SNX281 is a small molecule activator of the Stimulator of Interferon Genes (STING) protein,
with good drug-like properties. Activation of STING initiates the innate immune response and
enhances the adaptive immune response, which could potentially activate immune responses to
tumors and enhance the response to certain immunotherapies.
This study is a phase I, first in human, open-label study of SNX281 conducted in subjects
with advanced solid tumors and lymphomas. The study will comprise of two treatment arms: one
evaluating SNX281 as a single-agent, and the other evaluating SNX281 in combination with
pembrolizumab. Each treatment arm is designed to include a dose escalation phase followed by
a dose expansion phase intended to establish the recommended Phase 2 dose (RP2D).
In the dose escalation phase of each treatment arm, successive cohorts of participants will
receive increasing doses of SNX281 designed to determine the maximum tolerated dose (MTD),
the dose with maximum pharmacologic activity, or the maximum feasible dose, as a single-agent
and in combination with pembrolizumab.
The dose expansion phases of each treatment arm will begin following the determination of an
MTD or alternative dose of SNX281 in each respective treatment arm. The single-agent
treatment arm of SNX281 is planned to evaluate at least 2 expansion cohorts in ovarian cancer
and colorectal carcinoma while the combination treatment arm of SNX281 and pembrolizumab is
planned to enroll subjects with advanced cancer who have relapsed on or have become
refractory to prior immune checkpoint therapy given in an indicated setting.
Inclusion Criteria:
Subjects must meet the following criteria in order to be included in the research study:
1. Written informed consent, according to local guidelines, signed and dated by the
subject or by a legal guardian prior to the performance of any study-specific
procedures, sampling, or analyses
2. At least 18 years-of-age at the time of signature of the informed consent form (ICF)
3. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
4. Histological or cytological requirements as follows:
a. Dose Escalation: i. All treatment arms: Subjects with histological or cytological
documentation of advanced/recurrent solid tumors or lymphoma who have progressed on,
are intolerant of, or are ineligible for existing standard therapies
b. Dose Expansion: i. SNX281 Monotherapy: Subjects with histological or cytological
documentation of advanced/recurrent ovarian or colorectal cancer who have progressed
on, are intolerant of, or are ineligible for existing standard therapies. Subjects may
be checkpoint inhibitor naïve. Subjects who qualify to add pembrolizumab to their
treatment regimen, must meet all medical eligibility requirements for receiving
pembrolizumab (see Inclusion Criteria 9).
ii. SNX281 in Combination with Pembrolizumab: Subjects with histological or
cytological documentation of advanced/recurrent solid tumors or lymphoma who have
relapsed on or are refractory to prior checkpoint inhibitor therapy given in an
indicated setting. (Note: recruitment may be stopped in a given anatomical indication
if no evidence of clinical response is observed in 15 subjects.)
5. Measurable or evaluable disease according to disease-specific tumor assessment
criteria. Subjects in dose expansion portions of the study must have at least 1
measurable lesion that has not been previously irradiated, or has progressed after
prior irradiation.
6. Adequate organ function, defined as:
a. Hematologic systems i. Absolute neutrophil count (ANC) ≥1.5 × 109/L ii. Hemoglobin
≥9 g/dL iii. Platelets ≥100 × 109/L
b. Hepatic system i. Total bilirubin ≤1.5 × the upper limit of normal (ULN) (for
subjects with Gilbert's Syndrome ≤3.0 × ULN [if direct bilirubin ≤35%]) ii. Alanine
aminotransferase and aspartate aminotransferase ≤2.5 × ULN; and for subjects with
liver metastases ≤5.0 × ULN
c. Renal system i. Estimated glomerular filtration rate (eGFR) by Cockcroft-Gault
formula >50 mL/min
d. Cardiac system i. Ejection fraction ≥50% by echocardiogram (ECHO) or multi-gated
acquisition (MUGA) scan
7. Male subjects with female partners of childbearing potential and female subjects of
childbearing potential are required to use two forms of acceptable contraception,
including one barrier method, during their participation in the study and for 3 months
following the last dose of SNX281 for male subjects and 6 months following the last
dose of SNX281 for female subjects, and for 120 days following the last dose of
pembrolizumab for all subjects receiving pembrolizumab. Male subjects must also
refrain from donating sperm during their participation in the study and for 3 months
following the last dose of SNX281 and 120 days after the last dose of pembrolizumab
8. Life expectancy ≥12 weeks after the start of the treatment according to the
Investigator's judgment.
9. Subjects considered for any combination of pembrolizumab and SNX281 must meet, in the
opinion of the Investigator, any additional criteria necessary for the safe and proper
use of pembrolizumab.
Exclusion Criteria:
Subjects who meet any of the following criteria will be excluded from study entry:
1. Malignancy other than the disease under study with the exception of those from which
the subject has been disease-free for more than 2 years and not expected to affect the
safety of the subject or the endpoints of the trial. Curatively treated non-melanoma
skin cancer is permitted.
2. Symptomatic central nervous system metastases or asymptomatic CNS metastases must be
treated and stable for 2 weeks prior to initiation of study treatment. Follow-up scans
to confirm stability after 2 weeks are not required. Subjects with carcinomatous
meningitis or leptomeningeal spread are excluded regardless of clinical stability.
3. Active autoimmune disease that has required systemic disease modifying or
immunosuppressive treatment within the last 2 years. Replacement therapy (e.g.,
thyroxine or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, insulin for type 1 diabetes, etc.) is permitted.
4. Concurrent medical conditions requiring the use of systemic immunosuppressive
treatment within 28 days before the first dose of study treatment. Physiologic doses
of corticosteroids (not exceeding 10 mg/day prednisone or equivalent) for treatment of
endocrinopathies or steroids with minimal systemic absorption, including topical,
inhaled, or intranasal corticosteroids may be continued if the subject is on a stable
dose.
5. Current unstable liver or biliary disease per Investigator assessment defined by the
presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or
gastric varices, persistent jaundice, or cirrhosis. Stable chronic liver disease
(including Gilbert's syndrome or asymptomatic gallstones) or hepatobiliary involvement
of malignancy is acceptable if subject otherwise meets entry criteria
6. History of vasculitis at any time prior to study treatment
7. Evidence or history of significant active bleeding or coagulation disorder that would
compromise the subject's ability to adhere to the protocol.
8. Active infection requiring systematic treatment, known human immunodeficiency virus
infection (HIV), or positive test for hepatitis B surface (HBs) antigen or hepatitis C
virus (HCV).
9. QT interval corrected for heart rate according to Fridericia's formula >480 msec by
machine read or human over-read. Pre-existing bundle branch block is permitted at the
Investigator's discretion.
10. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel
disease, intra-abdominal abscess, or gastrointestinal obstruction.
11. Recent history (within 4 weeks of starting study) of allergen desensitization therapy
12. History or evidence of cardiovascular risk including any of the following: recent
(within the past 6 months) serious uncontrolled cardiac arrhythmia or clinically
significant electrocardiogram (ECG) abnormalities including second degree (Type II) or
third degree atrioventricular block; cardiomyopathy, myocardial infarction, acute
coronary syndromes (including unstable angina pectoris), coronary angioplasty,
stenting, or bypass grafting within the past 6 months before enrollment; congestive
heart failure (Class II, III, or IV) as defined by the New York Heart Association
functional classification system.
13. Recent (within the past 6 months) history of symptomatic pericarditis
14. History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing
pneumonia, or current pneumonitis or a history of non-infection pneumonitis that
required steroids. Note: post-radiation changes in the lung related to prior
radiotherapy and/or asymptomatic radiation-induced pneumonitis not requiring treatment
may be permitted if agreed upon by the Investigator and Sponsor
15. Symptomatic ascites or pleural effusions
16. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that
could interfere with the subject's safety, obtaining informed consent, or compliance
with study procedures
17. Prior treatment with the following agents:
- Systemic stimulator of interferon genes (STING) agonist at any time (prior
intra-tumoral STING agonist is acceptable)
o Subjects treated in Treatment Arm 1 (SNX281 Monotherapy) who experience disease
progression (PD) may be allowed to receive pembrolizumab in combination with
SNX281 with Sponsor approval
- Anticancer therapy or investigational therapy within 28 days or 5 half-lives of
the drug, whichever is shorter
- PD-1, PD-L1, and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitors
within 28 days of the start of study treatment (SNX281 Monotherapy treatment arm
only)
- Prior radiation therapy: permissible if at least 1 non-irradiated evaluable
lesion is available for assessment according to disease-specific tumor response
criteria, or if a solitary evaluable lesion was irradiated, objective progression
of that lesion is documented. A washout period of at least 14 days before start
of study treatment for radiation of any intended use to the extremities for bone
metastases and 28 days for radiation to the chest or visceral organs is required.
For radiation to the brain, a washout period of at least 14 days for stereotactic
body radiation therapy (SBRT) or stereotactic radiosurgery (SRS) and 28 days for
whole brain radiotherapy (WBRT) is required. Palliative radiation is permissible
at any other time before or during the study.
- Strong inhibitors and inducers of CYP3A4 must be discontinued 7 days or for a
time equivalent to 5-half-lives of the medication (whichever is longer) prior to
initiation of SNX281 treatment.
18. Receipt of any live vaccine within 30 days of the start of treatment
19. Prior allogeneic or autologous bone marrow transplantation or other solid organ
transplantation
20. Toxicity from previous treatment including toxicity Grade .3 related to prior
immunotherapy and that led to study treatment discontinuation; toxicity related to
prior treatment that has not resolved to Grade ≤1 (except alopecia, hearing loss, or
Grade ≤2 neuropathy or endocrinopathy managed with replacement therapy).
21. Received transfusion of blood products (including platelets or red blood cells) or
administration of colony stimulating factors (including granulocyte colony stimulating
factor, granulocyte-macrophage colony stimulating factor, and recombinant
erythropoietin) within 7 days before the first dose of study treatment.
22. Major surgery ≤28 days before the first dose of study treatment. Subjects must have
also fully recovered from any surgery (major or minor) and/or its complications before
initiating treatment. Port-a-cath placement is permitted.
23. Active drug or alcohol abuse
