Ovarian Cancer, Primary Peritoneal Cavity Cancer
Conditions
Keywords
ovarian clear cell cystadenocarcinoma, ovarian endometrioid adenocarcinoma, primary peritoneal cavity cancer, ovarian mixed epithelial carcinoma, ovarian mucinous cystadenocarcinoma, ovarian serous cystadenocarcinoma, ovarian undifferentiated adenocarcinoma, recurrent ovarian epithelial cancer, Brenner tumor
Brief summary
RATIONALE: A gene-modified virus may be able to kill tumor cells without damaging normal cells. PURPOSE: This phase I trial is studying the side effects and best dose of an attenuated oncolytic measles virus therapy and oncolytic virus therapy in treating patients with progressive, recurrent, or refractory ovarian epithelial cancer or primary peritoneal cancer (measles virus vaccine therapy study closed as of 06/02/2008).
Detailed description
OBJECTIVES: * Determine the safety and toxicity of recombinant carcinoembryonic antigen (CEA)-expressing measles virus (MV-CEA) and oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) in patients with progressive, recurrent, or refractory ovarian epithelial or primary peritoneal cavity cancer ( MV-CEA closed as of 06/02/2008). * Determine the maximum-tolerated dose of MV-CEA and MV-NIS in these patients ( MV-CEA closed as of 06/02/2008). * Characterize viral gene expression at each dose level as manifested by CEA titers in these patients. * Assess viremia, viral replication, and measles virus shedding or persistence after study therapy. * Determine humoral and cellular immune response to the injected virus in these patients. * Assess, preliminarily, the antitumor efficacy of this therapy, by assessing CA-125 levels, radiographic response, and time to progression, in these patients. * Determine 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 computed tomography (SPECT/CT) imaging. * Assess viremia, viral replication, and measles virus shedding/persistence following intraperitoneal administration of MV-NIS. OUTLINE: This is a dose-escalation study. Patients receive recombinant carcinoembryonic antigen-expressing measles virus (MV-CEA) or oncolytic measles virus encoding thyroidal sodium iodide symporter (MV-NIS) intraperitoneally over 30 minutes on day 1. Treatment repeats every 28 days for up to 6 courses in the absence of disease progression or unacceptable toxicity ( MV-CEA closed as of 06/02/2008). Cohorts of 3-6 patients receive escalating doses of MV-CEA until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity ( MV-CEA closed as of 06/02/2008). Peripheral blood mononuclear cells are collected at baseline and periodically during and after treatment to assess viremia. Throat gargle and urine specimens are assessed periodically during course 1 for viral shedding by reverse transcriptase-polymerase chain reaction (RT-PCR). Peritoneal aspirate is tested at baseline and periodically during treatment for viral replication by RT-PCR, co-culture with Vero cells, and measles virus N-specific mRNA in situ hybridization. Patients may undergo single photon emission computed tomography (SPECT/CT) imaging at baseline and periodically during study. After completion of study therapy, patients are followed periodically for up to 15 years. PROJECTED ACCRUAL: A total of 46 patients will be accrued for this study.
Interventions
GENETICreverse transcriptase-polymerase chain reaction
OTHERlaboratory biomarker analysis
Sponsors
National Cancer Institute (NCI)
Mayo Clinic
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 120 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years. * Must have persistent, recurrent or progressive ovarian cancer or primary peritoneal cancer after prior treatment with platinum and taxol compounds. Histologic confirmation of the original primary tumor is required. Prior bilateral oophorectomy is required. * Patients with the following histologic epithelial cell types are eligible: Serous adenocarcinoma, endometroid adenocarcinoma, mucinous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, transitional cell carcinoma, malignant Brenner's Tumor, or adenocarcinoma NOS * The following laboratory values obtained ≤7 days prior to registration: * ANC ≥ 1500/μL * PLT ≥ 100,000/μL * Total bilirubin ≤ upper normal limit * AST ≤ 2 x ULN * Creatinine ≤ 1.5 x ULN * Hgb ≥ 9.0 g/dL * Ability to provide informed consent. * Willingness to return to Mayo Clinic Rochester for follow-up. * Life expectancy ≥ 12 weeks. * Must have anti-measles immunity as demonstrated by serum IgG anti-measles antibody levels of ≥ 20.0 EU/ml as determined by Enzyme Immunoassay (Diamedix, FL). * Must have normal serum CEA levels (\<5 mg/ml) both at the time of study entry and in any prior testing. (NOTE: Not applicable for the MV-NIS cohort.) * Willingness to provide all biologic specimens as required by the protocol. * Measurable disease by exam or CT scan, or, for patients with CA-125 elevation or with microscopic residual but without measurable disease on imaging, willingness to undergo laparoscopy for evaluation of treatment effect if no radiographic progression after 6 treatment cycles. * CD4 count ≥200/μL or ≥15% of peripheral blood lymphocytes
Exclusion criteria
* Epithelial tumors of low malignant potential, stromal tumors, and germ cell tumors of the ovary. * Known standard therapy for the patient's disease that is potentially curative or definitely capable of extending life expectancy. Subjects will be excluded if this is their first relapse and they have recurred \>6 mo from completion of primary (adjuvant) chemotherapy. * ECOG performance status (PS) 3 or 4. * Active infection ≤5 days prior to registration. * History of tuberculosis or history of PPD positivity. * History of other malignancy ≤5 years except for non-melanoma skin cancer or carcinoma in situ of the cervix. * 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. 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 fully recover from acute, reversible effects of prior chemotherapy regardless of interval since last treatment. * New York Heart Association classification III or IV, known symptomatic coronary artery disease, or symptoms of coronary artery disease on systems review, or known cardiac arrhythmias (atrial fibrillation or SVT). * Requiring blood product support. * CNS metastases or seizure disorder. * 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-FDA-approved indication and in the context of a research investigation). * Any concurrent medications which could interfere with the trial. * Intra-abdominal disease \> 8 cm in diameter at the time of registration, intrahepatic disease, or disease beyond the abdominal cavity. * Treatment with oral/systemic corticosteroids, with the exception of topical or inhaled steroids. * 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. This does not include reactions to intravenous contrast materials.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity | up to 12 months after last treatment | If one patient experiences a Dose limiting Toxicity(DLT), up to three additional patients will be treated at the same dose level. If DLT is observed in only one of six patients treated at a given dose level, the next cohort of three patients will be treated at the next higher dose level. If two or more patients experience DLT at a particular dose level, then the dose escalation will cease and any subsequent patients will be treated at a lower dose level. Thus finding the Max tolerated dose |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Responses (Complete and Partial, Stable and Progressive Disease) | up to 12 months after last treatment | Responses will be summarized separately for the MV-CEA virus and MV-NIS virus by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. CA125 levels and time to progression will also be summarized descriptively. Modified Response Evaluation Criteria in Solid Tumors(RECIST v1.0) criteria will be used. For target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter(LD) of target lesions; Progression (PD): As least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD |
| Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | baseline and up to 18 months | CA-125 tests are measured in units per milliliter (U/mL) and taken every cycle (up to 6-28 day cycles) during treatment and every three months up to 12 months after treatment. The change in CA-125 is calculated as the baseline CA-125 value subtracted by the last recorded value of CA-125 (up to 18 months from baseline. |
| Time to Progression | up to 12 months after last treatment | Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 Includes all dose levels of Cohort 1 | 21 |
| Cohort 2 Includes all dose levels of Cohort 2 | 16 |
| Total | 37 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Total |
|---|---|---|---|
| Age, Continuous | 57 years | 57.5 years | 57 years |
| Ascites Present | 7 participants with ascites | 13 participants with ascites | 20 participants with ascites |
| Region of Enrollment United States | 21 participants | 16 participants | 37 participants |
| Sex: Female, Male Female | 21 Participants | 16 Participants | 37 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 21 / 21 | 16 / 16 |
| serious Total, serious adverse events | 3 / 21 | 2 / 16 |
Outcome results
Primary
Dose Limiting Toxicity
If one patient experiences a Dose limiting Toxicity(DLT), up to three additional patients will be treated at the same dose level. If DLT is observed in only one of six patients treated at a given dose level, the next cohort of three patients will be treated at the next higher dose level. If two or more patients experience DLT at a particular dose level, then the dose escalation will cease and any subsequent patients will be treated at a lower dose level. Thus finding the Max tolerated dose
Time frame: up to 12 months after last treatment
Population: All patients that received study drug for at least 4 weeks were evaluated for dose limiting toxicities.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Dose Limiting Toxicity | 0 participants with DLTs |
| Cohort 2 | Dose Limiting Toxicity | 0 participants with DLTs |
Secondary
Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months)
CA-125 tests are measured in units per milliliter (U/mL) and taken every cycle (up to 6-28 day cycles) during treatment and every three months up to 12 months after treatment. The change in CA-125 is calculated as the baseline CA-125 value subtracted by the last recorded value of CA-125 (up to 18 months from baseline.
Time frame: baseline and up to 18 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | -20.2 U/ml |
| Cohort 2 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | 97 U/ml |
| Cohort 1, Dose Level 3 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | 52 U/ml |
| Cohort 1, Dose Level 4 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | 42.5 U/ml |
| Cohort 1, Dose Level 5 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | 129 U/ml |
| Cohort 1, Dose Level 6 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | -112 U/ml |
| Cohort 1, Dose Level 7 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | 11 U/ml |
| Cohort 2, Dose Level 1 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | 1200 U/ml |
| Cohort 2, Dose Level 2 | Change in CA-125 Levels From Baseline to Last Recorded Value (up to 18 Months) | 18 U/ml |
Secondary
Number of Responses (Complete and Partial, Stable and Progressive Disease)
Responses will be summarized separately for the MV-CEA virus and MV-NIS virus by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease. CA125 levels and time to progression will also be summarized descriptively. Modified Response Evaluation Criteria in Solid Tumors(RECIST v1.0) criteria will be used. For target lesions: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter(LD) of target lesions; Progression (PD): As least a 20% increase in the sum of LD of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions; Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as references the smallest sum LD
Time frame: up to 12 months after last treatment
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Number of Responses (Complete and Partial, Stable and Progressive Disease) | CR | 0 participants |
| Cohort 1 | Number of Responses (Complete and Partial, Stable and Progressive Disease) | PR | 0 participants |
| Cohort 1 | Number of Responses (Complete and Partial, Stable and Progressive Disease) | SD | 14 participants |
| Cohort 1 | Number of Responses (Complete and Partial, Stable and Progressive Disease) | PD | 7 participants |
| Cohort 2 | Number of Responses (Complete and Partial, Stable and Progressive Disease) | PD | 3 participants |
| Cohort 2 | Number of Responses (Complete and Partial, Stable and Progressive Disease) | CR | 0 participants |
| Cohort 2 | Number of Responses (Complete and Partial, Stable and Progressive Disease) | SD | 13 participants |
| Cohort 2 | Number of Responses (Complete and Partial, Stable and Progressive Disease) | PR | 0 participants |
Secondary
Time to Progression
Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time frame: up to 12 months after last treatment
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 | Time to Progression | 55 Days |
| Cohort 2 | Time to Progression | 64.5 Days |