Pembrolizumab and Recombinant Interleukin-12 in Treating Patients With Solid Tumors

PRIMARY OBJECTIVES:

I. Establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of
recombinant human interleukin (rhIL)-12 in combination with MK-3475 (pembrolizumab).

SECONDARY OBJECTIVES:

I. Evaluate the safety of the regimen by continuously monitoring adverse events that will be
documented utilizing Common Terminology Criteria for Adverse Events (CTCAE) version (v).5.0.

II. Evaluate the overall response rate (Response Evaluation Criteria in Solid Tumors [RECIST]
v.1.1) and the progression free survival of patients enrolled on the study.

II. Measure CD8+ T cell infiltration by immunohistochemistry in tumor biopsies obtained at
baseline, after one week of rhIL-12 and after 2 cycles of MK-3475 (pembrolizumab) in
combination with rhIL-12.

IV. Conduct exploratory translational laboratory correlative studies utilizing banked
biospecimens (tumor and blood) obtained at baseline and during therapy.

OUTLINE: This is a dose-escalation study of recombinant interleukin-12.

Patients receive recombinant interleukin-12 subcutaneously (SC) on days 2, 5, 9, and 12 and
pembrolizumab intravenously (IV) over 30 minutes on day 8 of course 1 and day 1 of subsequent
courses. Treatment continues for 28 days for course 1 and repeats every 21 days for
subsequent courses for up to 8 courses in the absence of disease progression or unacceptable
toxicity. Patients then receive recombinant interleukin-12 SC on days 2, 5, 9, and 12.
Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up for 3 years.

Inclusion Criteria:

- Patients must have histologically confirmed malignancy that is metastatic or
unresectable and for which standard Food and Drug Administration (FDA)-approved
systemic curative or palliative antitumor therapies do not exist or are no longer
effective or for which MK-3475 (pembrolizumab) is FDA-approved as standard of care
therapy

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Life expectancy of greater than 12 weeks

- Within 14 days of treatment initiation: Leukocytes >= 2,000/mcL

- Within 14 days of treatment initiation: Absolute neutrophil count >= 1,500/mcL

- Within 14 days of treatment initiation: Platelets >= 100,000/mcL

- Within 14 days of treatment initiation: Hemoglobin >= 9 g/dL OR >= 5.6 mmol/L

- Within 14 days of treatment initiation: Serum total bilirubin =< upper limit of normal
(ULN) OR direct bilirubin =< ULN for patients with total bilirubin levels > ULN;
(except patients with Gilbert's syndrome, who must have a total bilirubin less than
3.0 mg/dL)

- Within 14 days of treatment initiation: Aspartate aminotransferase (AST) serum
glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT) serum
glutamate pyruvate transaminase (SGPT) =< 2.5 x institutional ULN

- Within 14 days of treatment initiation: Serum creatinine =< 1.5 x ULN OR measured or
calculated creatinine clearance (CrCl) (glomerular filtration rate [GFR] can also be
used in place of creatinine or CrCl) >= 60 mL/min for subject with creatinine levels >
1.5 X institutional ULN

- Within 14 days of treatment initiation: International normalized ratio (INR) or
prothrombin time (PT) =< 1.5 X ULN unless subject is receiving anticoagulant therapy
as long as (PT) or partial thromboplastin time (PTT) is within therapeutic range of
intended use of anticoagulants

- Within 14 days of treatment initiation: Activated partial thromboplastin time (aPTT)
=< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as prothrombin
time (PT) or partial thromboplastin time (PTT) is within therapeutic range of intended
use of anticoagulants

- Optional tumor biopsies: Patients will be asked permission (consent) to provide tissue
from a recent (within 6 weeks of study entry) archival tissue sample or newly obtained
core or excisional biopsy of a tumor lesion; in addition, for on-study biopsies (after
one week and after 7 weeks of initiating study therapy) and for baseline tumor biopsy
if an archival tissue sample is not available: willingness to undergo biopsies will be
asked; patients who consent to provide tumor biopsies for research should have tumors
deemed relatively safely accessible for biopsies with low likelihood of complication

- Patients must have measurable disease based on RECIST 1.1

- Women of child-bearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control; abstinence) prior to study entry and for
the duration of study participation

- Female patients of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study
medication; if the urine test is positive or cannot be confirmed as negative, a
serum pregnancy test will be required

- Female patients of childbearing potential should be willing to use 2 methods of
birth control or be surgically sterile, or abstain from heterosexual activity for
the course of the study through 120 days after the last dose of study medication;
patients of childbearing potential are those who have not been surgically
sterilized or have not been free from menses for > 1 year

- Should a woman become pregnant or suspect she is pregnant while she is
participating in this study, she should inform her treating physician immediately

- Men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 4
months after completion of MK-3475 (pembrolizumab) and/or rhIL-12 administration

- Ability to understand and the willingness to sign a written informed consent document

- Patients who are human immunodeficiency virus (HIV) positive may participate IF they
meet the following eligibility requirements:

- They must be stable on their anti-retroviral regimen, and they must be healthy
from an HIV perspective

- They must have an undetectable viral load

- They must have a CD4 count of greater than 250 cells/mcL

- They must not be receiving prophylactic therapy for an opportunistic infection

Exclusion Criteria:

- Patients who have had chemotherapy, targeted small molecule therapy, or radiotherapy
within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
or those who have not recovered from adverse events due to agents administered more
than 4 weeks earlier

- Note: patients with =< grade 2 neuropathy are an exception to this criterion and
may qualify for the study

- Note: if patients received major surgery, they must have recovered adequately
from the toxicity and/or complications from the intervention prior to starting
therapy

- Patients who are currently participating in or have participated in a study of an
investigational agent or using an investigational device within 4 weeks of the first
dose of treatment

- 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

- Has had a prior monoclonal antibody within 4 weeks prior to study Day 1 or who has not
recovered (i.e., =< grade 1 or at baseline) from adverse events (AEs) due to agents
administered more than 4 weeks earlier; non-clinically significant adverse events may
be considered as an exception after discussion with and approval by the principal
investigator

- Has a known additional 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

- Patients with known brain active and untreated metastases should be excluded from this
clinical trial

- Patients with carcinomatous meningitis should also be excluded

- Patients with previously treated brain metastases may participate provided they are
stable (without evidence of progression by imaging for at least 4 weeks prior to the
first dose of trial treatment and any neurologic symptoms have returned to baseline),
have no evidence of new or enlarging brain metastases, and are not requiring steroids
for at least 7 days prior to trial treatment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-3475 (pembrolizumab) and/or rhIL-12 or other agents used in study

- 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; patients with vitiligo or
resolved childhood asthma/atopy would be an exception to this rule; patients that
require intermittent use of bronchodilators or local steroid injections would not be
excluded from the study; patients with hypothyroidism stable on hormone replacement or
Sjogren's syndrome will not be excluded from the study

- Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the patient's
participation for the full duration of the trial, or is not in the best interest of
the patient to participate, in the opinion of the treating investigator

- Has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial

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

- Patients on any systemic corticosteroid therapy within one week before the planned
date for first dose on study would not be eligible; exception: patients on physiologic
replacement doses of corticosteroids are permitted

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, interstitial lung disease or active, non-infectious pneumonitis,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or
psychiatric illness/social situations that would limit compliance with study
requirements

- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment; pregnant women are excluded;
breastfeeding should be discontinued if the mother is treated MK-3475

- Men and non-pregnant, non-breast-feeding women may be enrolled if they are willing to
use 2 methods of birth control or are considered highly unlikely to conceive; highly
unlikely to conceive is defined as 1) surgically sterilized, or 2) postmenopausal (a
woman who is >= 45 years of age and has not had menses for greater than 2 years will
be considered postmenopausal), or 3) not heterosexually active for the duration of the
study; the two birth control methods can be barrier method or a barrier method plus a
hormonal method to prevent pregnancy; patients should start using birth control from
study visit 1 throughout the study period up to 120 days after the last dose of study
therapy; the following are considered adequate barrier methods of contraception:
diaphragm, condom (by the partner), copper intrauterine device, sponge, or spermicide;
appropriate hormonal contraceptives will include any registered and marketed
contraceptive agent that contains an estrogen and/or a progestational agent (including
oral, subcutaneous, intrauterine, or intramuscular agents)

- Has known active hepatitis B (e.g., hepatitis B surface antigen [HBsAg] reactive) or
hepatitis C (e.g., hepatitis C virus [HCV] ribonucleic acid [RNA] [qualitative] is
detected)

- Has received a live vaccine within 30 days prior to the first dose of trial treatment

- Patient would not be eligible if he/she has known psychiatric or substance abuse
disorders that would interfere with cooperation with the requirements of the trial