PRIMARY OBJECTIVE:
I. Establish the maximum tolerated dose (MTD) and the recommended phase II dose (RP2D) of
edodekin alfa (recombinant human interleukin [rhIL]-12) in combination with pembrolizumab
(MK-3475).
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.
III. Measure CD8+ T cell infiltration by immunohistochemistry in tumor biopsies obtained
pre-treatment, after one week of rhIL-12 and after 2 cycles of pembrolizumab (MK-3475) in
combination with rhIL-12.
EXPLORATORY OBJECTIVE:
I. Conduct exploratory translational laboratory correlative studies utilizing banked
biospecimens (tumor, blood, and stool) obtained pre-treatment 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 cycle 1 and day 1 of subsequent
cycles. Treatment continues for 28 days for cycle 1 and repeats every 21 days for subsequent
cycles for up to 8 cycles in the absence of disease progression or unacceptable toxicity.
Patient then receive pembrolizumab IV over 30 minutes on day 1. Treatment repeats every 21
days for up to 8 additional cycles in the absence of disease progression or unacceptable
toxicity.
After completion of study treatment, patients are followed up every 12 weeks for 2 year and
then every 24 weeks for up to 5 years.
Inclusion Criteria:
- Patients must have histologically confirmed malignancy that is metastatic or
unresectable
- Eligibility is restricted to patients who have tumors for which anti-PD-(L)1 therapy
is indicated; and must have progressed past anti-PD(L)1 singly or in combination.
There is no restriction on the number of prior lines of therapy
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- Life expectancy of greater than 12 weeks
- Leukocytes >= 2,000/mcL (within 28 days of treatment initiation)
- Absolute neutrophil count >= 1,500/mcL (within 28 days of treatment initiation)
- Platelets >= 100,000/mcL (within 28 days of treatment initiation)
- Hemoglobin >= 9 g/dL OR >= 5.6 mmol/L (within 28 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 28 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 28 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 28 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 28
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 (within 28 days of
treatment initiation)
- Willingness to undergo tumor biopsies at three timepoints: (1) pre-treatment; (2)
after one week of rhIL12; and (3) after 2 cycles of pembrolizumab
(MK-3475)-interleukin (IL) 12 (i.e., approximately 7 weeks from the first dose of
rhIL-12)
- At each timepoint, a core biopsy is preferable (although in suitable patients,
punch biopsy may be substituted)
- Cytopathologist should be present to ensure adequacy of tumor biopsy sample
- At least 4 16 gauge (G) core biopsies are to be obtained and triaged as
delineated in the Laboratory Manual
- Pre-treatment biopsy can be substituted with an archival tissue sample if the
sample is
- Adequate (capable of providing at least 20 unstained slides); and
- Recent (within 8 weeks of study entry); and
- Patient has not had any intervening therapy
- Patients must have measurable disease based on RECIST 1.1
- The effects of pembrolizumab (MK-3475) and/or rIL-12 on the developing human fetus are
unknown; for this reason, 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 pembrolizumab (MK-3475) 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 first dose of trial
treatment, 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 trial 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 active and untreated brain metastases should be excluded from this
clinical trial because of their poor prognosis and because they often develop
progressive neurologic dysfunction that would confound the evaluation of neurologic
and other adverse events
- Patients with primary brain tumors or 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 pembrolizumab (MK-3475) 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
- 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
from this study because pembrolizumab (MK-3475) is an agent with the potential for
teratogenic or abortifacient effects; because there is an unknown but potential risk
for adverse events in nursing infants secondary to treatment of the mother with
pembrolizumab (MK-3475), breastfeeding should be discontinued if the mother is treated
with pembrolizumab (MK-3475); these potential risks may also apply to other agents
used in this study; pembrolizumab (MK-3475) may have adverse effects on a fetus in
utero; furthermore, it is not known if pembrolizumab (MK-3475) has transient adverse
effects on the composition of sperm
- 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)
- Patients should be informed that taking the study medication may involve unknown
risks to the fetus (unborn baby) if pregnancy were to occur during the study; in
order to participate in the study they must adhere to the contraception
requirement (described above) for the duration of the study and during the
follow-up period of pregnancy and lactation; if there is any question that a
patient will not reliably comply with the requirements for contraception, that
patient should not be entered into the study
- Pregnancy: If a patient inadvertently becomes pregnant while on treatment with
pembrolizumab (MK-3475), the patient will immediately be removed from the study;
the site will contact the patient at least monthly and document the patient's
status until the pregnancy has been completed or terminated; the outcome of the
pregnancy will be reported without delay and within 24 hours if the outcome is a
serious adverse experience (e.g., death, abortion, congenital anomaly, or other
disabling or life-threatening complication to the mother or newborn); the study
investigator will make every effort to obtain permission to follow the outcome of
the pregnancy and report the condition of the fetus or newborn; if a male patient
impregnates his female partner the study personnel at the site must be informed
immediately and the pregnancy reported and followed
- It is unknown whether pembrolizumab (MK-3475) is excreted in human milk; since
many drugs are excreted in human milk, and because of the potential for serious
adverse reactions in the nursing infant, patients who are breast-feeding are not
eligible for enrollment
- 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
