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Safety and Tolerability of SYNB1891 Injection Alone or in Combination With Atezolizumab in Adult Subjects

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ClinicalTrials.gov Identifier: NCT04167137
Recruitment Status : Recruiting
First Posted : November 18, 2019
Last Update Posted : June 25, 2020
Sponsor:
Collaborator:
IQVIA Biotech
Information provided by (Responsible Party):
Synlogic

Brief Summary:
This study will evaluate SYNB1891 (investigational product) administered as intratumoral injections in subjects diagnosed with advanced/metastatic solid tumors and lymphoma for possible treatment. Eligible subjects will receive SYNB1891 intratumorally and will undergo imaging to assess tumor response, safety monitoring and subsequent follow-up after investigational product (IP) administration. Once dose limiting toxicity (DLT) for SYNB1891 is determined, it will be administered at one log dose level lower in combination with atezolizumab.

Condition or disease Intervention/treatment Phase
Metastatic Solid Neoplasm Lymphoma Drug: SYNB1891 Drug: Atezolizumab Phase 1

Detailed Description:

This phase 1, open-label, multicenter, 2-arm study of SYNB1891 in subjects diagnosed with advanced/metastatic solid tumors and lymphoma will evaluate safety and tolerability of escalating doses of intratumoral injections of SYNB1891 to determine single-agent maximum tolerated dose (MTD) as monotherapy and the recommended Phase 2 dose (RP2D) in combination with atezolizumab. The incidence of dose-limiting toxicities (DLTs), kinetics and pharmacodynamics will be evaluated in 2 arms:

Arm 1 comprises escalating doses of intratumoral injections of SYNB1891 monotherapy for up to four 21-day cycles with up to 24 months following initial treatment for those determined not to have progressive disease at the end of Cycle 4. Up to 7 dose cohorts will be evaluated to identify MTD within the dose range studied. Up to 35 patients may be enrolled in this arm of the study. Following attainment of MTD, Arm 2 will be initiated.

Arm 2 comprises escalating doses of intratumoral injections of SYNB1891 for up to four 21-day cycles with up to 24 months following initial treatment for those determined not to have progressive disease at the end of Cycle 4. In addition, atezolizumab will be administered as an intravenous (IV) infusion in accordance with its recommended dose and schedule during each of the planned 4 cycles with up to 24 months following initial treatment for those determined not to have progressive disease at the end of Cycle 4. Up to 3 dose cohorts will be evaluated to identify RP2D in combination with atezolizumab. Up to 12 patients may be enrolled in Arm 2. An additional 20 subjects may be enrolled in an extension combination.

Safety will be monitored continuously by documentation of adverse events (AEs), serious adverse events (SAEs), clinical laboratory measurements, vital signs and physical examinations. DLTs will be evaluated at the end of Cycle 1 in both Arms 1 and 2.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 70 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Dose-escalating, open-label
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-label, Multicenter Study of SYNB1891 Administered by Intratumoral Injection to Patients With Advanced/Metastatic Solid Tumors and Lymphoma Alone and in Combination With Atezolizumab
Actual Study Start Date : November 1, 2019
Estimated Primary Completion Date : May 17, 2021
Estimated Study Completion Date : June 17, 2023

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Arm 1: SYNB1891 Monotherapy
SYNB1891 is to be administered as an intratumoral injection in up to four 21-day cycles of escalating doses on days 1, 8 and 15 of cycle 1 and day 1 of cycles 2-4. The starting dose of SYNB1891 in the first cohort will be 1 × 10^6 live cells and will be increased in approximately 3-fold increments in subsequent cohorts until MTD determination. A de-escalation dose of 3 × 10^5 live cells is available if the starting dose is deemed not tolerable. Patients without progressive disease at the end of cycle 4 may receive additional cycles of SYNB1891 on day 1 of each cycle for up to 24 months after initial dose of study treatment.
Drug: SYNB1891
Up to four 21-day cycles of escalating doses of SYNB1891 intratumoral injection on Days 1, 8 and 15 of Cycle 1 and Day 1 of cycles 2-4.

Experimental: Arm 2: SYNB1891 in Combination with Atezolizumab
Once the MTD has been established in Arm 1, dosing of SYNB1891 will begin in Arm 2 at a 10-fold lower dose than the Arm 1 maximum tolerated dose (MTD) and will be increased in approximately 3-fold increments in subsequent cohorts until recommended Phase 2 dose (RP2D) determination. SYNB1891 is to be administered in the same manner and frequency as Arm 1. Atezolizumab will be administered in accordance with its recommended dose and schedule (1200 mg IV every 3 weeks) on day 1 of each of the 4 planned cycles. On days when atezolizumab and SYNB1891 are both administered, SYNB1891 will be administered first, followed by at least 1 hour of observation prior to the atezolizumab infusion. Combination doses will not be escalated above the SYNB1891 single-agent MTD established in Arm 1. Patients without progressive disease at the end of cycle 4 may receive additional cycles of SYNB1891 and atezolizumab on day 1 of each cycle for up to 24 months after initial dose of study treatment.
Drug: SYNB1891
Up to four 21-day cycles of escalating doses of SYNB1891 intratumoral injection on Days 1, 8 and 15 of Cycle 1 and Day 1 of cycles 2-4.

Drug: Atezolizumab
Administered in accordance with its recommended dose and schedule (1200 mg IV Q3W) on Day 1 of each of the 4 planned 21-day cycles.




Primary Outcome Measures :
  1. Incidence of dose-limiting toxicities (DLTs) [ Time Frame: Evaluated through the end of the first 21-day cycle. ]
    Percentage of patients who experience a DLT


Secondary Outcome Measures :
  1. Nature, incidence and severity of all adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Monitored continuously from time of informed consent signing through the Safety Follow-up visit which occurs 30 ± 5 days after the last dose of study treatment (up to 26 months). ]
    Rated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0

  2. Objective response rate (ORR) [ Time Frame: Assessed every 2 cycles (each cycle is 21 days) for the duration of study treatment administration (up to 24 months). ]
    Determined by the Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1), immune-related RECIST (iRECIST), and/or the Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC), with evaluations of the SYNB1891-injected tumor(s) and an overall response of up to 5 target (noninjected) lesions. Assessed by the local investigator using appropriate imaging.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Able and willing to voluntarily complete the informed consent process (patient or patient's representative).
  2. Adults aged ≥ 18 years (on the day of signing informed consent) with histologically- or cytologically-confirmed stage III or IV advanced/metastatic solid tumor or lymphoma that is not surgically resectable and for which no therapeutic options are available to extend survival or for which the patient is not a candidate for standard-of-care therapy.
  3. Eastern Cooperative Oncology Group performance status ≤ 1.
  4. Life expectancy ≥ 3 months.
  5. ≥ 1 injectable, measurable (≥ 10 mm in diameter, or ≥ 15 mm for nodal lesions), eligible lesion as defined by RECIST 1.1 (Eisenhauer et al 2009), iRECIST (Seymour et al 2017), and/or LYRIC (Cheson et al 2016) and as assessed by the Investigator. Eligible lesions must be nonvisceral and must not be located in either the thoracic, abdominal or pelvic cavities or in the cranium and must be amenable to percutaneous injection and away from major blood vessels or neurological structures.
  6. Able to provide biopsies for biomarker analysis from injected and (if available) noninjected lesions at baseline and other time points during the study.
  7. Normal oxygenation without the use of supplemental oxygen.
  8. Adequate cardiac function, defined as follows:

    1. Left ventricular ejection fraction (LVEF) > 50% by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO) performed within 6 months prior to the first dose of study treatment provided the patient has not received any potential cardiotoxic agents in the intervening period. Symptoms relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia must all be < Grade 1.
    2. QTc interval corrected for heart rate using Fridericia's formula (QTcF) < 480 msec at screening.
  9. Laboratory values within the following ranges:

    • Absolute neutrophil count ≥ 1500/µL
    • Lymphocyte count ≥ 500/µL
    • Platelets ≥ 100,000/µL without transfusion
    • Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L1 (patients may be transfused to meet this criterion)
    • Estimated glomerular filtration rate (eGFR) > 50 mL/min/1.73 m2
    • Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN (elevated indirect bilirubin because of Gilbert's syndrome is permitted)
    • Aspartate Aminotransferase (AST), Alanine Transaminase (ALT), and alkaline phosphatase ≤ 2.5 × ULN (AST and ALT ≤ 5 × ULN for participants with liver metastases and alkaline phosphatase ≤ 5 × ULN for participants with liver or bone metastases)
    • Albumin ≥ 2.5 g/dL
    • International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
    • (Thyroid stimulating hormone) TSH within the normal reference range or on stable thyroid replacement therapy
  10. Agree to use an acceptable method of contraception after informed consent, throughout the study, and for 5 months after the last dose of SYNB1891 or atezolizumab.

    Additional inclusion criteria that apply only to Arm 2 study participants are as follows:

  11. Patients must have progressed on treatment with an anti-PD-1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors (CPIs) or other therapies, if indicated (if CPI therapy is not indicated as a part of standard of care therapy, patients may be CPI naïve).

Exclusion Criteria:

  1. Chemotherapy, radiation, or biological cancer therapy within 14 days prior to the first dose of study treatment, or failure of any AEs to recover to Baseline or NCI CTCAE Grade 1, except for any grade of alopecia from AEs caused by cancer therapeutics administered > 28 days earlier.
  2. Systemic immunostimulatory agents (including, but not limited to, interferon (IFN) and (interleukin) IL-2) within 28 days or 5 drug elimination half-lives (whichever is longer) prior to initiation of study treatment.
  3. Allogeneic hematopoietic stem cell transplantation within the last 5 years (patients who have had a transplant > 5 years ago are eligible provided that no symptoms of graft versus-host disease are present) that requires current use of immunosuppressors.
  4. Receipt of a live vaccine within 90 days prior to the first dose of study treatment or anticipation of a need for such a vaccine during treatment.
  5. Receipt of warfarin or other oral anticoagulants within 7 days prior to the first dose of study treatment. Patients may switch to enoxaparin, with holding of the dose the day before i.t. injection of SYNB1891 (if holding the dose is not contraindicated).
  6. Receipt of antibiotics within 7 days prior to the first dose of study treatment.
  7. Participation in a study of an investigational agent and receipt of study therapy or use of an investigational device within 28 days prior to the first dose of study treatment.
  8. Diagnosed immunodeficiency or current use of chronic systemic steroid therapy in excess of replacement doses (prednisone ≤ 10 mg/day or equivalent is acceptable) or any other form of immunosuppressive medication within 7 days prior to the first dose of study treatment.
  9. Anticipated requirement of any other form of antineoplastic therapy while on study.
  10. History of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 2 years.
  11. Clinically active central nervous system (CNS) metastases and/or carcinomatous meningitis (stable brain metastases are permitted if treatment was completed ≥ 28 days prior to the first dose of study treatment).
  12. History of immune-mediated vasculitis, pancreatitis, colitis, hepatitis, or nephritis.
  13. History of immune-related AEs requiring discontinuation of prior PD-1/PD-L1 therapy.
  14. Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, with the following exceptions:

    1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study.
    2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
    3. Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., patients with psoriatic arthritis are excluded) are eligible for the study provided all of following conditions are met:
    1. Rash must cover < 10% of body surface area;
    2. Disease is well controlled at baseline and requires only low-potency topical corticosteroids;
    3. No occurrence of acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high potency or oral corticosteroids within the previous 12 months.
  15. Allergy to antibiotics that precludes treatment for infection with E. coli Nissle 1917.
  16. Human immunodeficiency virus (HIV) and/or hepatitis B or C infection(s) unless screening tests indicate negative viral load.
  17. Known active tuberculosis.
  18. Grade 3 or higher infection according to NCI CTCAE within 28 days prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia.
  19. Failure to fully recover from the effects of major surgery. Surgeries that required general anesthesia must be completed > 14 days before the first dose of study drug. Surgery requiring regional/epidural anesthesia must be completed > 72 hours before the first dose of study treatment and participants should be recovered.
  20. Heart failure of New York Heart Association Class 3 or greater, history of pericardial disease, restrictive cardiomyopathy, or unstable angina or recent myocardial infarction within 3 to 6 months prior to the first dose of study treatment.
  21. Any other medical condition that might confound the results of the study, interfere with the participant's participation, or is not in the best interest of the participant, in the opinion of the treating Investigator.
  22. Pregnant or breastfeeding or anticipated conception or fathering of children within the projected duration of the study and for 5 months after the last dose of SYNB1891 or atezolizumab.

    Additional exclusion criteria that apply only to Arm 2 study participants are as follows:

  23. History of a severe allergic anaphylactic reaction following treatment with a PD-1 mAb or to chimeric or humanized antibodies or fusion proteins.
  24. History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis requiring treatment, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04167137


Contacts
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Contact: Andrew Marsh (617) 401-9975 andrew.marsh@synlogictx.com

Locations
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United States, Colorado
University of Colorado Cancer Center Recruiting
Aurora, Colorado, United States, 80045
Contact: Matthew Skoch    720-848-0668    matthew.skoch@cuanschutz.edu   
Principal Investigator: Karl D Lewis, MD         
United States, New Jersey
Hackensack University John Theurer Cancer Center Recruiting
Hackensack, New Jersey, United States, 07601
Contact: Chelsea McCabe       chelsea.mccabe@hackensackmeridian.org   
Principal Investigator: Martin Gutierrez, MD         
United States, Pennsylvania
University of Pittsburgh Recruiting
Pittsburgh, Pennsylvania, United States, 15232
Contact: Krystle Eaton    412-623-7957    mientkiewiczk@upmc.edu   
Principal Investigator: Jason J Luke, MD         
United States, Texas
Mary Crowley Cancer Research Recruiting
Dallas, Texas, United States, 75230
Contact: Karina Martinez    972-566-3032    kmartinez@marycrowley.org   
Principal Investigator: James Strauss, MD         
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Abha Adat    713-745-4297    aadat@mdanderson.org   
Principal Investigator: Filip Janku, MD         
Sponsors and Collaborators
Synlogic
IQVIA Biotech
Investigators
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Study Director: Richard Riese, MD Synlogic
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Responsible Party: Synlogic
ClinicalTrials.gov Identifier: NCT04167137    
Other Study ID Numbers: SYNB1891-CP-001
First Posted: November 18, 2019    Key Record Dates
Last Update Posted: June 25, 2020
Last Verified: June 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Synlogic:
solid tumor
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Atezolizumab
Antineoplastic Agents