PRIMARY OBJECTIVE:
I. Determine the objective response rate of patients with metastatic colorectal cancer (mCRC)
treated with rintatolimod + pembrolizumab.
SECONDARY OBJECTIVES:
I. Establish the adverse event profile of combining rintatolimod and pembrolizumab.
II. Estimate the median progression free survival and overall survival of patients with mCRC
treated with rintatolimod and pembrolizumab.
III. Determine the immune objective response rate of patients with mCRC treated with
rintatolimod + pembrolizumab.
EXPLORATORY OBJECTIVES:
I. Assess modulation of the levels of CD8alpha expression and cytotoxic T-lymphocyte (CTL)
density pre- and post-therapy.
II. Assess chemokine levels in the tumor microenvironment and peripheral blood, including
effector T cell (Teff)-attracting and regulatory T cell (Treg)-favoring chemokines.
III. Characterize the fecal microbiotic profile and correlate those results with antitumor
immune responses.
OUTLINE:
Patients receive rintatolimod intravenously (IV) over 30 minutes on days 1-3 and
pembrolizumab IV over 30 minutes on day 3. Treatment repeats every 21 days for up to 3 cycles
in the absence of disease progression or unacceptable toxicity. Beginning in cycle 4,
patients receive rintatolimod IV over 30 minutes and pembrolizumab IV over 30 minutes on day
1. Cycles repeat every 21 days for up to 24 months from the first dose in the absence of
disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 30 and 90 days, and every 6
months for up to 2 years.
Inclusion Criteria:
- Biopsy proven colorectal adenocarcinoma which is metastatic or otherwise unresectable
- Microsatellite stable/mismatch-repair proficient (by immunohistochemistry [IHC] and/or
polymerase chain reaction [PCR])
- Progression following: a fluoropyrimidine, oxaliplatin, irinotecan, and anti-EGFR
targeted therapy (if anti-EGFR therapy is appropriate), bevacizumab (if appropriate)
- NOTE: Patients who could not tolerate standard agents because of unacceptable,
but reversible, toxicity necessitating their discontinuation will be allowed to
participate
- Amenable to undergoing serial tumor biopsy (x 2). NOTE: patients with inaccessible
lesions, where the investigator deems biopsy to be unsafe or where biopsy is otherwise
contraindicated, are still eligible to enroll, with review and approval of the
principal investigator (PI)
- Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
- Absolute neutrophil (ANC) count >= 1500/uL
- Platelets >= 100,000/uL
- Hemoglobin >= 9 g/dL
- Serum creatinine =< 1.5 X upper limit of normal (ULN) or measured or calculated
creatinine clearance by Cockcroft Gault Equation >= 30 ml/min for subjects with
creatinine levels > 1.5 x ULN
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x ULN or (=< 5 x ULN if the patient has liver metastases)
- Bilirubin =< 1.5 x ULN OR direct bilirubin =< ULN for participants with total
bilirubin levels > 1.5 x ULN
- International normalized ratio (INR) or prothrombin time (PT): =< 1.5 unless
participant is receiving anticoagulant therapy as long as PT or partial thromboplastin
time (PTT) is within therapeutic range of intended use of anticoagulants
- Activated partial thromboplastin time (aPTT): =< 1.5 x ULN unless participant is
receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of
intended use of anticoagulants
- Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
criteria present
- Female participants of childbearing potential are to have a negative serum pregnancy
test
- A female participant is eligible to participate if she is not pregnant, not
breastfeeding, and at least one of the following conditions applies:
- Not a woman of childbearing potential (WOCBP) OR
- A WOCBP who agrees to follow the contraceptive guidance during the treatment
period and for at least 120 days after the last dose of study treatment
- A male participant must agree to use an adequate method of contraception during the
treatment period and for at least 120 days after the last dose of study treatment and
refrain from donating sperm during this period
- Participant or legal representative must understand the investigational nature of this
study and sign an Independent Ethics Committee/Institutional Review Board approved
written informed consent form prior to receiving any study related procedure
Exclusion Criteria:
- Has received prior systemic anti-cancer therapy including investigational agents
within 4 weeks prior to start of study treatment
- Has received a live vaccine within 30 days prior to the first dose of study drug.
Examples of live vaccines include, but are not limited to, the following: measles,
mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus
Calmette?Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection
are generally killed virus vaccines and are allowed; however, intranasal influenza
vaccines (e.g., FluMist) are live attenuated vaccines and are not allowed
- Has received prior radiotherapy within 2 weeks of start of study treatment.
Participants must have recovered from all radiation-related toxicities, not require
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted
for palliative radiation (=< 2 weeks of radiotherapy) to non-central nervous system
(CNS) disease
- Is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of
prednisone equivalent) or any other form of systemic immunosuppressive therapy within
7 days prior to the first dose of study drug
- Has a known additional malignancy that is progressing or in the opinion of the
investigator is likely to interfere with properly assessing treatment efficacy. Note:
Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the
skin, and carcinoma in situ (e.g. breast carcinoma, cervical cancer in situ) that have
undergone potentially curative therapy are not excluded
- Has known active CNS metastases and/or carcinomatous meningitis. Participants with
previously treated brain metastases may participate provided they are radiologically
stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging
(note that the repeat imaging should be performed during study screening), clinically
stable and without requirement of steroid treatment for at least 14 days prior to
first dose of study treatment
- Has a history of (non-infectious) pneumonitis that required steroids or has current
pneumonitis
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, unstable
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements
- Have a severe hypersensitivity (>= grade 3) to pembrolizumab and/or any of its
excipients
- Has previously received rintatolimod, poly-ICLC or derivatives
- Has active autoimmune disease that has required systemic treatment in the past 2 years
(i.e., with use of disease modifying agents, corticosteroids or immunosuppressive
drugs). 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
- Woman of childbearing potential who has a positive urine pregnancy test within 72
hours prior to start of study treatment. If the urine test is positive or cannot be
confirmed as negative, a serum pregnancy test will be required
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV), unless on highly active
antiretroviral therapy (HAART) with undetectable viral load
- Has a known history of hepatitis B (defined as hepatitis B surface antigen [HBsAg]
reactive) or known active hepatitis C virus (defined as hepatitis C virus [HCV]
ribonucleic acid [RNA] [qualitative] is detected) infection
- Pregnant or nursing female participants
- Unwilling or unable to follow protocol requirements
- Any condition which in the investigator?s opinion deems the participant an unsuitable
candidate to receive study drug
