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

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ClinicalTrials.gov Identifier: NCT02978625
Recruitment Status : Recruiting
First Posted : December 1, 2016
Last Update Posted : June 14, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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. 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 in treating patients with lymphomas or non-melanoma skin cancers.

Condition or disease Intervention/treatment Phase
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 Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma Refractory Mycosis Fungoides Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma 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 Stage III Skin Cancer Stage IV Skin Cancer Sweat Gland Carcinoma Trichilemmocarcinoma Vulvar Squamous Cell Carcinoma Other: Laboratory Biomarker Analysis Biological: Nivolumab Biological: Talimogene Laherparepvec Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

I. To determine the local response rate to talimogene laherparepvec in injected tumors.

II. To determine the response rate to talimogene laherparepvec + 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. Cycles repeat every 21 for course 1 then every 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 68 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study of Talimogene Laherparepvec Followed by Talimogene Laherparepvec + Nivolumab in Refractory T Cell and NK Cell Lymphomas, Cutaneous Squamous Cell Carcinoma, Merkel Cell Carcinoma, and Other Rare Skin Tumors
Actual Study Start Date : September 18, 2017
Estimated Primary Completion Date : January 1, 2020
Estimated Study Completion Date : January 1, 2020


Arm Intervention/treatment
Experimental: Treatment (talimogene laherparepvec, nivolumab)
Patients receive talimogene laherparepvec IT on day 1. Patients without response at week 12, may also receive nivolumab IV over 60 minutes on day 1. Cycles repeat every 21 days for course 1 then every 14 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Biological: Talimogene Laherparepvec
Given IT
Other Names:
  • ICP34.5-, ICP47-deleted Herpes Simplex Virus 1 (HSV-1) Incorporating the Human GM-CSF Gene
  • Imlygic
  • JS1 34.5-hGMCSF 47- pA-
  • T-VEC




Primary Outcome Measures :
  1. Best overall response rate to talimogene laherparepvec alone [ Time Frame: Up to 1 year ]
    Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 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 response rate [RR] = 4/17 or 23.5%), talimogene laherparepvec (T-VEC) would be considered promising in that tumor type. Between-arm comparisons will not be performed


Secondary Outcome Measures :
  1. Best overall response rate to talimogene laherparepvec and nivolumab combination therapy [ Time Frame: Up to 1 year ]
    Will be assessed by RECIST version 1.1.

  2. Durable response rate [ Time Frame: Up to 1 year ]
    Will be defined as complete response or partial response lasting >= 6 months.

  3. Response rate by cancer type [ Time Frame: Up to 1 year ]
    Will be assessed by RECIST version 1.1.

  4. Response rate of injected lesions [ Time Frame: Up to 1 year ]
    Will be assessed by RECIST version 1.1.

  5. Response rate of non-injected lesions [ Time Frame: Up to 1 year ]
    Will be assessed by RECIST version 1.1.

  6. Frequency of curative surgery (unresectable lesion becomes resectable) [ Time Frame: Up to 1 year ]
  7. Progression free survival [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed at 1 year ]
  8. Progression free survival [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed at 2 years ]
  9. Overall survival [ Time Frame: At 1 year ]
  10. Overall survival [ Time Frame: At 2 years ]
  11. Incidence of adverse events [ Time Frame: Up to week 24 ]
    Will be assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.


Other Outcome Measures:
  1. Change in herpes simplex virus (HSV) serostatus assessed in blood specimens [ Time Frame: Baseline to week 6 ]
    Will be analyzed using descriptive statistics. A test of proportions will be performed.

  2. Biomarker analysis of %PD-L1, flow cytometry for HVEM, NECTIN1/2, and IDO, tryptophan and L-kynurenine, cytokine levels, Nanostring, number of non-synonymous mutations, and % T-cell receptor (TCR) clonality [ Time Frame: Up to 1 year ]
    Will be analyzed using descriptive statistics. Logistic regression of response rate on the variable will be performed.

  3. Biomarker analysis of necrosis and Nanostring [ Time Frame: Up to 1 year ]
    Will be analyzed using descriptive statistics. Logistic regression of response rate on the variable will be performed.

  4. Biomarker analysis of herpes simplex virus (HSV) status, Merkel cell polyomavirus status, and PD-L1 status [ Time Frame: Up to 1 year ]
    Will be analyzed using descriptive statistics. Test of proportions and logistic regression will be performed.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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
    • Other non-melanoma skin cancers

      • 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
      • Extramammary 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
  • 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
  • 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 (Cockcroft-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 ULN, 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 7 months after the last dose of the drug; WOCBP must have a negative serum pregnancy test within 14 days prior to randomization; 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 must agree to use adequate contraception prior to study entry, during the study participation and for 7 months after the last dose of the drug
  • 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 protuberans
    • 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 talimogene laherparepvec 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.
    • Recipients of solid organ, bone marrow, or stem cell transplants; auto transplant recipients are allowed
    • 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 talimogene laherparepvec treatment and through 30 days after the last dose of talimogene laherparepvec
  • 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 7 months after the last dose of treatment; female subject of childbearing potential who is unwilling to use acceptable method(s) of effective contraception during study treatment and through 7 months after the last dose of treatment; 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 talimogene laherparepvec
  • Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to talimogene laherparepvec or any of its components or nivolumab, or history of severe hypersensitivity reaction to any monoclonal antibody

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02978625


  Show 21 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Ann (Annie) W Silk Rutgers University - Cancer Institute of New Jersey LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02978625     History of Changes
Other Study ID Numbers: NCI-2016-01804
NCI-2016-01804 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
CINJ #091701
10057 ( Other Identifier: Rutgers University - Cancer Institute of New Jersey LAO )
10057 ( Other Identifier: CTEP )
UM1CA186716 ( U.S. NIH Grant/Contract )
First Posted: December 1, 2016    Key Record Dates
Last Update Posted: June 14, 2019
Last Verified: January 2019

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
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Lymphoma
Carcinoma
Carcinoma, Squamous Cell
Adenocarcinoma
Lymphoma, Non-Hodgkin
Mycoses
Mycosis Fungoides
Sezary Syndrome
Lymphoma, T-Cell
Lymphoma, T-Cell, Cutaneous
Carcinoma, Basal Cell
Skin Neoplasms
Lymphoma, Large-Cell, Anaplastic
Carcinoma, Adenoid Cystic
Carcinoma, Merkel Cell
Neoplasms, Unknown Primary
Lymphoma, T-Cell, Peripheral
Adenocarcinoma, Papillary
Carcinoma, Signet Ring Cell
Adenocarcinoma, Mucinous
Keratoacanthoma
Muir-Torre Syndrome
Eccrine Porocarcinoma
Carcinoma, Skin Appendage
Carcinoma, Basosquamous
Sweat Gland Neoplasms
Adenocarcinoma, Sebaceous
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders