Clinical Trials /

Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers

NCT02978625

Description:

This phase II trial studies how well talimogene laherparepvec and nivolumab work in treating patients with lymphomas that do not responded to treatment (refractory) or non-melanoma skin cancers that have spread to other places in the body (advanced) or do not responded to treatment. Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving talimogene laherparepvec and nivolumab may work better compared to usual treatments in treating patients with lymphomas or non-melanoma skin cancers.

Related Conditions:
  • Lymphoma
  • Merkel Cell Carcinoma
  • Skin Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Talimogene Laherparepvec and Nivolumab in Treating Patients With Refractory Lymphomas or Advanced or Refractory Non-melanoma Skin Cancers
  • Official Title: A Phase II Study of T-VEC Followed by T-VEC + Nivolumab in Refractory T Cell and NK Cell Lymphomas, Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma, and Other Rare Skin Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01804
  • SECONDARY ID: NCI-2016-01804
  • SECONDARY ID: 10057
  • SECONDARY ID: 10057
  • SECONDARY ID: P30CA072720
  • SECONDARY ID: UM1CA186716
  • NCT ID: NCT02978625

Conditions

  • Adenoid Cystic Carcinoma
  • Adnexal Carcinoma
  • Apocrine Carcinoma
  • Eccrine Porocarcinoma
  • Extraocular Cutaneous Sebaceous Carcinoma
  • Hidradenocarcinoma
  • Keratoacanthoma
  • Malignant Sweat Gland Neoplasm
  • Merkel Cell Carcinoma
  • Microcystic Adnexal Carcinoma
  • NK-Cell Lymphoma, Unclassifiable
  • Non-Melanomatous Lesion
  • Paget Disease
  • Papillary Adenocarcinoma
  • Primary Cutaneous Mucinous Carcinoma
  • Refractory Anaplastic Large Cell Lymphoma
  • Refractory Cutaneous T-Cell Non-Hodgkin Lymphoma
  • Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
  • Refractory Mycosis Fungoides
  • Refractory T-Cell Non-Hodgkin Lymphoma
  • Sezary Syndrome
  • Signet Ring Cell Carcinoma
  • Skin Basal Cell Carcinoma
  • Skin Basosquamous Cell Carcinoma
  • Skin Squamous Cell Carcinoma
  • Spiradenocarcinoma
  • Squamous Cell Carcinoma of Unknown Primary Origin
  • Stage III Skin Cancer
  • Stage IV Skin Cancer
  • Sweat Gland Carcinoma
  • Trichilemmocarcinoma
  • Vulvar Squamous Cell Carcinoma

Interventions

DrugSynonymsArms
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (talimogene laherparepvec, nivolumab)
Talimogene LaherparepvecICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene, Imlygic, JS1 34.5-hGMCSF 47- pA-, T-VECTreatment (talimogene laherparepvec, nivolumab)

Purpose

This phase II trial studies how well talimogene laherparepvec works and nivolumab in treating patients with lymphomas that do not responded to treatment or non-melanoma skin cancers that have spread to other places in the body or do not responded to treatment. Biological therapies, such as talimogene laherparepvec, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop tumor cells from growing. Monoclonal antibodies, such as nivolumab, may block a protein needed by tumor cells to grow and spread. Giving talimogene laherparepvec and nivolumab may work better in treating patients with lymphomas or non-melanoma skin cancers.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the frequency of patients responding (response rate) to talimogene
      laherparepvec (T-VEC) monotherapy.

      SECONDARY OBJECTIVES:

      I. To determine the local response rate to T-VEC in injected tumors. II. To determine the
      response rate to T-VEC + nivolumab (NIVO). III. To identify potential pre-treatment and
      on-treatment correlative biomarkers of local and systemic immune response.

      OUTLINE:

      Patients receive talimogene laherparepvec intratumorally (IT) on day 1. Patients without
      response at week 12, may also receive nivolumab intravenously (IV) over 60 minutes on day 1.
      Courses repeat every 21 or 14 days for up to 1 year in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 12 weeks for 3 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (talimogene laherparepvec, nivolumab)ExperimentalPatients receive talimogene laherparepvec IT on day 1. Patients without response at week 12, may also receive nivolumab IV over 60 minutes on day 1. Courses repeat every 21 or 14 days for up to 1 year in the absence of disease progression or unacceptable toxicity.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Patients must have histologic or cytologic diagnosis of non-melanoma skin cancer
                 (NMSC) or lymphomas other than B-cell lymphomas; as both of those terms are
                 categories rather than specific diagnoses, specific guidance on eligible tumor types
                 is provided below
    
              -  Included tumor types
    
                   -  T cell and NK cell lymphomas, including, but not limited to: cutaneous T-cell
                      lymphomas (CTCL), mycosis fungoides (MF), Sezary syndrome (SS), peripheral
                      T-cell lymphoma (PTCL), ALK-positive and ALK-negative anaplastic large cell
                      lymphoma (ALCL), and NK-cell lymphomas
    
                   -  Merkel cell carcinoma
    
                   -  Squamous cell carcinoma of the skin, including keratoacanthomas, vulvar squamous
                      carcinoma, and mixed histology tumors, such as basosquamous carcinoma, and
                      squamous cell carcinoma of unknown primary consistent with skin origin
    
                   -  Basal cell carcinoma
    
                   -  Malignant sweat gland tumors, including porocarcinoma, hidradenocarcinoma,
                      spiradenocarcinoma, cylindrocarcinoma, microcystic adnexal carcinoma and related
                      entities, squamoid eccrine ductal carcinoma, cutaneous adenoid cystic carcinoma,
                      digital papillary adenocarcinoma, primary cutaneous mucinous carcinoma,
                      endocrine mucin-producing sweat gland carcinoma, primary cutaneous signet ring
                      cell carcinoma, cutaneous apocrine gland carcinoma, and extraocular sebaceous
                      carcinoma
    
                   -  Adnexal carcinoma
    
                   -  Trichilemmal carcinoma
    
                   -  Paget's disease
    
                   -  Any other rare tumor of the skin with approval of principle investigator (PI)
    
              -  Patients with T cell and natural killer (NK) cell lymphomas must be refractory to, be
                 intolerant of, have relapsed following, or have refused all standard life-prolonging
                 therapies
    
              -  Patients with non-melanoma skin cancers (NMSC) must have advanced or refractory
                 tumors
    
                   -  Advanced/unresectable is defined by at least 1 of the following criteria: tumors
                      2 cm or more, tumors considered unresectable, tumors invading deep tissues such
                      as muscle, cartilage or bone, tumors showing perineural invasion, and/or tumors
                      metastatic to loco-regional lymph nodes and/or distant sites
    
                   -  Refractory is defined by persistent or recurrent tumor despite prior therapy
                      consisting of at least 1 of the following: surgery, radiation therapy,
                      intralesional therapy, topical therapy, or systemic therapy
    
              -  Subjects must have at least 1 cutaneous, subcutaneous, or nodal lesion that is
                 suitable for intralesional injection, with or without the use of ultrasound; lesions
                 in mucosal surfaces (periocular, nasal, etc) are not eligible for injection because
                 the area cannot be properly contained with an occlusive dressing
    
              -  Subjects must have radiographically or clinically measurable disease, defined as at
                 least one lesion that is >= 10 mm in diameter in at least 1 dimension, or an
                 aggregate of lesions that measures >= 10 mm in diameter in at least 1 dimension
    
              -  Subjects must be able and willing to undergo serial biopsies of injected lesion(s)
                 and, when applicable and clinically feasible, non-injected lesions
    
              -  Subjects who are on immunosuppressive medications must be stable on their regimen for
                 > 60 days prior to study entry
    
              -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
    
              -  Absolute neutrophil count (ANC) >= 1.2 x 10^9/L
    
              -  Hemoglobin >= 9 g/dL without transfusion in the preceding 7 days
    
              -  Platelets >= 75 x 10^9/L
    
              -  Albumin >= 2.5 g/dL
    
              -  Serum total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (patients
                 with Gilbert's syndrome with a total bilirubin < 3.0 mg/dL)
    
              -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x
                 institutional ULN
    
              -  Serum creatinine =< 1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault
                 formula) >= 50 mL/min OR 24-hour urine creatinine clearance >= 50 mL/min
    
              -  Prothrombin time (PT)/international normalized ratio (INR) and partial thromboplastin
                 time (PTT) =< 1.5 x institutional UNL, unless the subject is on anticoagulant
                 therapy; (if the subject is receiving anticoagulant therapy, PT, and activated PTT
                 (aPTT) must be within therapeutic range of intended use of anticoagulants)
    
              -  Women of child-bearing potential (WOCBP) and men must agree to use adequate
                 contraception (hormonal or barrier method of birth control; abstinence from
                 heterosexual intercourse) prior to study entry, during the study participation, and
                 for three months after the last dose of the drug; WOCBP must have a negative serum
                 pregnancy test within 14 days prior to randomization and agree to use effective
                 contraception throughout the treatment period and for 3 months after the last dose of
                 study treatment; 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
    
              -  Ability to understand and the willingness to sign a written informed consent document
    
            Exclusion Criteria:
    
              -  Excluded tumor types
    
                   -  Melanoma
    
                   -  Bone sarcomas
    
                   -  Soft tissue sarcomas, including angiosarcoma, primary cutaneous leiomyosarcoma,
                      dermatofibrosarcoma protruberans
    
                   -  Leukemias
    
                   -  Myeloid sarcoma, leukemia cutis, and chloroma
    
                   -  Hodgkin's lymphoma
    
                   -  B cell lymphoma
    
              -  Patients who have had systemic therapy or radiotherapy within 3 weeks prior to the
                 first dose of study therapy
    
              -  Untreated central nervous system (CNS) involvement
    
              -  Previous treatment with T-VEC or other herpes virus based therapy; (prior therapy
                 with checkpoint inhibitors and/or other immunotherapy is allowed)
    
              -  Patients who have not recovered from adverse events due to prior anti-cancer therapy
                 (i.e., have residual toxicities > grade 1 excepting alopecia, peripheral sensory
                 neuropathy, and stable endocrine insufficiencies such as thyroid and adrenal
                 insufficiency)
    
              -  Second primary malignancy, only if it would affect the safety of the treatment or the
                 subject's ability to complete study-related procedures
    
              -  History or evidence of active autoimmune disease (e.g., pneumonitis,
                 glomerulonephritis, vasculitis, or other); or history of active autoimmune disease
                 that has required systemic treatment (i.e., use of corticosteroids, immunosuppressive
                 drugs or biological agents used for treatment of autoimmune diseases) within 2 months
                 of enrollment; (replacement therapy [e.g., thyroxine for hypothyroidism, insulin for
                 diabetes or physiologic corticosteroid replacement therapy for adrenal or pituitary
                 insufficiency] is not considered a form of systemic treatment for autoimmune disease)
    
              -  Evidence of clinically significant immunosuppression such as the following:
    
                   -  Primary immunodeficiency state such as severe combined immunodeficiency disease
    
                   -  Receiving systemic immunosuppressive therapy including prednisone > 10 mg per
                      day (or equivalent), tacrolimus, everolimus, sirolimus, mycophenolate mofetil,
                      etanercept, infliximab, etc.
    
                   -  Patients currently receiving extracorporeal photopheresis for treatment of graft
                      versus host disease (GVHD) are excluded
    
                   -  Notes: Oral steroid doses =< 10 mg/day of prednisone (or equivalent) are not
                      considered immunosuppressive and are permitted; inhaled and intraarticular
                      corticosteroids are permitted
    
              -  Active herpetic skin lesions or prior complications of herpetic infection (e.g.,
                 herpetic keratitis or encephalitis)
    
              -  Viral infections requiring intermittent or chronic systemic (intravenous or oral)
                 treatment with an antiherpetic drug (e.g., acyclovir), other than intermittent
                 topical use
    
              -  Other viral infections:
    
                   -  Known to have acute or chronic active hepatitis B or hepatitis C infection
    
                   -  Known to have human immunodeficiency virus (HIV) infection
    
                   -  Prior therapy with viral-based tumor vaccine
    
                   -  Received live vaccine within 28 days prior to enrollment
    
              -  Subject who is unwilling to minimize exposure with his/her blood or other body fluids
                 to individuals who are at higher risks for human herpesvirus 1 (HSV-1) induced
                 complications such as immunosuppressed individuals, individuals known to have HIV
                 infection, pregnant women, or children under the age of 1 year, during T-VEC
                 treatment and through 30 days after the last dose of T-VEC
    
              -  Has a history of (non-infectious) pneumonitis that required steroids or current
                 pneumonitis
    
              -  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
    
              -  Female subject is pregnant or breast-feeding, or planning to become pregnant during
                 study treatment and through 3 months after the last dose of T-VEC; female subject of
                 childbearing potential who is unwilling to use acceptable method(s) of effective
                 contraception during study treatment and through 3 months after the last dose of
                 T-VEC; sexually active subjects and their partners unwilling to use male or female
                 latex condom to avoid potential viral transmission during sexual contact while on
                 treatment and within 30 days after treatment with T-VEC
    
              -  HIV-positive patients on combination antiretroviral therapy are ineligible;
                 appropriate studies will be undertaken in patients receiving combination
                 antiretroviral therapy when indicated
    
              -  Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to T-VEC
                 or any of its components or nivolumab, or history of severe hypersensitivity reaction
                 to any monoclonal antibody
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:All
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Best overall response rate to talimogene laherparepvec alone as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:Arm assignment is based on tumor type: Merkel cell carcinoma, squamous cell carcinoma, other non-melanoma skin cancers, and refractory T cell lymphomas and NK cell lymphomas. If at least 4 responses were observed in an arm (observed RR = 4/17 or 23.5%), T-VEC would be considered promising in that tumor type. Between-arm comparisons will not be performed

    Secondary Outcome Measures

    Measure:Best overall response rate to talimogene laherparepvec and nivolumab combination therapy as assessed by RECIST version 1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Durable response rate defined as complete response or partial response lasting >= 6 months
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Frequency of curative surgery (unresectable lesion becomes resectable)
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
    Time Frame:Up to week 24
    Safety Issue:
    Description:
    Measure:Overall survival
    Time Frame:At 1 year
    Safety Issue:
    Description:
    Measure:Overall survival
    Time Frame:At 2 years
    Safety Issue:
    Description:
    Measure:Progression free survival
    Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed at 1 year
    Safety Issue:
    Description:
    Measure:Progression free survival
    Time Frame:From start of treatment to time of progression or death, whichever occurs first, assessed at 2 years
    Safety Issue:
    Description:
    Measure:Response rate by cancer type assessed by RECIST version 1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Response rate of injected lesions assessed by RECIST version 1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:
    Measure:Response rate of non-injected lesions assessed by RECIST version 1.1
    Time Frame:Up to 1 year
    Safety Issue:
    Description:

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Not yet recruiting
    Lead Sponsor:National Cancer Institute (NCI)

    Last Updated

    April 18, 2017