Patient case: 86-year-old female with melanoma; genetic feature: high tumor mutational burden

Clinical trial: CDX-1401 and Poly-ICLC Vaccine Therapy With or Without CDX-301in Treating Patients With Stage IIB-IV Melanoma

Summary: This randomized phase II trial studies how well DEC-205/NY-ESO-1 fusion protein CDX-1401 (CDX-1401) and neoantigen-based melanoma-poly-ICLC vaccine (poly-ICLC) vaccine therapy work when given with or without recombinant flt3 ligand (CDX-301) in treating patients with stage IIB-IV melanoma. The cancer vaccine CDX-1401 attaches to a protein that is made in tumor cells. The vaccine helps the body recognize the tumor to fight the cancer. The CDX-301 vaccine may help the body make more of the tumor fighting cells, known as dendritic cells. The poly-ICLC vaccine stimulates the immune system and may help these dendritic cells mature so that they can recognize the tumor. It is not yet known whether CDX-1401 and poly-ICLC will work better with or without CDX-301 in treating melanoma.

Detailed description: PRIMARY OBJECTIVES:
  I. To determine whether the immune response to cancer/testis antigen 1B (NY-ESO-1) elicited by vaccination with CDX-1401 (anti-DEC205-NY-ESO-1 fusion protein vaccine) plus polyinosinic-polycytidylic acid stabilized with poly-L-lysine and carboxymethylcellulose (poly-ICLC) is substantially increased by prior expansion in the number of circulating dendritic cells (DC) by therapy with CDX-301 (fms-related tyrosine kinase 3 ligand [Flt3L]) (recombinant flt3 ligand).
  SECONDARY OBJECTIVES:
  I. To assess the effect of the vaccine regimen on immune responses to other ongoing and nascent antitumor response antigens associated with melanoma (e.g., preferentially expressed antigen in melanoma [PRAME], melanoma antigen family A, 3 [MAGE-A3], tumor protein p53 [p53], and premelanosome protein [gp100]) as well as memory viral responses (influenza A) and chronic viral responses (cytomegalovirus [CMV], Epstein-Barr virus [EBV]).
  II. To assess the effect of the vaccine regimen on the frequency and phenotypic character of peripheral blood mononuclear cell (PBMC) subsets including DCs, monocyte populations, T cells, and natural killer (NK) cells.
  III. To assess the safety, tolerability, and clinical efficacy of the vaccine regimens.
  OUTLINE: Patients are randomized to 1 of 2 treatment arms.
  ARM I: Patients receive recombinant flt3 ligand subcutaneously (SC) on days -7 to -1, 1-3, and 22-28 of course 1 and on days 1-3 of course 2 only; DEC-205/NY-ESO-1 fusion protein CDX-1401 SC or intradermally (ID) on day 1; and poly-ICLC SC on day 1.
  ARM II: Patients receive DEC-205/NY-ESO-1 fusion protein CDX-1401and poly-ICLC as in Arm I.
  In both arms, treatment repeats every 28 days for 4 courses in the absence of disease progression or unacceptable toxicity.
  After completion of study treatment, patients are followed up at 4 and 12 weeks and then annually thereafter.

Eligibility: Inclusion Criteria:
  -  Patients with fully resected stage IIb through IV melanoma, with melanoma validated by histology or cytology, who have NOT received prior therapy
  -  Patients may have had primary cutaneous, mucosal, or ocular melanoma or metastasis from an unknown primary site
  -  Tissue should be submitted for evaluation of NY-ESO-1 expression and T-cell infiltrates; however, availability of tissue and/or positivity for NY-ESO-1 is not mandatory
  -  Prior therapy requirements:
  -  Prior radiation, chemotherapy or biologics NOT allowed
  -  Not currently receiving any anticancer therapy
  -  Eastern Cooperative Oncology Group (ECOG) performance score of 0-1
  -  Life expectancy of at least 6 months
  -  Leukocytes >= 3,000/mcL
  -  Absolute neutrophil count >= 1,000/mcL
  -  Platelets >= 75,000/mcL
  -  Hemoglobin > 9 g/dL
  -  Total bilirubin < 1.5 x institutional upper limit of normal (bilirubin < 3 x institutional upper limit of normal for Gilbert's syndrome)
  -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal
  -  Creatinine < 1.5 x institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  -  The first six patients enrolled in the Flt3L arm of the study cannot be human immunodeficiency virus (HIV)-positive; after the evaluation of safety in the first 6 patients, HIV-positive patients with adequate immune function as evidenced by stable cluster of differentiation (CD)4 counts >= 350/mm^3 are allowed to participate if the following criteria are met:
  -  Maintained on stable antiretroviral therapy with no significant drug interactions, and
  -  No recent history of acquired immune deficiency syndrome (AIDS) indicator conditions (> 2 years from enrolling in trial), and
  -  Physician providing patient's care for HIV must also approve of patient entering the study
  -  Both men and women of all races and ethnic groups are eligible for this trial
  -  Females of childbearing potential must have a negative pregnancy test within 7 days before the initiation of protocol therapy
  -  Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) before study entry and for the duration of study participation; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception before the study, for the duration of study participation, and 4 months after completion of CDX-1401 or CDX-301 administration
  -  NOTE: Subjects are considered not of child bearing potential if they are surgically sterile, they have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy, or they are postmenopausal; menopause is the age associated with complete cessation of menstrual cycles, menses, and implies the loss of reproductive potential; by a practical definition, it assumes menopause after 1 year without menses with an appropriate clinical profile at the appropriate age
  -  Ability to understand and the willingness to sign a written informed consent document
  Exclusion Criteria:
  -  Patients who have had cytotoxic chemotherapy, radiotherapy, interferon (IFN), or ipilimumab before entering the study
  -  Immunosuppressive therapy within 30 days prior to initiation of protocol therapy
  -  Steroid therapy, or steroid therapy with more than 7 consecutive days of steroids within the prior 4 weeks
  -  The use of prednisone or equivalent < 0.125 mg/kg/day (absolute maximum of 10 mg/day) as replacement therapy is permitted
  -  Inhaled or topical corticosteroids are permitted
  -  Patients who are receiving any other investigational agents
  -  Current or history of systemic autoimmune disease requiring systemic therapy
  -  NOTE: The following will not be exclusionary:
  -  The presence of laboratory evidence of autoimmune disease (e.g., positive ANA titer) without associated symptoms
  -  Clinical evidence of vitiligo
  -  Other forms of depigmenting illness
  -  Cardiovascular disease that meets one of the following: congestive heart failure (New York Heart Association class III or IV), active angina pectoris, or recent myocardial infarction (within the last 6 months)
  -  Cirrhosis or chronic hepatitis C virus positivity or chronic hepatitis B infection
  -  NOTE: A positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B surface antibody [HBsAb]-positive and hepatitis B core antibody [HBcAb]-negative), or a fully resolved acute hepatitis B virus infection is not an exclusion criterion
  -  Known history of immunodeficiency disorder other than HIV-positive status
  -  Extensive active brain disease including symptomatic brain metastases or presence of leptomeningeal disease
  -  NOTE: Patients with brain metastasis, after definitive therapy with surgery or stereotactic radiation and stable off steroids for >= 4 weeks, are eligible
  -  Other invasive cancers that are clinically active
  -  Pregnancy or nursing or unwilling to take adequate birth control during therapy
  -  NOTE: Breastfeeding should be discontinued if the mother is treated with CDX-1401 or CDX-301 and poly-ICLC
  -  History of allergic reactions attributed to compounds of similar chemical or biologic composition to CDX-1401 or CDX-301 or poly-ICLC
  -  Prior organ allograft or allogeneic transplantation, if the transplanted tissue is still in place
  -  Uncontrolled intercurrent illness including, but not limited to, 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
  -  Medical or psychiatric illness that would, in the opinion of the investigator, preclude participation in the study or the ability of patients to provide informed consent for themselves
  -  History of pulmonary disease such as emphysema or chronic obstructive pulmonary disease (COPD) (forced expiratory volume in one second [FEV1] < 60% of predicted for height and age); pulmonary function tests (PFTs) are required in patients with prolonged smoking history or symptoms of respiratory dysfunction
  -  Vaccinations other than those given as part of this research study (with the exception of influenza vaccine) are prohibited throughout the duration of study participation
  -  NOTE: Influenza vaccination (inactivated) is permitted during the flu season; the preferred time is 7 to 14 days after CDX-1401 administration

Relevance to patient case: not relevant