PRIMARY OBJECTIVE:
I. To evaluate the objective response rate (confirmed complete and partial responses) of
treatment with talimogene laherparepvec (T-VEC) in combination with pembrolizumab (MK-3475)
following progression on prior anti-PD-1 or anti-PD-L1 therapy alone or in combination with
other agents different from talimogene laherparepvec (T-VEC).
SECONDARY OBJECTIVES:
I. To estimate the durable response rate. II. To estimate the objective response rate (ORR)
defined as confirmed and unconfirmed, complete and partial responses in the injected lesions.
III. To estimate the ORR in the non-visceral, non-injected lesions. IV. To estimate the ORR
in the visceral lesions (Cohort A). 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.
TRANSLATIONAL OBJECTIVES:
I. To evaluate whether adding talimogene laherparepvec (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 talimogene laherparepvec (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 talimogene laherparepvec (T-VEC) can
improve the tumor immune microenvironment.
IV. To evaluate whether tumor mutational load, mutations in the IFN pathway, and circulating
tumor deoxyribonucleic acid (DNA) profile are is associated with response to talimogene
laherparepvec (T-VEC) plus pembrolizumab (MK-3475) 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 36
cycles in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 1 year
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 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,
or the limbs is required only if the patient has a lesion(s) in these areas; 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's 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
- Patients must, in the opinion of the treating physician, be candidates for
intralesional administration into cutaneous, subcutaneous, or nodal lesions
- Patients may have brain metastases if all lesions have been treated with stereotactic
radiation therapy, craniotomy, or gamma knife therapy 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; patients who
have progressed after adjuvant anti-PD1/L1 agents are eligible
- Patients must have Zubrod performance status =< 2
- Absolute neutrophil count (ANC) >= 1,500/mcL (within 28 days prior to registration)
- Hemoglobin >= 8 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 (=< 3 x IULN is eligible) (within 28 days prior to
registration)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 3 x IULN
(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 be offered the opportunity to submit archival tissue for translational
medicine; patients must also be willing to undergo biopsies and submit tissue and
blood for translational medicine; with patients consent, any remaining specimens will
be banked for future use
- 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
Exclusion Criteria:
- Cohort B: Patients must not have any visceral lesions
- 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 14 days prior to registration; patients
must not have had a monoclonal antibody for cancer treatment, 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 neuropathy, =< grade 2 hypothyroidism, 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);
prior treatment with T-VEC is defined as receiving at least one injection with 1 x
10^8 plaque forming units (pfu)
- 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 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, or human
immunodeficiency virus (HIV) due to contraindication of talimogene laherparepvec
(T-VEC) in immune-compromised patients and that administration of talimogene
laherparepvec (T-VEC) has not been tested in HIV-positive patients; 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 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 active autoimmune disease (e.g., pneumonitis,
glomerulonephritis, vasculitis, or other) that requires systemic treatment (i.e., use
of corticosteroids, immunosuppressive drugs or biological agents used for treatment of
autoimmune diseases) in the past 2 years; 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
- Patients must not have any other malignancy that requires active treatment
- Patients must not be pregnant or nursing due to risk of fetal or nursing infant harm;
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
