Talimogene Laherparepvec and Pembrolizumab in Treating Patients With Stage III-IV Melanoma

PRIMARY OBJECTIVES:

I. To evaluate the durable response rate of treatment with talimogene laherparepvec (T-VEC)
in combination with MK-3475 (pembrolizumab) following progression on prior anti-PD-1 or
anti-PD-L1 therapy alone or in combination with other agents different from T-VEC.

SECONDARY OBJECTIVES:

I. To estimate the objective response rate (confirmed and unconfirmed, complete and partial
responses) in the injected lesions.

II. To estimate the objective response rate (ORR) in the non-visceral, non-injected lesions.

III. To estimate the objective response rate (ORR) in the visceral lesions (Cohort A).

IV. To estimate the overall objective response rate (ORR). V. To estimate the median
progression-free survival (PFS). VI. To estimate the median overall survival (OS). VII. To
evaluate the toxicity of the regimen.

TERTIARY OBJECTIVES:

I. To evaluate whether adding T-VEC to PD1 blockade can increase T-cell infiltration into
tumors and whether change in T-cell infiltration is associated with response.

II. To evaluate whether adding T-VEC to PD1 blockade can increase T-cell receptor (TCR)
clonality in tumors and in peripheral blood and whether increased TCR clonality is associated
with response.

III. To evaluate whether intra-tumoral injection of T-VEC is associated with the tumor immune
microenvironment.

IV. To evaluate whether tumor mutational load and mutations in the IFN pathway is associated
with response to T-VEC plus MK-3475 (pembrolizumab) therapy in the anti-PD1/L1 therapy
refractory melanoma patients.

OUTLINE:

Patients receive talimogene laherparepvec intralesionally (IL) and pembrolizumab
intravenously (IV) over 30 minutes on day 1. Treatment repeats every 21 days for up to 18
courses for talimogene laherparepvec and 36 courses for pembrolizumab in the absence of
disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months for up to 2
years and then annually for a total of 5 years.

Inclusion Criteria:

- Patients must have pathologically confirmed stage IV or unresectable stage III
melanoma; patients must not have disease that is suitable for local therapy,
administered with curative intent

- Patients must have measurable disease per Response Evaluation Criteria in Solid Tumors
(RECIST) 1.1; contrast-enhanced computed tomography (CT) scans of the neck, chest,
abdomen and pelvis are required; a whole body positron emission tomography (PET)/CT
scan with diagnostic quality images and intravenous iodinated contrast may be used in
lieu of a contrast enhanced CT of the chest, abdomen and pelvis; imaging of the head
and neck is required only if the patient has a head/neck primary; contrast may be
omitted if the treating investigator believes that exposure to contrast poses an
excessive risk to the patient; if skin lesions are being followed as measurable
disease, photograph with a ruler included and physician measurements, must be kept in
the patients chart as source documentation; all measurable lesions must be assessed
within 28 days prior to registration; tests to assess non-measurable disease must be
performed within 42 days prior to registration; all disease must be assessed and
documented on the baseline tumor assessment form (RECIST 1.1)

- Cohort A: Patients must have at least one measurable visceral lesion (per RECIST 1.1);
a visceral lesion is any solid organ except for skin, lymph node, and musculoskeletal
tissue; at least one of these visceral lesions must be measurable per RECIST 1.1

- Cohort B: Patients must not have any visceral lesions

- Patients must, in the opinion of the treating physician, be candidates for
intralesional administration into cutaneous, subcutaneous, or nodal lesions; patients
must have at least 2 injectable lesions

- Patients may have brain metastases if all lesions have been treated with stereotactic
radiation therapy, craniotomy, or gamma knife therapy with no evidence of progression
(demonstrated by identical imaging modality for 2 consecutive assessments/scans
[magnetic resonance imaging (MRI) or CT scans], at least 4 weeks apart) and have not
required steroids for at least 14 days prior to registration

- Patient must have had prior treatment with anti-PD-1 or anti-PD-L1 agents and have
documented disease progression on these agents prior to registration; patient must
have received anti-PD-1 or PD-L1 based therapy as the immediate previous line of
treatment and within 56 days prior to registration

- Patients must not have had surgery, biologic therapy, or hormonal therapy within 14
days prior to registration; patients must not have had chemotherapy, targeted small
molecule therapy, or radiation therapy within 28 days (42 days for nitrosoureas or
mitomycin C) prior to registration; patients must not have had an investigational
agent or monoclonal antibodies, except anti-PD1/L1 antibodies, within 28 days prior to
registration

- Patients must have recovered from all adverse events due to prior anti-cancer
therapy (residual toxicity =< grade 1) prior to registration, with the exception
of patients with =< grade 2 neuropath or =< grade 2 alopecia

- If patients received major surgery, they must have recovered adequately from
toxicity and/or complications from the intervention prior to registration

- Patients must not have received prior treatment with talimogene laherparepvec (T-VEC)
or other oncolytic virus agents

- Patients must not have received any live vaccine within 30 days prior to registration;
seasonal flu vaccines that do not contain live virus are permitted

- Patients must not be planning to receive other biologic therapy, radiation therapy,
hormonal therapy, chemotherapy, surgery, or other therapy while on this protocol;
palliative radiation therapy or surgery can be considered for symptomatic non-target
lesions after discussions with the study team

- Patients must have Zubrod performance status =< 2

- Absolute neutrophil count (ANC) >= 1,500/mcL within 28 days prior to registration

- Hemoglobin >= 9 g/dL within 28 days prior to registration

- Platelets >= 100,000/mcL within 28 days prior to registration

- Albumin >= 2.5 g/dL within 28 days prior to registration

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) except patients
with documented Gilbert's syndrome within 28 days prior to registration

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both < 2.5 x IULN
within 28 days prior to registration

- Serum creatinine < 2.0 x IULN within 28 days prior to registration

- Patients must have prothrombin time (PT) / international normalized ratio (INR) and
partial thromboplastin time (PTT) =< 2.0 x institutional upper limit of normal (IULN)
unless the patient is on anticoagulant therapy within 28 days prior to registration
(if the patient is receiving anticoagulant therapy, PT, and a PTT must be within
therapeutic range of intended use of anticoagulants)

- Activated partial thromboplastin time (aPTT) =< 2.0 x IULN if not using anticoagulants
within 28 days prior to registration; if using anticoagulants, then the value must be
within therapeutic range according to the condition for which the patient is being
treated within 28 days prior to registration

- Patients must have lactate dehydrogenase (LDH) obtained prior to registration

- Patients must have complete physical examination and medical history obtained within
28 days prior to registration

- Patients must not require use of systemic corticosteroid within 14 days prior to
registration or during protocol treatment; patients with preexisting severe autoimmune
disease requiring systemic corticosteroids or ongoing immunosuppression are not
eligible

- Patients must not have known history of hepatitis B, hepatitis C, human
immunodeficiency virus (HIV); the use of physiologic doses of corticosteroids may be
approved after consultation with the study chair

- Patients must not have history of (non-infectious) pneumonitis that required steroids
or current pneumonitis

- Patients must not have an active infection requiring systemic therapy nor a viral
infection requiring intermittent treatment with an antiherpetic drug, other than
intermittent topical use

- Patients must not have active herpetic skin lesions or prior complications of herpetic
infection (e.g., herpetic keratitis or encephalitis) which requires intermittent or
chronic treatment with an anti-herpetic drug other than intermittent topical use

- Patients must not have organ allografts

- Patients must not have an uncontrolled intercurrent illness including, but not limited
to, nonmalignant medical illnesses that are uncontrolled or whose control may be
jeopardized by the treatment with the study therapy, or psychiatric illness/social
situations which would limit compliance with study requirements

- Patients must not have 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 registration; 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

- Patient must not have evidence of any clinically significant immunosuppression such as
the following:

- Primary immunodeficiency state such as severe combined immunodeficiency disease;

- Concurrent opportunistic infection;

- Receiving systemic immunosuppressive therapy (> 2 weeks) including oral steroid
doses > 10 mg/day of prednisone or equivalent within 2 months prior to enrollment

- No other prior malignancy is allowed except for the following: adequately treated
basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated
stage I or II cancer from which the patient is currently in complete remission, or any
other cancer from which the patient has been disease free for two years

- Patients must not be pregnant or nursing; women of reproductive potential must have a
negative serum pregnancy test within 7 days prior to registration; women/men of
reproductive potential must have agreed to use an effective contraceptive method while
on study and for 120 days after last study treatment; a woman is considered to be of
"reproductive potential" if she has had menses at any time in the preceding 12
consecutive months; in addition to routine contraceptive methods, "effective
contraception" also includes heterosexual celibacy and surgery intended to prevent
pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy,
bilateral oophorectomy or bilateral tubal ligation; however, if at any point a
previously celibate patient chooses to become heterosexually active during the time
period for use of contraceptive measures outlined in the protocol, he/she is
responsible for beginning contraceptive measures

- Patients must be willing to submit blood and tissue specimens for translational
medicine

- Patients must be offered the opportunity to participate in specimen banking for future
research

- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines

- As a part of the Oncology Patient Enrollment Network (OPEN) registration process the
treating institution's identity is provided in order to ensure that the current
(within 365 days) date of institutional review board approval for this study has been
entered in the system