Patient case: 14-year-old female with Li-Fraumeni syndrome; genetic feature: TP53

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

Summary: 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.

Eligibility: 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

Relevance to patient case: not relevant