GEM, that patient would not be considered resistant to GEM])
- Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 3 or 4
- History of other malignancy =< 5 years prior to registration except for non-melanoma
skin cancer, carcinoma in situ of the cervix, and ductal carcinoma in situ (DCIS)
- Active infection =< 7 days prior to study entry
- Any of the following prior therapies:
- Chemotherapy =< 3 weeks prior to study entry
- Immunotherapy =< 4 weeks prior to study entry
- Biologic therapy =< 4 weeks prior to study entry
- Extensive abdominal surgery if it includes enterotomy(ies) =< 3 weeks prior to
study entry; (NOTE: this criterion does not apply to placement of the peritoneal
Port-A-Cath or lysis of adhesions at the time of study entry)
- Any viral or gene therapy prior to study entry
- Failure to recover to =< grade 1 from acute, reversible effects of prior chemotherapy,
excluding alopecia regardless of interval since last treatment; (NOTE: patients with
residual peripheral neuropathy are allowed)
- New York Heart Association classification III or IV congestive heart failure, known
symptomatic coronary artery disease, symptoms of coronary artery disease on systems
review, or known cardiac arrhythmias (atrial fibrillation or supraventricular
tachycardia [SVT])
- Other cardiac or pulmonary disease that, at the investigator's discretion, can impair
treatment safety
- Central nervous system (CNS) metastases or seizure disorder
- Human immunodeficiency virus (HIV)-positive test result, or history of other
immunodeficiency
- History of organ transplantation
- History of chronic hepatitis B or C
- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational (utilized for a non-Food and Drug Administration
[FDA]-approved indication and in the context of a research investigation)
- Any concurrent medications which could interfere with the trial
- History of tuberculosis or history of purified protein derivative (PPD) positivity
- Treatment with oral/systemic corticosteroids, with the exception of topical or inhaled
steroids or steroids given for the purpose of adrenal replacement given at physiologic
doses
- Exposure to household contacts =< 15 months old or household contact with known
immunodeficiency
- Allergy to measles vaccine or history of severe reaction to prior measles vaccination
- Allergy to iodine; (NOTE: this does not include reactions to intravenous contrast
materials)
- Any other pathology or condition which the principal investigator may deem to
negatively impact treatment safety
- On anticoagulation and unable to discontinue temporarily for up to 7 days
