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

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.

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