Squamous Cell Carcinoma of the Head and Neck

Primary Objective: Phase 3: To evaluate the efficacy, as assessed by overall survival (OS), of treatment with talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab in subjects with recurrent or metastatic SCCHN Secondary Objective(s): Phase 3 o To evaluate the efficacy of talimogene laherparepvec with pembrolizumab versus placebo with pembrolizumab, as assessed by: oCRR and PFS (response evaluation by investigator using irRECIST) oORR, BOR; DOR, and DCR (response evaluation by investigator using irRECIST) o 1-year, 2-year, and 3-year survival oSubject incidence of treatment-emergent and treatment-related adverse events (all adverse events, grade • 3 adverse events, serious adverse events, fatal adverse events, adverse events and serious adverse events leading to discontinuation of treatment, and adverse events defined as events of interest) o To evaluate patient reported outcomes (PRO) as assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) Global Health Status/Quality of life (GHS/QoL) subscale.

IMLYGIC

Talimogene laherparepvec

solution for injection

10^6 PFU/mL or 10^8 PFU/mL

Primary Endpoint:
Phase 3
x OS

Secondary Endpoint(s):
Phase 3
x CRR and PFS (response evaluation by investigator using irRECIST)
x ORR, BOR; DOR, and DCR (response evaluation by investigator using irRECIST)
x 1-year, 2-year, and 3-year survival
x Subject incidence of treatment-emergent and treatment-related adverse events (all
adverse events and serious adverse events leading to discontinuation of treatment, and
adverse events defined as events of interest).
x Summary scores at each assessment and changes from baseline of PROs as
assessed by QLQ-C30 GHS/QoL subscale.

Inclusion Criteria
101 Subject has provided informed consent prior to initiation of any study-specific
activities/procedures
102 Male or female age ≥ 18 years at the time of informed consent
103 Histologically confirmed diagnosis of metastatic or recurrent SCCHN of the oral
cavity, oropharynx, hypopharynx, or larynx. Disease must be unsuitable for
curative surgical resection and must not be amenable to curative radiotherapy.
104 Disease must have progressed after treatment with a platinum-containing
regimen and should be defined as one of the following:
• disease progression or recurrence between 3 to 6 months of prior curatively
intended multimodal therapy (which includes platinum therapy) for
locoregionally advanced SCCHN.
Note: This criterion is only applicable for subjects who have not had
treatment in the recurrent/metastatic setting.
• disease progression or recurrence after prior platinum therapy in the
recurrent or metastatic setting
105 Subject must be candidate for intralesional therapy administration defined as one
or more of the following:
• at least 1 injectable cutaneous, subcutaneous, or nodal SCCHN tumor
≥ 10 mm in longest diameter
• multiple injectable cutaneous, subcutaneous, or nodal SCCHN tumors that in
aggregate have a longest diameter of ≥ 10 mm
Note: Mucosal surfaces of tumor lesions and visceral metastases should not be
injected.
106 Subject must have radiographically measurable disease per RECIST 1.1
(Eisenhauer et al, 2009). Target lesions must not be chosen from a previously
irradiated field unless there has been radiographically and/or pathologically
documented tumor progression in that lesion prior to enrollment
107 ECOG performance status of 0 or 1
108 Adequate organ function determined within 14 days prior to enrollment, defined
as follows:
• Hematological
− ANC ≥ 1.5 x 109/L
− platelet count ≥ 100 x 109/L
− hemoglobin ≥ 9 g/dL
Note: Subjects who have received transfusion of blood products (including
platelets or red blood cells, or administration of colony stimulating factors
[including G-CSF, GM-CSF, or recombinant erythropoietin) within 4 weeks prior
to the first study treatment will be excluded.
• Renal
− serum creatinine ≤ 1.5 x upper limit of normal (ULN), OR creatinine
clearance ≥ 60 mL/min for a subject with creatinine levels > 1.5 x ULN.
(Note: Creatinine clearance need not be determined if the baseline serum
creatinine is within normal limits. Creatinine clearance should be
determined per institutional standard).
• Hepatic
− total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for a subject with total
bilirubin level > 1.5 x ULN
− aspartate aminotransferase (AST) ≤ 2.5 x ULN OR ≤ 5 x ULN for a
subject with liver metastases
− alanine aminotransferase (ALT) ≤ 2.5 x ULN OR ≤ 5 x ULN for a subject
with liver metastases
• Coagulation
− international normalization ratio (INR) or prothrombin time (PT)
≤ 1.5 x ULN, unless the subject is receiving anticoagulant therapy, in
which case PT and partial thromboplastin time (PTT)/activated PTT
(aPTT) must be within therapeutic range of intended use of
anticoagulants
109 PTT or aPTT ≤ 1.5 x ULN unless the subject is receiving anticoagulant therapy
as long as PT and PTT/aPTT is within therapeutic range of intended use of
anticoagulantsFemale subject of childbearing potential must have a negative
pregnancy test within 72 hours prior to enrollment. If urine pregnancy test is
positive or cannot be confirmed as negative, a serum pregnancy test will be
required.
110 Phase 1b: Subject has a formalin fixed paraffin-embedded tumor sample (within
6 months prior to week 0, day 1 of the study, or newly obtained biopsy) from the
primary or metastatic lesion that must be submitted within 4 weeks of
enrollment for PD-L1, HPV-testing of oropharyngeal cancer (if not
performed locally) and biomarker analyses.
Phase 3: Subject has a formalin fixed paraffin embedded tumor sample (within
6 months prior to week 0, day 1 of study or newly obtained biopsy) from the
primary or metastatic lesion that is adequate for PD-L1 assessment prior to
randomization (sites will be blinded to PD-L1 analysis). Tumor tissue from the
subject must be submitted to a central laboratory during screening. Subjects with
an inadequate or indeterminate tumor sample may obtain a new biopsy and
subjects with an inadequate or indeterminate newly obtained biopsy may
undergo re-biopsy at the discretion of the investigator. If applicable, biopsies
should be obtained outside of the field of maximum radiation dose delivered,
whenever possible. A fine needle aspirate will not satisfy tumor sample
requirements and a core biopsy or tumor block is required. Refer to the
laboratory manual for more detailed tissue collection procedures.
111 Phase 3: Have results from local testing of HPV of tumor specimen for
oropharyngeal cancer defined as p16 IHC testing using the CINtec assay and a
70% cutoff point. If the assay is unavailable locally, sites must submit archived or
recently biopsied formalin-fixed paraffin-embedded tumor tissue (block or
unstained tumor slides) from either the primary or metastatic lesion for central
laboratory testing. Note: HPV stratification in this trial will be performed using
local or central testing of HPV status in subjects with oropharynx cancer. Oral
cavity, hypopharynx, and larynx cancer are not required to undergo HPV testing
by p16 IHC as by convention, they are assumed to be HPV negative. Please
note that results from local testing of HPV of tumor specimen for
oropharyngeal cancer patients are required for both phases of the study.
Performing p16-IHC testing using the CINtec assay is only required for
phase 3.

Exclusion Criteria
201 Has known active CNS metastases and/or carcinomatous meningitis. Subjects
with previously treated brain metastases may participate provided they are stable
(without evidence of progression by imaging for at least four weeks prior to the
first dose of trial treatment and any neurologic symptoms have returned to
baseline), and are not using steroids for at least 7 days prior to trial treatment.
This exception does not include carcinomatous meningitis which is excluded
regardless of clinical stability.
202 Primary nasopharyngeal carcinoma.
203 Subject at risk of airway compromise in the event of postinjection tumor
swelling/inflammation based on investigator judgment.
204 Phase 3: Previous treatment with 3 or more systemic regimens given for
recurrent and/or metastatic disease.
205 History of other malignancy within the past 3 years with the following exceptions:
• malignancy treated with curative intent and with no known active disease
present and has not received chemotherapy for ≤ 3 years before enrollment
and felt to be at low risk for recurrence by the treating physician
• adequately treated non-melanoma skin cancer without evidence of disease at
the time of enrollment
• adequately treated cervical carcinoma in situ without evidence of disease at
the time of enrollment
• adequately treated breast ductal carcinoma in situ without evidence of
disease at the time of enrollment
• prostatic intraepithelial neoplasia without evidence of prostate cancer at the
time of enrollment
• adequately treated superficial or in situ carcinoma of the bladder without
evidence of disease at the time of enrollment
207 History of interstitial lung disease (ILD).
208 Prior therapy with talimogene laherparepvec, pembrolizumab, other anti-PD-1,
any other antibody or drug specifically targeting T-cell co-stimulation or immune
check point pathway.
210 History or evidence of active autoimmune disease that has required systemic
treatment in the past 2 years (ie, with use of disease modifying agents,
corticosteroids or immunosuppressive drugs).
Note: Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid
replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a
form of systemic treatment.
211 Evidence of clinically significant immunosuppression such as the following:
• organ transplant/bone marrow transplant or other signs or symptoms of
clinical immune system suppression
• any severe congenital or acquired cellular and/or humoral immune deficiency
• diagnosis of immunodeficiency
• concurrent opportunistic infection
• receiving systemic immunosuppressive therapy > 2 weeks or within 7 days
prior to the first dose of study treatment, including oral steroid doses
> 10 mg/day of prednisone or equivalent
Note: Subjects that require intermittent use of bronchodilators or local steroid
injection are not excluded from the study.
212 Active herpetic skin lesions or prior complications of herpetic infection
(eg, herpetic keratitis or encephalitis).
213 Requires intermittent or chronic treatment with an antiherpetic drug
(eg, acyclovir), other than intermittent topical use.
214 Prior chemotherapy, radiotherapy, biological cancer therapy, targeted therapy, or
major surgery within 28 days prior to enrollment or has not recovered to CTCAE
grade 1 or better from adverse event due to cancer therapy administered more
than 28 days prior to enrollment.
Note: Subjects with ≤ grade 2 neuropathy and/or alopecia are an exception to
this criterion and may qualify for the study.
215 Currently participating or have participated in a study (treatment period only) of
an investigational agent or used an investigational device within 28 days of
enrollment/randomization.
216 Expected to require other cancer therapy while on study with the exception of
local palliative radiation treatment to the site of bone and other metastasis.
217 Subject who is unwilling to forgo other investigational procedures during study
treatment.
218 Known human immunodeficiency virus (HIV) disease.
219 Has acute or chronic active hepatitis B virus or hepatitis C virus infection or
received treatment with nucleotide analogs such as those used in the treatment
of hepatitis B virus (eg, lamivudine, adefovir, tenofovir, telbivudine, entecavir),
ribavirin, or interferon alpha within 12 weeks of initiation of study treatment.
220 Received live vaccine within 28 days prior to enrollment/randomization.
221 Subject is pregnant or breast-feeding, or expecting to conceive or father children
within the duration of the trial, starting with the screening visit and through 3
months after the last dose of talimogene laherparepvec/placebo or 4 months
after the last dose of pembrolizumab, whichever is later.
222 Female subject of childbearing potential or male subject of reproductive potential
who is unwilling to use acceptable method(s) of effective contraception during
study treatment and through 3 months after the last dose of talimogene
laherparepvec/placebo or 4 months after the last dose of pembrolizumab,
whichever is later. Note: Women not of childbearing potential are defined as:
• Postmenopausal (defined as at least 12 months with no menses without an
alternative medical cause; in women < 45 years of age a high follicle stimulating
hormone [FSH] level in the postmenopausal range may be used to confirm a
postmenopausal state in women not using hormonal contraception or hormonal
replacement therapy. In the absence of 12 months of amenorrhea, a single FSH
measurement is insufficient)
OR
• Have had a hysterectomy and/or bilateral oophorectomy, or bilateral
salpingectomy at least 6 weeks prior to screening
OR
• Has a congenital or acquired condition that prevents childbearing
For this trial, male subjects will be considered to be of non-reproductive potential
if they have azoospermia (whether due to having had a vasectomy or due to an
underlying medical condition).Note: Acceptable methods of effective
contraception are defined in the informed consent form. Additional
country-specific contraception requirements may be defined in a country-specific
protocol supplement at the end of the Appendix Section of the protocol as
required by local laws and regulations.
If there is any question that a subject of reproductive potential will not reliably
comply with the requirements for contraception, that subject should not be
enrolled into the study.
223 Sexually active subjects or 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/placebo.
224 Subject has known sensitivity to any of the products or components to be
administered during study treatment.
225 Subject likely to not be available to complete all protocol-required study visits or
procedures, and/or to comply with all required study procedures to the best of the
subject and investigator’s knowledge.
226 History or evidence of psychiatric, substance abuse, or any other clinically
significant disorder, condition or disease (with the exception of those outlined
above) that, in the opinion of the investigator or sponsor medical monitor, if
consulted, would pose a risk to subject safety or interfere with the study
evaluation, procedures or completion.
227 Subject or subject’s immediate family member (eg, spouse, parent/legal
guardian, sibling, or child) is investigational site or sponsor staff directly involved
in this trial.
Note: If prospective institutional review board (IRB)/independent ethics
committee (IEC) approval (by chair or designee) is given, an exception to this
criterion for a specific subject is permitted.
228 Subject who is unwilling to minimize exposure with his/her blood or other body
fluids to individuals who are at higher risks for HSV-1 induced complications (eg,
immunosuppressed individuals, HIV-positive individuals, 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/placebo.
229 Has a known history of active bacillus tuberculosis.
230 Has a history of (non-infectious) pneumonitis that required steroids or
current pneumonitis.
231 Subjects with tumor that directly contacts or encases a major blood vessel
AND there is ulceration and/or fungation onto the skin surface.
232 Subject has undergone re-irradiation.