Clinical trial NCT02978625: 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 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Anaplastic Large Cell Lymphoma, ALK-Negative
Anaplastic Large Cell Lymphoma, ALK-Positive
Apocrine Carcinoma
Carcinoma Arising From Cylindroma
Carcinoma Arising From Spiradenoma
Digital Papillary Adenocarcinoma
Endocrine Mucin-Producing Sweat Gland Carcinoma
Extramammary Paget Disease
Extraocular Sebaceous Carcinoma
Hidradenocarcinoma
Malignant Sweat Gland Neoplasm
Merkel Cell Carcinoma
Microcystic Adnexal Carcinoma
NK-Cell Lymphoma, Unclassifiable
Papillary Adenocarcinoma
Porocarcinoma
Primary Cutaneous Mucinous Carcinoma
Recurrent Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Recurrent T-Cell Non-Hodgkin Lymphoma
Refractory Anaplastic Large Cell Lymphoma
Refractory Mature T-Cell and NK-Cell Non-Hodgkin Lymphoma
Refractory Merkel Cell Carcinoma
Refractory Mycosis Fungoides
Refractory Primary Cutaneous T-Cell Non-Hodgkin Lymphoma
Refractory Skin Squamous Cell Carcinoma
Refractory T-Cell Non-Hodgkin Lymphoma
Sezary Syndrome
Signet Ring Cell Adenocarcinoma
Skin Adenoid Cystic Carcinoma
Skin Adnexal Carcinoma
Skin Basal Cell Carcinoma
Skin Basosquamous Cell Carcinoma
Skin Keratoacanthoma
Skin Squamous Cell Carcinoma
Squamoid Eccrine Ductal Carcinoma
Squamous Cell Carcinoma of Unknown Primary
Sweat Gland Carcinoma
Trichilemmal Carcinoma
Vulvar Squamous Cell Carcinoma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2016-12-01
Enrollment: 68
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: PRIMARY OBJECTIVE:

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) and nivolumab intravenously (IV) over 30 minutes on day 1. Cycles repeat every 21 days for cycle 1 then every 14 days for up to 1 year in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT) scan or positron emission tomography (PET)/CT scan on study. Patients also undergo blood sample collection and biopsies on study.

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

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
* PART I (before February 2020 amendment): 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)
* PART II (after February 2020 amendment):

  * The Merkel cell carcinoma (MCC)-2 cohort will include patients with MCC
  * The squamous cell carcinoma (SCC)-2 cohort will include patients with SCC
* PART I (before February 2020 amendment): 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
* PART I (before February 2020 amendment): 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
* PART I (before February 2020 amendment): 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
* PART I (before February 2020 amendment): 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
* PART I (before February 2020 amendment): Subjects must be able and willing to undergo serial biopsies of injected lesion(s) and, when applicable and clinically feasible, non-injected lesions
* PART I (before February 2020 amendment): Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
* PART I (before February 2020 amendment): Absolute neutrophil count (ANC) \>= 1.2 x 10\^9/L
* PART I (before February 2020 amendment): Hemoglobin \>= 9 g/dL without transfusion in the preceding 7 days
* PART I (before February 2020 amendment): Platelets \>= 75 x 10\^9/L
* PART I (before February 2020 amendment): 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)
* PART I (before February 2020 amendment): Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x institutional ULN
* PART I (before February 2020 amendment): 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
* PART I (before February 2020 amendment): 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)
* PART I (before February 2020 amendment): Talimogene laherparepvec, nivolumab and other therapeutic agents used in this trial may cause fetal harm when administered to a pregnant woman; women of child-bearing potential (WOCBP) and 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
* PART I (before February 2020 amendment): Ability to understand and the willingness to sign a written informed consent document
* PART II (after February 2020 amendment): Subjects in expansion cohorts MCC-2 and SCC-2 must have a diagnosis of MCC or SCC, respectively
* PART II (after February 2020 amendment): Subjects must have refractory disease, defined as evidence of progressive disease despite prior therapy with a PD-1 or PD-L1 blocking antibody (avelumab, pembrolizumab, nivolumab, cemiplimab, etc.); progression must have occurred during PD-1 or PD-L1 directed therapy or within 6 months of the last dose of PD-1 or PD-L1 directed therapy
* PART II (after February 2020 amendment): 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
* PART II (after February 2020 amendment): 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
* PART II (after February 2020 amendment): Subjects must be able and willing to undergo serial biopsies of injected lesion(s) and, when applicable and clinically feasible, non-injected lesions
* PART II (after February 2020 amendment): ECOG performance status =\< 2 (Karnofsky \>= 60%)
* PART II (after February 2020 amendment): Absolute neutrophil count (ANC) \>= 1.2 x 10\^9/L
* PART II (after February 2020 amendment): Hemoglobin \>= 9 g/dL without transfusion in the preceding 7 days
* PART II: P (after February 2020 amendment): Platelets \>= 75 x 10\^9/L
* PART II (after February 2020 amendment): 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.)
* PART II (after February 2020 amendment): Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x institutional ULN
* PART II (after February 2020 amendment): 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
* PART II (after February 2020 amendment): 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 aPTT must be within therapeutic range of intended use of anticoagulants)
* PART II (after February 2020 amendment): Talimogene laherparepvec, nivolumab and other therapeutic agents used in this trial may cause fetal harm when administered to a pregnant woman; women of child-bearing potential (WOCBP) and 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
* PART II (after February 2020 amendment): 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; patients with known brain metastases are eligible if they have been treated and are stable in the view of the treating investigator
* 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

Primary outcomes:
measure: Response rate to talimogene laherparepvec alone (Part I)
timeFrame: Up to 1 year
measure: Best overall response rate to talimogene laherparepvec and nivolumab combination therapy (Part II)
timeFrame: Up to 1 year
Secondary outcomes:
measure: Durable response rate
timeFrame: Up to 1 year
measure: Response rate by cancer type
timeFrame: Up to 1 year
measure: Response rate of injected lesions
timeFrame: Up to 1 year
measure: Response rate of non-injected lesions
timeFrame: Up to 1 year
measure: Frequency of curative surgery (unresectable lesion becomes resectable)
timeFrame: Up to 1 year
measure: Progression free survival
timeFrame: From start of treatment to time of progression or death, whichever occurs first, assessed at 1 year
measure: Progression free survival
timeFrame: From start of treatment to time of progression or death, whichever occurs first, assessed at 2 years
measure: Overall survival
timeFrame: At 1 year
measure: Overall survival
timeFrame: At 2 years
measure: Incidence of adverse events
timeFrame: Up to week 24
Other outcomes:
measure: Change in herpes simplex virus (HSV) serostatus assessed in blood specimens
timeFrame: Baseline to week 6
measure: 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
timeFrame: Up to 1 year
measure: Biomarker analysis of necrosis and Nanostring
timeFrame: Up to 1 year
measure: Biomarker analysis of herpes simplex virus (HSV) status, Merkel cell polyomavirus status, and PD-L1 status
timeFrame: Up to 1 year
Locations:
city: Los Angeles
country: United States
facility: Los Angeles General Medical Center
state: California
city: Los Angeles
country: United States
facility: USC / Norris Comprehensive Cancer Center
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Pasadena
country: United States
facility: Keck Medical Center of USC Pasadena
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Aurora
country: United States
facility: UCHealth University of Colorado Hospital
state: Colorado
city: Aventura
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Aventura
state: Florida
city: Coral Gables
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Coral Gables
state: Florida
city: Deerfield Beach
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Deerfield Beach
state: Florida
city: Miami
country: United States
facility: University of Miami Miller School of Medicine-Sylvester Cancer Center
state: Florida
city: Miami
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Kendall
state: Florida
city: Plantation
country: United States
facility: UM Sylvester Comprehensive Cancer Center at Plantation
state: Florida
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Fairway
country: United States
facility: University of Kansas Clinical Research Center
state: Kansas
city: Overland Park
country: United States
facility: University of Kansas Cancer Center-Overland Park
state: Kansas
city: Overland Park
country: United States
facility: University of Kansas Hospital-Indian Creek Campus
state: Kansas
city: Westwood
country: United States
facility: University of Kansas Hospital-Westwood Cancer Center
state: Kansas
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Massachusetts General Hospital Cancer Center
state: Massachusetts
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Kansas City
country: United States
facility: University of Kansas Cancer Center - North
state: Missouri
city: Lee's Summit
country: United States
facility: University of Kansas Cancer Center - Lee's Summit
state: Missouri
city: North Kansas City
country: United States
facility: University of Kansas Cancer Center at North Kansas City Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Lebanon
country: United States
facility: Dartmouth Hitchcock Medical Center/Dartmouth Cancer Center
state: New Hampshire
city: New Brunswick
country: United States
facility: Rutgers Cancer Institute of New Jersey
state: New Jersey
city: Buffalo
country: United States
facility: Roswell Park Cancer Institute
state: New York
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Pittsburgh
country: United States
facility: University of Pittsburgh Cancer Institute (UPCI)
state: Pennsylvania
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: Salt Lake City
country: United States
facility: Huntsman Cancer Institute/University of Utah
state: Utah
Study officials:
affiliation: Dana-Farber - Harvard Cancer Center LAO
name: Ann (Annie) W Silk
role: PRINCIPAL_INVESTIGATOR
References: