Clinical Trials /

Study of SNX281 in Subjects With Advanced Solid Tumors and Lymphoma

NCT04609579

Description:

This clinical trial is evaluating a drug called SNX281 given by itself and in combination with pembrolizumab in participants with advanced solid tumors and lymphoma. The main goals of this study are to: - Find the recommended dose of SNX281 that can be given to participants safely alone and in combination with pembrolizumab. - Learn more about the side effects and safety profile of SNX281 alone and in combination with pembrolizumab - Learn more about pharmacological characteristics of SNX281 alone and in combination with pembrolizumab - Learn more about effectiveness of SNX281 alone and in combination with pembrolizumab

Related Conditions:
  • Colorectal Carcinoma
  • Lymphoma
  • Malignant Solid Tumor
  • Ovarian Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Study of SNX281 in Subjects With Advanced Solid Tumors and Lymphoma
  • Official Title: A Phase 1 Open-label of Study SNX281 Given as Monotherapy and in Combination With a Checkpoint Inhibitor in Subjects With Advanced Solid Tumors and Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: SNX281-001
  • NCT ID: NCT04609579

Conditions

  • Advanced Solid Tumor
  • Advanced Lymphoma

Interventions

DrugSynonymsArms
SNX281SNX281 Monotherapy
PembrolizumabKeytrudaSNX281 in Combination with Pembrolizumab

Purpose

This clinical trial is evaluating a drug called SNX281 given by itself and in combination with pembrolizumab in participants with advanced solid tumors and lymphoma. The main goals of this study are to: - Find the recommended dose of SNX281 that can be given to participants safely alone and in combination with pembrolizumab. - Learn more about the side effects and safety profile of SNX281 alone and in combination with pembrolizumab - Learn more about pharmacological characteristics of SNX281 alone and in combination with pembrolizumab - Learn more about effectiveness of SNX281 alone and in combination with pembrolizumab

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
SNX281 MonotherapyExperimentalSNX281 will be administered weekly in Cycle 1 and then once every 3 weeks of each cycle thereafter for up to 6 cycles, or until disease progression or unacceptable toxicity occurs. Participants who are, in the opinion of the investigators, benefitting from treatment may be allowed to continue treatment with SNX281 beyond Cycle 6 with Sponsor approval. It is expected that up to approximately 66 participants will take part in this arm of the study. Subjects enrolled in the dose expansion phase of this arm may be eligible to add pembrolizumab to their SNX281 therapy following identification of the maximum tolerated dose (MTD) or optimal dose of SNX281 in combination with pembrolizumab. Subjects must, in the opinion of the Investigator, have demonstrated tolerance to SNX281 and have experienced sub-optimal response to therapy (i.e., disease stability for 4 cycles or progression on treatment with SNX281 at any time).
  • SNX281
SNX281 in Combination with PembrolizumabExperimentalSNX281 will be administered weekly in Cycle 1 and then once every 3 weeks of each cycle thereafter. Participants will also receive pembrolizumab once every cycle for up to 6 cycles. The combination of SNX281 and pembrolizumab will be given for up to 6 cycles, or until disease progression or unacceptable toxicity occurs. Participants who are, in the opinion of the investigators, benefitting from treatment may be allowed to continue treatment with SNX281 and pembrolizumab (or SNX281 alone) beyond Cycle 6 with Sponsor approval. It is expected that up to approximately 62 participants will take part in this arm of the study.
  • SNX281
  • Pembrolizumab

Eligibility Criteria

        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

          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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of dose limiting toxicities to determine the maximum tolerated dose (MTD) and Recommended Phase II dose of SNX281
Time Frame:Up to 28 Days
Safety Issue:
Description:Percentage of participants with dose limiting toxicities associated with SNX281 alone or SNX281 combined with Pembrolizumab during the first cycle. Toxicity will be assessed using the NCI CTCAE Version 5.0

Secondary Outcome Measures

Measure:Plasma concentration of SNX281 to characterize the pharmacokinetics (PK) parameters of SNX281 given as a single agent and in combination with pembrolizumab
Time Frame:Up to 20 weeks
Safety Issue:
Description:Plasma concentration of SNX281 from all participants given as a single agent and in combination with pembrolizumab.
Measure:Plasma concentration of biomarker to determine pharmacodynamics (PD) response to SNX281 given as a single agent and in combination with pembrolizumab
Time Frame:Up to 20 weeks
Safety Issue:
Description:Plasma concentration of biomarker from all participants receiving SNX281 as a single agent and in combination with pembrolizumab
Measure:Objective response rate (ORR) to assess the clinical activity of SNX281 given as a single agent and in combination with pembrolizumab
Time Frame:Up to 40 months
Safety Issue:
Description:Proportion of participants with confirmed complete response (CR) or partial response (PR) according to disease specific response criteria Per RECIST 1.1: A CR is the complete disappearance of all target and non-target lesions. A PR is a ≥30% decrease in the sum of diameters of target lesions from the baseline sum Per RECIL2017: A CR is the complete disappearance of all non-target/target lesions/all nodes with long axis <10 mm, or ≥30% decrease in the sum of longest diameters of target lesions (PR) with normalization of FDG-PET and no bone marrow involvement or appearance of new lesion A PR is ≥30% decrease in the sum of longest diameters of target lesions, with positive FDG-PET with any bone marrow involvement and no appearance of new lesions and no progression of non-target lesions.
Measure:Duration of response (DoR) to assess the clinical activity of SNX281 given as a single agent and in combination with pembrolizumab
Time Frame:Up to 40 months
Safety Issue:
Description:Defined as: Time from first documented response (Complete response (CR) or partial response (PR)) to first evidence of progressive disease (PD) per disease-specific response criteria or death due to any cause. RECIST 1.1- CR: Disappearance of all target/non-target lesions. PR: ≥30% decrease in the sum of diameters of target lesions from baseline sum. PD: ≥20% increase in target lesions and ≥5mm from smallest sum, any new lesions, or unequivocal progression of non-target lesions. RECIL 2017- CR: Disappearance of non-target, target/nodal lesions or ≥30% decrease in the sum of longest diameters of target lesions with normal FDG-PET, no bone marrow (BM) involvement or new lesion. PR: ≥30% decrease in the sum of longest diameters of target lesions but not a CR with any BM involvement but no new lesion or non-target lesions progression. PD: New lesion appearance or ≥20% increase in sum of target lesions. If lymph N<15 mm post therapy,a ≥5 mm increase with longest diameter exceeds 15mm
Measure:Progression free survival (PFS) to assess the clinical activity of SNX281 given as a single agent and in combination with pembrolizumab
Time Frame:Up to 40 months
Safety Issue:
Description:Progression free survival is defined as the time from the first day of study drug administration to disease progression (PD) as defined by disease-specific response criteria (RECIST 1.1 or RECIL2017), or death on study. RECIST 1.1: PD: ≥20% increase in target lesions sum and ≥5mm from smallest sum, any new lesions, or unequivocal progression of non-target lesions. RECIL 2017: PD: New lesion appearance or ≥20% increase in sum of longest diameters of target lesions. For lymph nodes measuring <15 mm post therapy, a ≥5 mm increase with longest diameter exceeds 15mm
Measure:Overall survival (OS) to assess the clinical activity of SNX281 given as a single agent and in combination with pembrolizumab
Time Frame:Up to 40 months
Safety Issue:
Description:Overall survival (OS) is defined as the time from the first day of study drug administration (Day 1) to death
Measure:Disease control rate (DCR) to assess the clinical activity of SNX281 given as a single agent and in combination with pembrolizumab
Time Frame:Up to 40 months
Safety Issue:
Description:DCR is defined as:The proportion of subjects who achieved either a complete response (CR), partial response (PR), or stable disease (SD)at their first scheduled disease assessment according to disease-specific response criteria RECIST 1.1 CR: disappearance of all target/non-target lesions. PR: ≥30% decrease in the sum of diameters of target lesions from baseline sum. SD: Neither sufficient shrinkage to qualify for a PR nor sufficient increase in lesions for a PD RECIL2017 CR: Disappearance of all target/nodal lesions or ≥30% decrease in the sum of longest diameters of target lesions with normal FDG-PET and no bone marrow (BM) involvement or new lesion. PR: ≥30% decrease in the sum of longest diameters of target lesions with positive FDG-PET with any BM involvement and no new lesion. SD: Less than 10% decrease or up to 20% increase in the sum of longest diameter of target lesions with any FDG-PET result or any bone marrow involvement and no appearance of new lesion

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Stingthera, Inc.

Trial Keywords

  • Stimulator of interferon genes
  • STING agonist
  • Ovarian Neoplasms
  • Colorectal Neoplasms
  • Microsatellite stable colorectal
  • Microsatellite instable colorectal
  • Lymphoma
  • B-Cell Lymphomas
  • Solid Tumor
  • Advanced Tumor

Last Updated

April 22, 2021