A Phase II Trial of MK-3475 (Pembrolizumab) and Interferon Gamma 1-b Combination Immunotherapy in Patients With Previously Treated Mycosis Fungoides and Sezary Syndrome (Treatment Group 1) and in Patients With Advanced Synovial Sarcoma (Treatment Group 2)
Overview
- Phase
- Phase 2
- Intervention
- Not specified
- Conditions
- Metastatic Myxoid Liposarcoma
- Sponsor
- National Cancer Institute (NCI)
- Enrollment
- 28
- Locations
- 7
- Primary Endpoint
- Overall Response Rate (ORR)
- Status
- Completed
- Last Updated
- 2 years ago
Overview
Brief Summary
This phase II trial studies how well pembrolizumab and interferon gamma-1b work in treating patients with stage IB-IVB mycosis fungoides and Sezary syndrome that has come back (relapsed) or has not responded to previous treatment (refractory). 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. Interferon gamma-1b may boost the immune system activity. Giving pembrolizumab and interferon gamma-1b together may work better in treating patients with stage IB-IVB mycosis fungoides and Sezary syndrome.
Detailed Description
PRIMARY OBJECTIVES: I. To assess the overall response rate (ORR) of MK-3475 (pembrolizumab) and interferon gamma-1b (IFN-G) (Actimmune) combination immunotherapy in subjects with previously treated mycosis fungoides or Sezary syndrome. (Treatment Group 1) II. To determine whether the combination of interferon gamma-1b (ACTIMMUNE) and MK-3475 (pembrolizumab) improves the ORR of pembrolizumab in patients with unresectable or metastatic synovial sarcoma. (Treatment Group 2) SECONDARY OBJECTIVES: I. To explore the safety/tolerability and clinical activity of MK-3475 (pembrolizumab) and IFN-G (Actimmune) in subjects with previously treated mycosis fungoides or Sezary syndrome with respect to (Treatment Group 1): Ia. Safety and tolerability. Ib. Time to response (TTR). Ic. Duration of response (DOR). Id. Progression-free survival (PFS). Ie. Event-free survival (EFS). If. Percentage of all patients who have a response duration of at least 12 months (ORR12). II. To determine the progression-free survival (PFS) and overall survival (OS) for patients with advanced synovial sarcoma receiving interferon gamma-1b and MK-3475 (pembrolizumab). (Treatment Group 2) III. To determine the tolerability of the combination of interferon gamma-1b and MK-3475 (pembrolizumab) based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. (Treatment Group 2) EXPLORATORY OBJECTIVES: I. To investigate the relationship between the following putative biomarkers for combination immunotherapy of MK-3475 pembrolizumab) and IFN-gamma (Actimmune) and clinical outcomes (as measured by safety/tolerability and ORR, DOR, PFS, EFS) in subjects with previously treated mycosis fungoides or Sezary syndrome, including tumor/microenvironment (PD-1/PD-L1/PD-L2 expression, cytotoxic T lymphocyte \[CTL\]s, regulatory T cell \[Treg\]s, macrophages, dendritic cell \[DC\]s; nanostring gene expression profile), systemic immune response (flow cytometry, mass cytometry \[CyTOF\], Luminex multiplexed cytokine profile), and molecular/genomic immune correlates (exome sequencing, high throughput sequencing \[HTS\] for T cell receptor \[TCR\]). (Treatment Group 1) II. To investigate paired, serial biopsy specimens from pre-treatment and 8-12 weeks after starting treatment for the following (Treatment Group 2): IIa. MHC class I expression (scored by pathologist). IIb. Number of infiltrating T cells per mm\^2. IIc. Tumor associated macrophage number and phenotype using multiplex immunohistochemistry. IId. T cell clonality. IIe. Gene expression profiling. III. To investigate peripheral blood samples from patients to determine (Treatment Group 2): IIIa. The number and phenotype of T cells specific for computed tomography (CT) antigens and potential neo-antigens. IIb. The phenotype and activation state of circulating monocytes and peripheral blood mononuclear cell (PBMC). IIc. Cytokines associated with response. OUTLINE: Patients are assigned to 1 of 2 groups. GROUP I: Patients with Mycosis Fungoides and Sezary Syndrome receive pembrolizumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity. Patients also receive interferon gamma-1b subcutaneously (SC) 3 times per week for 12 weeks, and then follow 3 weeks on and 3 weeks off schedule for up to 2 years in the absence of disease progression or unexpected toxicity. GROUP II: Patients with advanced synovial sarcoma receive pembrolizumab IV over 30 minutes on day 1 and interferon gamma-1b SC once a week. Cycles repeat every 3 weeks for up to 2 years in the absence of disease progression or unexpected toxicity. After completion of study treatment, patients are followed up for 30 days and then every 12 weeks for up to 1 year.
Investigators
Eligibility Criteria
Inclusion Criteria
- •MYCOSIS FUNGOIDES /SEZARY SYNDROME (TREATMENT GROUP I)
- •Stage IB-IVB Mycosis Fungoides or Sezary syndrome, and who have relapsed, are refractory, or progressed after at least one standard systemic therapy; maximal stage since diagnosis will determine eligibility; current disease stage at time of entry will also be documented but will not be used for eligibility
- •Subjects must have the following minimum wash-out from previous treatments and without treatment between documentation of relapse/progression and enrollment:
- •\>= 2 weeks for local radiation therapy
- •\>= 8 weeks for low dose (12 Gy or less) Total Skin Electron Beam Therapy (TSEBT)
- •\>= 4 weeks for systemic cytotoxic anticancer agents, anticancer investigational agents that are not defined as immunotherapy, or for tumor-targeting monoclonal antibodies (mAbs) with the exception of alemtuzumab for which the washout is at least 16 weeks
- •\>= 15 weeks for anti-CD137 or anti-CTLA-4 (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways)
- •\>= 2 weeks from resolution (i.e., \< grade 1 or at baseline) from adverse event (AE)s due to procedures performed or therapeutic agents administered
- •\>= 2 weeks for retinoids, interferons, vorinostat, romidepsin and denileukin diftitox
- •\>= 4 weeks for doses of systemic corticosteroids greater than 10 mg/day of prednisone or equivalent; patients who are on physiologic doses of corticosteroids (prednisone equivalent 10 mg/day or less) may participate, however, they must be on a stable dose for at least 4 weeks before enrollment; patients who are on low or moderate potency topical corticosteroids may participate if they are on a stable dose for at least 4 weeks before enrollment; inhaled corticosteroids are acceptable; local injections of corticosteroids are acceptable; all corticosteroids will be reported as concomitant medications
Exclusion Criteria
- •MYCOSIS FUNGOIDES /SEZARY SYNDROME (TREATMENT GROUP I):
- •Has disease that is suitable for local therapy administered with curative intent
- •Patients who have had chemotherapy or targeted small molecule therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) before entering the study
- •Patients who have had an allogeneic stem cell transplant are excluded because such transplants disrupt the normal immune response to a very substantial degree; in addition, emerging data suggests exacerbation of lethal graft versus host disease (GVHD) may occur in such patients when treated post allotransplant with PD-1 blockade
- •Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2
- •Patients who have received an investigational agent or have used an investigational device within 4 weeks of the first dose of study drug
- •Has a history of a well-characterized and defined immune deficiency before the diagnosis of mycosis fungoides or Sezary syndrome or is receiving systemic steroid therapy greater than 10 mg/day of prednisone or equivalent within 4 weeks or any other form of immunosuppressive therapy within 7 days before the first dose of trial treatment
- •Has had a prior monoclonal antibody within 4 weeks before study day 1 or who has not recovered (i.e., =\< grade 1 or at baseline) from AEs due to agents administered more than 4 weeks earlier
- •Note: the following will not be exclusionary: patients may have any grade alopecia or lymphopenia and still participate if other inclusion/exclusion criteria are met; patients may have grade 1 or 2 neuropathy at baseline and still participate if other inclusion/exclusion criteria are met
- •Has a known additional malignancy that is progressing or requires active treatment; exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy, or in situ cervical cancer
Outcomes
Primary Outcomes
Overall Response Rate (ORR)
Time Frame: Up to 2 years
Participants in Treatment Group 1 will be assessed for response and progression using standard response criteria in patients with Mycosis Fungoides and Sezary syndrome. Per Global Response Score determined by evaluating skin, lymph nodes, internal organs (viscera), and blood specimens: Complete Response (CR), complete disappearance of all clinical evidence of disease; Partial Response (PR), regression of measurable disease. Participants in Treatment Group 2 will be assessed for response and progression using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Complete Response (CR) disappearance of all lesions and no new lesion; Partial Response (PR), 30% or greater reduction in tumor size and no new lesions. The ORR is defined as CR combined with PR. Will be assessed using binomial proportion. Best response at any timepoint was used to determine ORR.
Secondary Outcomes
- Incidence of Adverse Events(Up to 2 years and 1 months)
- Time to Response (TTR)(Time interval between the date of first treatment and the date of response (complete response [CR]/partial response [PR]), up to 2 years)
- Duration of Response (DOR)(Time interval between the date of first response (CR/PR) and the date of progression, up to 2 years and 11 months)
- Progression-free Survival (PFS)(Time from enrollment to disease progression or death, whichever occurs earlier, based upon investigator assessment, up to 3 years)
- Event-free Survival (EFS)(Termination due to toxicity, initiation of next significant treatment, progressive disease, or death of any cause, up to 2 years)
- Rate of Overall Response Duration Beyond 12 Months (ORR12)(From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date beyond 12 months that recurrent disease is objectively documented, up to 2 years)