Clinical Trials /

P53MVA and Pembrolizumab in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

NCT03113487

Description:

This phase II trial studies how well modified vaccinia virus ankara vaccine expressing p53 (p53MVA) and pembrolizumab work in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving p53MVA and pembrolizumab together may work better in treating patients with ovarian, primary peritoneal, or fallopian tube cancer.

Related Conditions:
  • Fallopian Tube Carcinoma
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: P53MVA and Pembrolizumab in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer
  • Official Title: P53MVA and Pembrolizumab in Treating Patients With Recurrent Ovarian, Primary Peritoneal, or Fallopian Tube Cancer

Clinical Trial IDs

  • ORG STUDY ID: 16448
  • SECONDARY ID: NCI-2017-00555
  • SECONDARY ID: 16448
  • NCT ID: NCT03113487

Conditions

  • PD-L1 Positive
  • Recurrent Fallopian Tube Carcinoma
  • Recurrent Ovarian Carcinoma
  • Recurrent Primary Peritoneal Carcinoma
  • TP53 Gene Mutation

Interventions

DrugSynonymsArms
Modified Vaccinia Virus Ankara Vaccine Expressing p53MVA-p53, MVA-p53 Vaccine, MVAp53 Vaccine, p53-MVA Vaccine, p53MVATreatment (pembrolizumab, p53MVA)
PembrolizumabKeytruda, Lambrolizumab, MK-3475, SCH 900475Treatment (pembrolizumab, p53MVA)

Purpose

This phase II trial studies how well modified vaccinia virus ankara vaccine expressing p53 (p53MVA) and pembrolizumab work in treating patients with ovarian, primary peritoneal, or fallopian tube cancer that has come back. Vaccines made from a gene-modified virus may help the body build an effective immune response to kill tumor cells. Monoclonal antibodies, such as pembrolizumab, may interfere with the ability of tumor cells to grow and spread. Giving p53MVA and pembrolizumab together may work better in treating patients with ovarian, primary peritoneal, or fallopian tube cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To assess response rate (complete response [CR] + partial response [PR]) after treatment
      with p53MVA and pembrolizumab.

      SECONDARY OBJECTIVES:

      I. To assess median progression free survival (PFS), clinical benefit (CR+PR+ stable disease
      [SD] > 6 months), overall survival, safety and tolerability.

      EXPLORATORY OBJECTIVES:

      I. Evaluate if the CD8+ T cell signal exceeds that detected in the single agent p53MVA trial.

      OUTLINE: This is a dose-escalation study of modified vaccinia virus ankara vaccine expressing
      p53.

      Patients receive pembrolizumab intravenously (IV) over 30 minutes every 3 weeks and modified
      vaccinia virus ankara vaccine expressing p53 subcutaneously (SC) every 3 weeks for up to 3
      vaccines. Courses with pembrolizumab repeat every 3 weeks for up to 49 weeks in the absence
      of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (pembrolizumab, p53MVA)ExperimentalPatients receive pembrolizumab IV over 30 minutes every 3 weeks and modified vaccinia virus ankara vaccine expressing p53 SC every 3 weeks for up to 3 vaccines. Courses with pembrolizumab repeat every 3 weeks for up to 49 weeks in the absence of disease progression or unacceptable toxicity.
  • Modified Vaccinia Virus Ankara Vaccine Expressing p53
  • Pembrolizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with histologically or cytologically confirmed, epithelial ovarian, primary
             peritoneal or fallopian tube cancer who experienced recurrence or progression within 6
             months after completion of platinum based chemotherapy; patients must have measurable
             disease or detectable disease:

               -  Measurable disease is defined as at least one lesion that can be accurately
                  measured in at least one dimension (longest dimension to be recorded); each
                  lesion must be greater than or equal to 10 mm when measured by computed
                  tomography (CT), positron emission tomography (PET)/CT or magnetic resonance
                  imaging (MRI); lymph nodes must be greater than or equal to 15 mm in short axis
                  when measured by CT, PET/CT, or MRI

               -  Detectable disease in a patients is defined as one who does not have measurable
                  disease, but has at least one of the following condition:

                    -  Baseline values of CA-125 at least 2 x upper limit of normal (ULN)

                    -  Ascites and/ or pleural effusion attributed to tumor

                    -  Solid and/ or cystic abnormalities on radiographic imaging that do not meet
                       modified Response Evaluation Criteria in Solid Tumors (RECIST) criteria,
                       immune-related response criteria (irRC) for target lesions

          -  Patients whose ovarian cancer recurs/progresses within 0-6 months following
             platinum-based chemotherapy have platinum resistant disease; these patients are not
             considered to benefit from additional platinum-based therapy and are treated with
             other sequential single agents; such patients are eligible for this trial

          -  Patients with documented disease recurrence/progression within 6-12 months of
             completing platinum-based therapy, are considered to have 'borderline' platinum
             sensitivity; these patients will not be eligible for this trial

          -  Patients who relapse more than 12 months after completion of platinum-based treatment
             are considered 'platinum sensitive' and will not be eligible for this trial, since
             they have a favorable (33-59%) chance of responding to further rounds of platinum
             based chemotherapy

          -  Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status =<
             2 (Karnofsky >= 60 %) and a life expectancy of at least 3 months

          -  Absolute neutrophil count >= 1,500/ul

          -  Platelets >= 100,000/ul

          -  The hemoglobin level must be greater than 9g/dl

               -  N.B. low hemoglobin may be corrected with transfusion to achieve eligibility for
                  study

          -  Calculated or measured creatinine clearance >= 50ml/min or serum creatinine =<
             1.6mg/dl

          -  Total bilirubin =< 1.5 x institutional upper limit of normal

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 times
             institutional upper limit of normal level; (AST and ALT =< 5 times institutional upper
             normal level, if there is evidence of liver metastasis)

          -  Left ventricle ejection fraction (LVEF) of >= 55%

          -  Women of child-bearing potential must agree to use adequate contraception (hormonal or
             barrier method of birth control or abstinence) prior to study entry and for six months
             following duration of study participation; should a woman become pregnant or suspect
             that she is pregnant while participating on the trial, she should inform her treating
             physician immediately

          -  Patients with confirmed p53 mutation by molecular analysis and/or evidence of p53
             overexpression by immunohistochemistry (>= 10% of cells within tumor staining
             positive) will be eligible; this will be assessed semi-quantitatively by a Clinical
             Laboratory Improvement Act (CLIA) approved pathology core pathologist, using CLIA
             approved mutational analysis or immuno-histochemistry techniques on formalin-fixed
             paraffin-embedded tissue; in the case of equivocal immunohistochemistry (IHC) results,
             p53 involvement may be confirmed by detection of p53 molecular analysis on tumor
             deoxyribonucleic acid (DNA); patients on whom molecular analysis of p53 mutations is
             already available, will not require IHC analysis; molecular analysis may be performed
             as an additional research procedure at the end of the study (distinct from eligibility
             determination) if the principal investigator (PI) deems it of scientific value and
             research funding is available to cover the cost; patients must have PD-L1 positive
             ovarian cancer in order to be eligible for this clinical trial (defined as >= 1% PD-L1
             expression within the tumor section, assessed by immunohistochemical staining)

          -  Subjects (or the legally-authorized representatives of cognitively impaired patients)
             must have the ability to understand and the willingness to sign a written informed
             consent

          -  Up to 4 prior chemotherapy regimens for recurrent disease are allowed; adjuvant
             chemotherapy and maintenance Taxol after completion of six cycles of adjuvant
             carboplatin - Taxol will not be counted as a "prior chemotherapy regimen" for the
             purpose of this study; treatment with targeted agents or hormones would not be
             considered as a systemic chemotherapy regimen

          -  Eligible patients are those with documented disease recurrence/progression within 0-6
             months of completing platinum-based chemotherapy

          -  Patients should not have received any non-oncology, viral vaccines within 30 days
             prior to starting protocol treatment

        Exclusion Criteria:

          -  Patients should not have any uncontrolled illness including ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  No other malignancy is allowed except for the following: adequately treated basal or
             squamous cell carcinoma, superficial bladder cancer, any carcinoma in situ or any
             other cancer from which the patient has been disease free for at least 3 years

          -  Has active infection with hepatitis A (as determined by an acute hepatitis panel), a
             known history of hepatitis B (hepatitis B surface antigen [Ag] reactive), or active
             hepatitis C virus (qualitative hepatitis C virus [HCV] ribonucleic acid [RNA]
             detectable)

          -  Active tuberculosis (TB) infection (as determined by quantiferron test)

          -  Patients may not be receiving any additional investigational agents or radiation
             therapy

          -  History of severe environmental allergies or allergy to egg proteins

          -  Pregnant women are excluded from this study

          -  Patients with known brain metastases will be excluded

          -  Patients who have received chemotherapy, biological agents or investigational therapy
             within 4 weeks prior to entering the study

          -  Patients who have had palliative radiotherapy within 3 weeks prior to entering the
             study

          -  Patients who have received any hormonal therapy directed at the malignancy within 2
             weeks prior to entering the study

          -  STUDY-SPECIFIC EXCLUSIONS

          -  Patients with a family history or Li-Fraumeni syndrome will not be eligible

          -  Concurrent use of corticosteroids (exceptions: nasal corticosteroids, inhaled
             steroids, adrenal replacement steroids and steroid creams are allowed)

          -  Due to immunostimulatory mechanism of the investigational drug, patients with a
             history of immunodeficiency, including organ grafts and human immunodeficiency virus
             (HIV), will not be eligible

          -  Patients with any active autoimmune disease or a condition that requires systemic
             corticosteroids or other immunosuppressive medications will be excluded; exceptions to
             this are subjects with vitiligo, type I diabetes mellitus and autoimmune thyroiditis
             only requiring hormone replacement, who will be permitted to enroll

          -  Patients with a history of cardiac disease are excluded: myocardial infarction or
             arterial thromboembolic events within 6 months prior to baseline, severe or unstable
             angina, New York Heart Association class III or IV disease, QTCB (corrected according
             to Bazett's formula) interval > 470 msec, serious uncontrolled hypertension (systolic
             > 150 and/or diastolic > 100 mm Hg); baseline electrocardiography and assessment of
             serum troponin (I) are included in the screening exams; subjects in whom these assays
             are abnormal (electrocardiogram [EKG] excluding first (1st) degree branch block, sinus
             bradycardia, sinus tachycardia or non-specific T wave changes, serum troponin >= grade
             2) are ineligible

          -  Patients previously treated with the p53MVA vaccine or checkpoint inhibitors
             (anti-CTLA-4, anti- PD-1 and anti-PDL-1) are not eligible

          -  Subjects, who in the opinion of the investigator, may not be able to comply with the
             safety monitoring requirements of the study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Response rate (CR+PR)
Time Frame:Up to 24 months
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Biomarker analysis
Time Frame:Up to 24 months
Safety Issue:
Description:Peripheral blood samples will be collected pre- and post-immunization for assessment of anti-p53 T cell responses and immunophenotyping. Immunosuppressive cell types (myeloid-derived suppressor cell, regulatory T cells) and other selected lymphocyte subsets and markers including PD-1, PDL-1 and PDL-2 will be quantified. Will evaluate if CD8+ T cell signal exceeds that detected in the single agent p53MVA trial. Estimates will be obtained using Wilcoxon rank-sum test based on residual re-sampling simulations based on historic area under the curve values.
Measure:Clinical benefit (CR+PR+SD > 6 months)
Time Frame:Up to 6 months
Safety Issue:
Description:
Measure:Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.3
Time Frame:Up to 24 months
Safety Issue:
Description:
Measure:Overall survival
Time Frame:From start of the treatment until death, assessed up to 24 months
Safety Issue:
Description:
Measure:PFS
Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed up to 24 months
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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