Study of Talimogene Laherparepvec In Children With Advanced Non CNS Tumors

This is a phase 1, multicenter, open-label study of talimogene laherparepvec in pediatric
subjects with advanced non-CNS tumors that are amenable to direct injection in the clinical
setting. Approximately 18 -27 treated pediatric subjects are expected to be enrolled into 2
cohorts stratified by age (permissible based on the incidence of DLTs, a minimum of 6
subjects/cohort and a minimum of 18 subjects total). DLT will be evaluated based on 6 to 12
DLT-evaluable subjects in each cohort. The DLT evaluation period is 35 days from the initial
administration of talimogene laherparepvec.

Inclusion Criteria

- Subject's legally acceptable representative has provided informed consent/assent when
the subject is legally too young to provide informed consent/assent and the subject
has provided written assent based on local regulations and/or guidelines prior to any
study-specific activities/procedures being initiated.

- Should be willing to submit local HSV-1 serostatus within 28 days prior to enrollment.

- Subject must be a candidate for intralesional injection, defined as one or more of the
following:

- at least 1 injectable lesion ≥ 10 mm in longest diameter

- multiple injectable lesions that in aggregate have a longest diameter of ≥ 10 mm

- Life expectancy > 4 months from the date of enrollment.

- Male or female subjects 2 to ≤ 21 years of age at the time of informed consent/assent.

- Histologically or cytologically confirmed non-CNS solid tumor that recurred after
standard/frontline therapy, or for which there is no standard/frontline therapy
available.

- Presence of measurable or non-measurable lesions as defined by irRC-RECIST

- Performance status as per protocol

- Female subject of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to dosing.

Exclusion Criteria

- Diagnosis of leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, or other hematologic
malignancy.

- Radiotherapy to the bone marrow within 6 weeks prior to enrollment OR within 3 months
prior to enrollment if prior radiotherapy to the craniospinal axis or to at least 60%
of the pelvis was received; within 2 weeks prior to enrollment if local palliative
radiotherapy was received.

- CNS tumor or clinically active brain metastases.

- Primary ocular or mucosal melanoma.

- History of other malignancy within the past 5 years with the following exception:

• malignancy treated with curative intent and with no known active disease present and
has not received chemotherapy for > 5 years before enrolment and felt to be at low
risk for recurrence by the treating physician.

- History or evidence of active autoimmune disease that requires systemic treatment (ie,
with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
systemic treatment.

- Active herpetic skin lesions or prior complications of herpetic infection (eg,
herpetic keratitis or encephalitis).

- Prior treatment with talimogene laherparepvec or any other oncolytic virus.

- Prior treatment with a tumor vaccine.

- Requires intermittent or chronic treatment with an antiherpetic drug (eg, acyclovir),
other than intermittent topical use.

- Currently receiving treatment in another investigational device or drug study, or less
than 28 days since ending treatment on another investigational device or drug
study(ies). Other investigational procedures while participating in this study are
excluded.

- Major surgery ≤ 28 days prior to enrollment.

- Expected to require other cancer therapy while on study with the exception of local
palliative radiation treatment.

- 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, and entecavir),
ribavirin, or interferon alpha within 12 weeks of initiation of study treatment.

- Known or suspected human immunodeficiency virus (HIV) infection.

- Received live vaccine within 28 days prior to enrollment.

- No antiplatelet or anticoagulation medications allowed within 7 days prior
totalimogene laherparepvec injection except low-dose heparin needed to maintain venous
catheter patency.

- Female subject is pregnant or breast-feeding, or planning to become pregnant during
study treatment and through 3 months after the last dose of talimogene laherparepvec.

- Female subject of childbearing 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. Note: Acceptable methods of effective contraception
are defined in the informed consent/assent form. Where required by local laws and
regulations, additional country-specific contraception requirements may be outlined in
a country-specific protocol supplement at the end of the Appendix Section of protocol.

- Subject has known sensitivity to any of the products or components to be administered
during dosing.

- 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.

- History or evidence of any psychiatric disorder, 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 Amgen physician, if
consulted, would pose a risk to subject safety or interfere with the study evaluation,
procedures or completion.

- 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
(immunosuppressed individuals, HIV-positive individuals, pregnant women, or children
under the age of 1 year) during talimogene laherparepvec treatment and through 28 days
after the last dose of talimogene laherparepvec.

- Evidence of 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 prior to enrollment),
including oral steroid doses (with the exception of maintenance physiologic
replacement). Subjects who require intermittent use of steroids for inhalation or
local steroid injection will not be excluded from the study

- less than 6 months from autologous bone marrow transplant or stem cell infusion

- history of allogeneic bone marrow transplant

- History or evidence of xeroderma pigmentosum.

- Sexually active subjects and their partners unwilling to use a 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. For those with latex
allergies, polyurethane condoms may be used.

- Prior chemotherapy, treatment dose radiotherapy, or biological cancer therapy within
14 days prior to enrollment or has not recovered to Common Terminology Criteria for
Adverse Events version 4.0 (CTCAE) grade 1 or better from adverse event due to cancer
therapy administered more than 14 days prior to enrollment.