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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Metastatic Solid Neoplasm, Lymphoma

Intervention / Treatment
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* Drug: SYNB1891
* Drug: Atezolizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able and willing to voluntarily complete the informed consent process (patient or patient's representative). 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. Eastern Cooperative Oncology Group performance status ≤ 1. Life expectancy ≥ 3 months. ≥ 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. Able to provide biopsies for biomarker analysis from injected and (if available) noninjected lesions at baseline and other time points during the study. Normal oxygenation without the use of supplemental oxygen. Adequate cardiac function, defined as follows: 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. QTc interval corrected for heart rate using Fridericia's formula (QTcF) < 480 msec at screening. 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 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: 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: 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. 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. 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. 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. 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). Receipt of antibiotics within 7 days prior to the first dose of study treatment. 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. 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. Anticipated requirement of any other form of antineoplastic therapy while on study. History of a second malignancy, unless potentially curative treatment has been completed, with no evidence of malignancy for 2 years. 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). History of immune-mediated vasculitis, pancreatitis, colitis, hepatitis, or nephritis. History of immune-related AEs requiring discontinuation of prior PD-1/PD-L1 therapy. 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: Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for the study. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study. 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: Rash must cover < 10% of body surface area; Disease is well controlled at baseline and requires only low-potency topical corticosteroids; 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. Allergy to antibiotics that precludes treatment for infection with E. coli Nissle 1917. Human immunodeficiency virus (HIV) and/or hepatitis B or C infection(s) unless screening tests indicate negative viral load. Known active tuberculosis. 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. 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. 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. 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. 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: History of a severe allergic anaphylactic reaction following treatment with a PD-1 mAb or to chimeric or humanized antibodies or fusion proteins. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Dose-escalating, open-label
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1: SYNB1891 Monotherapy<br>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<br>* 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.<br>|
| Experimental: Arm 2: SYNB1891 in Combination with Atezolizumab<br>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<br>* 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.<br>Drug: Atezolizumab<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) | Percentage of patients who experience a DLT | Evaluated through the end of the first 21-day cycle. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nature, incidence and severity of all adverse events (AEs) and serious adverse events (SAEs) | Rated according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 | 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). | 
| Objective response rate (ORR) | 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. | Assessed every 2 cycles (each cycle is 21 days) for the duration of study treatment administration (up to 24 months). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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solid tumor