Study of SNX281 in Subjects With Advanced Solid Tumors and Lymphoma

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 (CNS) metastases or asymptomatic CNS 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 the study screening), clinically stable and without the requirement of steroid treatment for at least 14 days prior to first dose of study treatment. 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. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority(ies).
• •9. Has a known history of hepatitis B (defined as hepatitis B surface antigen \[HBsAg\] reactive) or known hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. No testing for hepatitis B or hepatitis C is required unless mandated by local health authority(ies).
• •10. Has an active infection requiring systemic therapy.
• •11. 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.
• •12. Recent history (within the past 6 months) of acute diverticulitis, inflammatory bowel disease, intra-abdominal abscess, or gastrointestinal obstruction.
• •13. Recent history (within 4 weeks of starting study) of allergen desensitization therapy
• •14. 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.
• •15. Recent (within the past 6 months) history of symptomatic pericarditis
• •16. History of idiopathic pulmonary fibrosis, interstitial lung disease, organizing pneumonia, non-infection pneumonitis that required steroids, or radiation pneumonitis. Note (SNX281 monotherapy only): 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
• •17. Symptomatic ascites or pleural effusions
• •18. Has known hypersensitivity (Grade ≥3) to pembrolizumab (KEYTRUDA®) and/or any of its excipients (for subjects receiving pembrolizumab (KEYTRUDA®) only).
• •19. 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
• •20. Prior treatment with the following agents:
• •* Systemic stimulator of interferon genes (STING) agonist at any time (prior intra-tumoral STING agonist is acceptable)
• •* Subjects treated in Treatment Arm 1 (SNX281 Monotherapy) who experience disease progression (PD) may be allowed to receive pembrolizumab (KEYTRUDA®) 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)
• •* Received treatment with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX40, CD137), and was discontinued from that treatment due to Grade 3 or higher immune related AE for subjects receiving pembrolizumab (KEYTRUDA®) 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. Participants must have recovered from all radiation-related toxicities, must not require corticosteroids, and must not have had radiation pneumonitis. 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 with a 1-week washout is permissible at any other time for non-CNS disease before or during the study.
• •* Subjects with mesothelioma, non-small cell lung cancer or small-cell lung cancer receiving pembrolizumab (KEYTRUDA®) with a history of radiation therapy to the lung \>30Gy within 6 months of the first dose of pembrolizumab (KEYTRUDA®) are excluded.
• •* 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.
• •21. Receipt of any live vaccine within 30 days of the start of treatment
• •22. Prior allogeneic or autologous bone marrow transplantation or other solid organ transplantation
• •23. 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).
• •24. 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. Note: For subjects receiving pembrolizumab (KEYTRUDA®) only, packed red blood cell transfusions are not permitted within 2 weeks of treatment with pembrolizumab (KEYTRUDA®).
• •25. 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.
• •26. Active drug or alcohol abuse