A Study of Nivolumab and Intrapleural Talimogene Laherparepvec for Malignant Pleural Effusion

This is a phase 1b/II clinical trial that includes a safety run-in cohort to investigate the
novel approach of administering intrapleural talimogene laherparepvec via a pleurX catheter
in patients with known malignant pleural effusion (MPE).

In Phase Ib of this study, the safety of infusing talimogene laherparepvec directly into the
pleural cavity of subjects diagnosed with MPE, through pleurX catheter, will be tested.

In Phase II of this study, after establishing the safety of the above mentioned approach, 24
subjects will enrolled and treated with intrapleural talimogene laherparepvec and IV
nivolumab.

Inclusion Criteria:

Patients must meet the following inclusion criteria to participate in this study:

1. Be ≥ 18 years of age on day of signing informed consent.

2. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 2

3. Histologically or cytologically confirmed stage IV metastatic cancer.

4. Confirmation of malignant pleural effusion via imaging (Computer tomography (CT) scan,
chest x-ray (CXR), MRI, ultrasound, Positron Emission Tomography (PET)/CT), and
cytology for which pleurX catheter placement is standard of care

5. Recovered from all reversible toxicities related to their previous treatment (other
than alopecia) to ≤grade 1 or baseline; exceptions to this criterion may be allowed
following review by the principal investigator for toxicities that are not expected to
be exacerbated by nivolumab or talimogene laherparepvec. Grade 2 peripheral neuropathy
will not result in exclusion as neither study agent would be expected to exacerbate
it.

6. No history of untreated brain metastasis. Treated brain metastases must not be known
to be progressive, symptomatic, or currently requiring > 10 mg of prednisone or
prednisone equivalents within two weeks prior to study drug administration.

7. Females of childbearing potential must have a negative serum pregnancy test within 72
hours prior to receiving the first dose of study medication. Females of childbearing
potential must agree to use 2 methods of effective contraception or abstain from
heterosexual sex throughout the treatment period and for 5 months after the last dose
of study treatment. Females of childbearing potential are women who have not been
surgically sterilized (have undergone a hysterectomy, bilateral tubal ligation, or
bilateral oophorectomy) or have not been free of menses for >1 year.

8. Male patients with female partners must have had a prior vasectomy or agree to use an
adequate method of contraception (i.e. double barrier method: condom plus spermicidal
agent) starting with the first dose of study therapy through 7 months after the last
dose of study treatment.

Exclusion Criteria:

Patients meeting any of the following exclusion criteria will not be able to participate in
this study:

1. Receiving any investigational agent, or using an investigational device, currently or
within 28 days or 5 half-lives of Day 1 of treatment on this study, whichever is
longer.

2. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy
within 2 weeks prior to study Day 1

3. Has had a prior monoclonal antibody within 4 weeks prior to study Day 1, or who has
not recovered to, ≤ Grade 1 toxicity at baselines from adverse events due to agents
administered more than 4 weeks earlier. Exceptions to these criteria may be allowed at
the discretion of the investigator for toxicities that are not expected to be
exacerbated by nivolumab or talimogene laherparepvec (e.g., alopecia, peripheral
neuropathy, etc).

4. Has received prior therapy with an anti-programmed cell death receptor (PD)-1,
anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated
antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug
specifically targeting T-cell co-stimulation or checkpoint pathways).

5. Any concurrent chemotherapy, intraperitoneal (IP), biologic or hormonal therapy for
cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions
(e.g., hormone replacement therapy) is acceptable.

6. Major surgery within 28 days prior to day 1 of study treatment from which the patient
has not completely recovered.

7. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment.

8. Has a known secondary malignancy that is progressing or requires active treatment.
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, or in situ cervical cancer that has undergone potentially curative therapy.

9. Has a history of non-infectious pneumonitis that required steroids; currently active
non-infectious pneumonitis; or evidence of interstitial lung disease.

10. Has an active infection requiring systemic therapy or history of uncontrolled
infection.

11. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator. This includes
known psychiatric or substance abuse disorders that would interfere with cooperation
with the requirements of the trial. This also includes unstable angina, serious
uncontrolled cardiac arrhythmia, uncontrolled infection, or myocardial infarction ≤ 6
months prior to study entry.

12. Has inadequate home environment or social support to safely complete the trial
procedures

13. Is pregnant or breastfeeding

14. Known human immunodeficiency virus (HIV), hepatitis C virus (HCV) or evidence of
active hepatitis B virus (HBV).

15. Has a multi-loculated pleural effusion that would not lead to relief of dyspnea from
drainage of a single loculation.

16. Current active hepatic or biliary disease (with exception of patients with Gilbert's
syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator
assessment).

17. Active herpetic skin lesions or prior complications of herpetic infection or requires
intermittent or chronic systemic (intravenous or oral) treatment with an antiherpetic
drug (e.g., acyclovir), other than intermittent topical use.

18. Has an active autoimmune disease requiring systemic treatment within the past 3 months
or a documented history of clinically severe autoimmune disease, or a syndrome that
requires systemic steroids or immunosuppressive agents; subjects with resolved
childhood asthma/atopy would be an exception to this rule. Subjects that require
intermittent use of bronchodilators or local steroid injections would not be excluded
from the study. Subjects with hypothyroidism stable on hormone replacement or
Sjorgen's syndrome will not be excluded from the study. Replacement therapy (e.g.,
thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or
pituitary insufficiency, etc.) is not considered a form of systemic treatment.
Subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment
(within the past 2 years) are not excluded.