NeoVax and Nivolumab for the Treatment of Patients with Newly-Diagnosed, Stage IIIC or IV or Recurrent Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
This phase I trial evaluates whether it is possible to make and safely administer a vaccine against ovarian cancer by using information gained from specific characteristics of the ovarian cancer. Poly-ICLC is a ''viral mimic'' and an activator of immunity. Poly-ICLC binds proteins on the surface of certain immune cells to make it appear as if a virus is present. When the cells detect the vaccine, they think it is a virus and turn on the immune system. Poly-ICLC is a compound that has been used to help the body in its fight against cancer. Nivolumab is an antibody that acts against PD-1. PD-1 is a molecule that controls a part of the immune system by shutting it down. An antibody against PD-1 can stop PD-1 from turning off the immune system, allowing the immune reaction to continue, which may help the body to destroy cancer cells. Giving a personalized neoantigen cancer vaccine with nivolumab may work better in treating patients with ovarian cancer.
Inclusion Criteria
- Diagnosis of epithelial ovarian cancer, primary peritoneal or fallopian tube cancer. High grade serous, high grade endometrioid, clear cell and carcinosarcoma (carcinosarcomas only with high grade serous epithelial component) histologies are allowed. Low grade histologies and mucinous histology are not allowed
- Participants must be classified into one of two cohorts: Cohort A: Patients with newly diagnosed stage IIIC or stage IV epithelial ovarian, fallopian tube, or primary peritoneal cancer who are planned to undergo neoadjuvant chemotherapy. Patients must be candidates for platinum-based chemotherapy and previously untreated. At the time of pre-screening consent, patients must have disease that is amenable to biopsy and are agreeable and can safely undergo biopsy OR have already undergone biopsy with tumor specimen that can be used for vaccine preparation Cohort B: Patients with recurrent (first recurrence only) epithelial ovarian, primary peritoneal or fallopian tube cancer with platinum sensitive disease defined as disease progression greater or equal than 24 months after completion of their last dose of first line platinum chemotherapy. Prior hormonal therapy is allowed but no other therapy for recurrence is allowed, including no chemotherapy, no targeted therapy, and no antiangiogenic therapy. Maintenance therapy after first line chemotherapy is allowed. At the time of pre-screening consent, patients must have measurable disease by RECIST 1.1 and disease that is amenable to biopsy and are agreeable and can safely undergo biopsy OR have already undergone biopsy with tumor specimen that can be used for vaccine preparation
- Eastern Cooperative Group (ECOG) performance status =< 2
- Age >= 18 years
- Hemoglobin >= 8.0 g/dL
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
- White blood cells (WBC) > 2 x 10^9/L
- Platelet count >= 100 x 10^9/L
- Total bilirubin =< 1.5 x institutional upper limit of normal
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal unless liver metastases are present in which case it must be =< 5 x ULN
- Serum creatinine =< 1.5 x institutional upper limit of normal (ULN)
- Negative serum beta-human chorionic gonadotropin (B-HCG) or urine pregnancy test
- Ability to understand and the willingness to sign a written informed consent document
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures
- Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for the duration of study treatment with nivolumab and 5 months after the last dose of study treatment (i.e., 30 days [duration of ovulatory cycle] plus the time required for the investigational drug to undergo approximately five half-lives). Patients of non-childbearing potential are defined as those fulfilling at least one of the following criteria: * Have undergone a documented hysterectomy and/or bilateral oophorectomy * Have medically confirmed ovarian failure * Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed by having a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state
Exclusion Criteria
- Non-epithelial tumors or ovarian tumors with low malignant potential (i.e. borderline tumors)
- Mucinous or low grade histologies (i.e. low grade serous or low grade endometrioid)
- Cohort A and B patients who have signed prescreening consent form and then, in the opinion of the investigator, have progressed after 3 or 4 cycles of platinum-based chemotherapy, are ineligible for the treatment part of the study and no vaccine will be manufactured
- Prior immunotherapy with IL-2, IFN-alpha, or anti-PD-1, anti-PD-L1, anti-PD-L2, antiCD137, or anti-cytotoxic T lymphocyte associated antigen 4 (anti-CTLA-4) antibody (including ipilimumab), or any other antibody or drug specifically targeting T cell co-stimulation or immune checkpoint pathways
- Major surgery (other than debulking surgery for ovarian, primary peritoneal or fallopian tube cancer) for any reason within 4 weeks prior to initiation of vaccination and/or incomplete recovery from surgery
- Known brain metastases or leptomeningeal metastases because of their poor prognosis and because patients often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. A scan to confirm the absence of brain metastases is not required
- Active or history of autoimmune disease (known or suspected). Exceptions are permitted for vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition requiring only hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger
- Have a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to the first dose of study drug (nivolumab). Inhaled or topical steroids and adrenal replacement doses (=< 10 mg daily prednisone equivalents) are permitted in the absence of active autoimmune disease
- Known human immunodeficiency virus (HIV) infection, active chronic hepatitis B or C, life-threatening illnesses unrelated to cancer, or any serious medical or psychiatric illness that could, in the investigator’s opinion, interfere with participation in this study
- Known allergy to tetanus toxoid
- Have an uncontrolled intercurrent illness including, but not limited to, ongoing or active infection requiring treatment, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
- Have any underlying medical condition, psychiatric condition, or social situation that, in the opinion of the investigator, would compromise study administration as per protocol or compromise the assessment of adverse events (AEs)
- Pregnant women are excluded from this study because nivolumab, personalized neoantigen peptides, and poly-ICLC are agents with unknown risks to the developing fetus
- Nursing women are excluded from this study because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with nivolumab, personalized neoantigen peptides, and poly-ICLC
- Have a history of an invasive malignancy, except for the following circumstance: individuals with a history of invasive malignancy are eligible if they have been disease free for at least 2 years or are deemed by the investigator to be at low risk for recurrence of that malignancy; individuals with the following cancers are eligible if diagnosed and treated carcinoma in situ of the breast, oral cavity or cervix, localized prostate cancer, basal cell or squamous cell carcinoma of the skin
- Participants who are receiving any other investigational agents
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04024878.
PRIMARY OBJECTIVE:
I. To evaluate the feasibility and safety of administering NeoVax with nivolumab in each of two cohorts of epithelial ovarian cancer (EOC) patients: i) patients with newly diagnosed ovarian cancer who are opted for neoadjuvant chemotherapy (Cohort A) and ii) patients with recurrent platinum sensitive ovarian cancer (Cohort B).
SECONDARY OBJECTIVES:
I. To determine anti-tumor activity as assessed by objective response rate (ORR) based on Response Criteria in Solid Tumors (RECIST) and based on immune-related RECIST (irRECIST) for patients with residual measurable disease after completion of chemotherapy.
II. For patients in cohort B who do not have residual measurable disease after completion of chemotherapy, we will determine whether the second progression free survival (PFS) PFS2 (measured as the interval from the start of secondary therapy to the date of the second relapse) is longer than the first PFS (PFS1, measured as the interval from the start of primary therapy to date of first relapse).
III. To evaluate progression-free survival (PFS) and overall survival (OS).
IV. To evaluate duration of response (DOR).
V. To evaluate ORR among patients who were retreated with NeoVax with nivolumab at the time of disease progression or recurrence.
EXPLORATORY OBJECTIVES:
I. Define the evolution of T cell reactivity, state and repertoire following NeoVax/nivolumab.
II. Define evolution of the tumor and the tumor microenvironment following standard of care chemotherapy and NeoVax/Nivolumab, and correlate this with T cell and clinical responses.
III. Identify mechanisms of immune escape to NeoVax/nivolumab.
OUTLINE: Patients are assigned to 1 of 2 arms.
ARM I (NEWLY DIAGNOSED): Patients with newly diagnosed ovarian cancer undergo surgical or core needle biopsy for NeoVax generation. Patients then receive 3-4 cycles of platinum-based chemotherapy per standard of care. Patients may undergo interval debulking surgery per standard-of-care (SOC). Beginning 3-8 weeks after the completion of chemotherapy, patients receive NeoVax intradermally (ID) and subcutaneously (SC) on days 1, 4, 8, 15, and 22 over 3 weeks. Beginning day 29, patients may receive olaparib or niraparib orally (PO) if clinically indicated. Patients receive two booster vaccinations ID and SC on days 78 and 134. On day 92 (i.e., 2 weeks after the first booster dose of NeoVax), patients receive nivolumab IV over 30 minutes. Treatment repeats every 2 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. At week 24, nivolumab may be switched to every 4 weeks at investigators discretion. At time of disease progression, patients who experience a clinical benefit may undergo another biopsy for generation of another NeoVax vaccine followed by revaccination with NeoVax followed by nivolumab using the same schedule as previously administered.
ARM II (RECURRENT): Patients with recurrent ovarian cancer undergo surgical or core needle biopsy for NeoVax generation. Patients then receive 3-4 cycles of platinum-based chemotherapy per standard of care. Beginning 3-8 weeks after the completion of chemotherapy, patients receive NeoVax ID and SC on days 1, 4, 8, 15, and 22 over 3 weeks. Beginning day 29, patients may receive olaparib or niraparib PO if clinically indicated. Patients receive two booster vaccinations ID and SC on days 78 and 134. On day 92 (i.e., 2 weeks after the first booster dose of NeoVax), patients receive nivolumab IV over 30 minutes. Treatment repeats every 2 weeks for up to 24 months in the absence of disease progression or unacceptable toxicity. At week 24, nivolumab may be switched to every 4 weeks at investigators discretion. At time of disease progression, patients who experience a clinical benefit may undergo another biopsy for generation of another NeoVax vaccine followed by revaccination with NeoVax followed by nivolumab using the same schedule as previously administered. Bevacizumab may be given IV during and/or after chemotherapy as clinically indicated.
All patients undergo computed tomography (CT) or magnetic resonance imaging (MRI) and collection of blood samples throughout the study.
After completion of study treatment, patients are followed up every 3 months for up to 5 years.
Trial PhasePhase I
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center
Principal InvestigatorPanagiotis A. Konstantinopoulos
- Primary ID18-318
- Secondary IDsNCI-2020-10071
- ClinicalTrials.gov IDNCT04024878