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

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.

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