Metastatic Solid NeoplasmPhase 1NCT04167137
Safety and Tolerability of SYNB1891 Injection Alone or in Combination With Atezolizumab in Adult Participants
A Phase 1 study testing SYNB1891 and Atezolizumab in people with Metastatic Solid Neoplasm and Lymphoma, run by Synlogic at 6 sites in United States.
Trial summary
This Phase 1, open-label, multicenter, 2-arm study was designed to evaluate SYNB1891 when administered either as monotherapy (Arm 1) or in combination with atezolizumab (Arm 2) in participants with advanced/metastatic solid tumors or lymphoma. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Metastatic Solid Neoplasm, Lymphoma
- What is being tested?
- SYNB1891 and Atezolizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 32 participants
- Where
- 6 sitesUnited States
- Study dates
- 12 Dec 2019to 9 Dec 2021
- Phase
- Phase 1
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Able and willing to voluntarily complete the informed consent process (participant or participant'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 for which no therapeutic options were available to extend survival or for which the participant was 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Eisenhauer et al 2009), immune-related RECIST (iRECIST) (Seymour et al 2017), and/or Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson et al 2016) and as assessed by the Investigator. Eligible lesions must not have been located in the thoracic cavity, spleen, pancreas, gastrointestinal tract (liver injection allowed), or cranium and must have been 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.
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- Oxygen saturation > 90% 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 participant had not received any potential cardiotoxic agents in the intervening period. Symptoms relating to left ventricular dysfunction, cardiac arrhythmia, or cardiac ischemia must all have been Grade < 1 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
- 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 (participants may have been transfused to meet this criterion)
- Estimated glomerular filtration rate (eGFR) > 50 mL/min/1.73 m^2 per the Cockcroft-Gault formula
- Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels > 1.5 × ULN or ≤ 3 × ULN for participants with Gilbert's syndrome
- Aspartate aminotransferase (AST), alanine aminotransferase (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)
- International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN unless participant was receiving anticoagulant therapy as long as PT or aPTT was within therapeutic range of intended use of anticoagulants
- Agreed 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 applied only to Arm 2 study participants were as follows:
- Thyroid-stimulating hormone (TSH) within the normal reference range or the participant was receiving stable thyroid replacement therapy.
- Participants must have received treatment with an anti-programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors (CPIs) or other therapies, if indicated (if CPI therapy was not indicated as a part of standard-of-care therapy, participants may have been CPI naïve).
Who cannot join
- Chemotherapy, radiation, or biological cancer therapy within 14 days prior to the first dose of study treatment, or failure of any adverse events (AEs) to recover to Baseline or NCI CTCAE version 5.0 Grade 1, except for any grade of alopecia caused by cancer therapeutics administered > 28 days earlier.
- Systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 28 days or 5 drug elimination half-lives (whichever was longer) prior to initiation of study treatment. CPIs were not considered systemic immunostimulatory agents for this criterion and were subject to the washout period listed in exclusion criterion #1.
- Allogeneic hematopoietic stem cell transplantation that required 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 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.
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- Diagnosed immunodeficiency or current use of chronic systemic steroid therapy in excess of replacement doses (prednisone ≤ 10 mg/day or equivalent was acceptable) or any other form of immunosuppressive medication within 7 days prior to the first dose of study treatment.
- For injection and biopsy of visceral (deep) lesions: participants must not have been on long-acting antiplatelet agents such as aspirin or clopidogrel or on therapeutic doses of anticoagulants, with the exception of participants receiving a preventative dose of low molecular weight heparin. In participants receiving preventative low molecular weight heparin, treatment must have been stopped 24 hours before the intratumoral injection and resumed again 24 hours after the injection (Marabelle et al 2018).
- Previous or concurrent malignancy, with the exception of:
- Adequately treated basal or squamous cell carcinoma, in situ carcinoma of the cervix, or ductal carcinoma in situ of the breast;
- Localized prostate cancer definitively treated with surgery or radiation or stable on hormone therapy;
- Other cancer from which the participant had been disease free for at least 2 years.
- Clinically active central nervous system metastases and/or carcinomatous meningitis (treated brain metastases were permitted if radiologically stable for ≥ 28 days prior to the first dose of study treatment).
- Allergy to antibiotics that precluded treatment for infection with Escherichia coli Nissle 1917.
- Hepatitis B or C infection(s) unless screening tests indicated a negative viral load, and/or human immunodeficiency virus infection unless screening tests indicated a negative or below the limit of quantitation 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 have been completed > 14 days before the first dose of study drug. Surgery requiring regional/epidural anesthesia must have been completed > 72 hours before the first dose of study treatment and participants should have recovered.
- Heart failure of New York Heart Association Class 3 or greater, restrictive cardiomyopathy, or unstable angina or recent myocardial infarction within 3 months prior to the first dose of study treatment.
- Any other medical condition that might have confounded the results of the study, interfered with the participant's participation, or was 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 applied only to Arm 2 study participants were as follows:
- History of immune-mediated AEs on prior PD-1/PD-L1 therapies requiring discontinuation or immunosuppressor therapy, excluding endocrinopathies.
- Active or history of underlying 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:
- Participants with a history of autoimmune-related hypothyroidism who were on thyroid replacement hormone were eligible for the study.
- Participants with controlled Type 1 diabetes mellitus who were on an insulin regimen were eligible for the study.
- Participants with eczema, psoriasis, lichen simplex chronicus, or vitiligo with dermatologic manifestations only (e.g., participants with psoriatic arthritis are excluded) were eligible for the study provided all of following conditions were met:
- Rash covered < 10% of body surface area;
- Disease was well controlled at baseline and required 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.
- History of a Grade ≥ 3 allergic anaphylactic reaction following treatment with a PD-1 mAb or to chimeric, human, 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.
- Known hypersensitivity to Chinese hamster ovary cell products or any component of the atezolizumab formulation.
Trial locations and contacts
6 sites in 1 country.
6 sites in 1 country
United States6 sites
University of Colorado School of Medicine
Aurora, Colorado, 80045
Ohio State University College of Medicine
Columbus, Ohio, 43210
Mary Crowley Cancer Research
Dallas, Texas, 75230
Hackensack University John Theurer Cancer Center
Hackensack, New Jersey, 07601
University of Texas MD Anderson Cancer Center
Houston, Texas, 77030
University of Pittsburgh Hillman Cancer Center
Pittsburgh, Pennsylvania, 15232
About this study
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
This Phase 1, open-label, multicenter, 2-arm study was designed to evaluate SYNB1891 when administered either as monotherapy (Arm 1) or in combination with atezolizumab (Arm 2) in participants with advanced/metastatic solid tumors or lymphoma. The primary objective was to evaluate the safety and tolerability of study treatment, with a secondary objective of assessing preliminary tumor response to treatment and exploratory objectives of evaluating the pharmacokinetics/pharmacodynamics (PK/PD) of study treatment.
Read the detailed description
Arm 1 comprised intratumoral (IT) injections of SYNB1891 monotherapy to determine the single-agent maximum tolerated dose (MTD). The starting dose of SYNB1891 in the first cohort was 1 × 10^6 live cells and was increased in approximately 3-fold increments in subsequent cohorts until MTD determination in accordance with the modified toxicity probability interval (mTPI) algorithm (Ji et al 2013). Dose escalation was to proceed until the target dose-limiting toxicity (DLT) range (approximately 30%) for SYNB1891 monotherapy was determined based on DLTs observed in Cycle 1. The dose selected as achieving the target DLT range was to be considered the MTD. DLTs were defined in the protocol as certain treatment-related Grade 3/4 laboratory values, sepsis, toxicity resulting in death, discontinuation of Cycle 1, or delay of Cycle 2.
Arm 2 comprised IT injections of SYNB1891 combined with standard dose atezolizumab (1200 mg intravenously [IV] every 3 weeks [Q3W]). Arm 2 dosing began after all participants in Arm 1 Cohort 4 completed their Cycle 1 DLT safety evaluation. The starting dose of IT SYNB1891 in the first cohort of Arm 2 was at the SYNB1891 Arm 1 Cohort 3 dose level. SYNB1891 dosing in the Arm 2 cohorts increased in approximately 3-fold increments in subsequent cohorts until recommended Phase 2 dose (RP2D) determination. SYNB1891 combination dosing in Arm 2 was always at least 1 dose level below the SYNB1891 monotherapy dose being evaluated in Arm 1, with combination doses not escalated above the SYNB1891 single-agent MTD established in Arm 1.
In both arms, after an initial 4 cycles (21 days per cycle) of study treatment, participants who did not have progressive disease may have received additional cycles of their assigned study treatment for up to 24 months (i.e., Cycles 5 to 35) after the initial dose.
The maximum time of study participation for a participant may have been up to 26 months, including the screening period (up to 28 days), treatment administration period (up to 24 months), and Safety Follow-up period (30 ± 5 days after the last dose).
- Conditions
- Metastatic Solid Neoplasm, Lymphoma
- Being tested
- SYNB1891, Atezolizumab
- Keywords
- solid tumor
- Medical subject headings
- Neoplasm Metastasis, Lymphoma
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SYNB1891Drug
SYNB1891 was administered as an IT injection over a dose range of 1 x 10^6 to 3 x 10^8 live cells in Arm 1 and 1 x 10^7 to 3 x 10^7 in Arm 2.
AtezolizumabDrug
Atezolizumab was administered in accordance with its recommended dose and schedule (1200 mg IV Q3W).
| Study group | Role | What they receive |
|---|---|---|
| Arm 1: SYNB1891 Monotherapy | Experimental | SYNB1891 monotherapy was administered as an IT injection on Days 1, 8, and 15 of Cycle 1 and Day 1 of subsequent cycles for up to 24 months/35 cycles. The starting dose of SYNB1891 in the first cohort was 1 × 10^6 live cells and was increased in approximately 3-fold increments in subsequent cohorts. Receives: Drug: SYNB1891 |
| Arm 2: SYNB1891 in Combination with Atezolizumab | Experimental | SYNB1891 was administered as an IT injection on Days 1, 8, and 15 of Cycle 1 and Day 1 of subsequent cycles for up to 24 months/35 cycles. The dose of SYNB1891 in the first cohort was 1 × 10^7 live cells and was increased in an approximately 3-fold increment to 3 × 10^7 live cells in the second cohort.
Atezolizumab was administered in accordance with its recommended dose and schedule (1200 mg IV Q3W) on Day 1 of each cycle for up to 24 months/35 cycles. On days when atezolizumab and SYNB1891 were both administered, SYNB1891 was administered first, followed by at least 1 hour of observation prior to the atezolizumab infusion. Receives: Drug: SYNB1891; Drug: Atezolizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Number of Participants With Dose-limiting Toxicity
The following adverse events (AEs) were DLTs if they occurred in Cycle 1 and were assessed by the Investigator as related to treatment:
- Grade (Gr) 4 nonhematologic toxicity (not laboratory)
- Gr 4 hematologic toxicity ≥ 7 days, any Gr 4 thrombocytopenia, or Gr 3 thrombocytopenia with significant bleeding
- Gr ≥ 3 nonhematologic toxicity (exceptions: Gr 3 fatigue ≤ 3 days; Gr 3 diarrhea, nausea, or vomiting without treatment; Gr 3 rash without treatment)
- Gr 3/4 nonhematologic laboratory value for > 1 week or resulting in significant medical intervention, hospitalization, or drug-induced liver injury (exceptions: clinically nonsignificant, treatable, or reversible laboratory abnormalities)
- Gr 3/4 febrile neutropenia
- Sepsis, severe abscesses and/or ulcerations requiring surgical management
- Toxicity delaying Cycle 2 initiation >2 weeks
- Toxicity causing treatment discontinuation
- Gr 3 toxicity causing omission of > 33% of study doses
- Gr 5 toxicity
Measured: 21 days (1 cycle)
Secondary outcomes (2)
Number of Participants With Treatment-Emergent Adverse Events
Toxicity was graded in accordance with the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0, as follows: Grade 1 (mild/asymptomatic; no intervention); Grade 2 (moderate; minimal intervention); Grade 3 (severe/medically significant; hospitalization indicated; disabling); Grade 4 (life-threatening; urgent intervention required); or Grade 5 (fatal). Adverse events (AEs) were reported from clinical laboratory tests, vital sign and weight measurements, physical examinations, and any other medically indicated assessments, including participant interviews, from the time informed consent was signed through the end of the safety follow-up period. AEs were considered to be treatment-emergent adverse events (TEAEs) if they occurred or worsened in severity after the first dose of study treatment. TEAEs were considered treatment-related if the relationship to study drug was possibly, probably, or definitely related.
Measured: Up to 13 months
Number of Participants With Best Tumor Response as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Appropriate imaging of the SYNB1891-injected tumor(s) and up to 5 target (noninjected) lesions was performed at baseline and every 2 cycles during the treatment period. Tumor response was assessed by the local investigator using RECIST 1.1 (Eisenhauer et al 2009). Per RECIST 1.1, target lesions are categorized as follows: complete response (CR): disappearance of all target lesions (no evaluable disease); partial response (PR): ≥ 30% decrease in the sum of the longest diameter of target lesions; progressive disease (PD): ≥ 20% increase in the sum of the longest diameter of target lesions; stable disease (SD): small changes that do not meet above criteria.
Measured: Up to 13 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted18 Nov 2019
- Study start12 Dec 2019
- Primary completion9 Dec 2021
- Study completion9 Dec 2021
Why it stopped: Business reasons
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (6)Papers the sponsor has linked to this study.
- Other trials for Metastatic Solid NeoplasmStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Model description
- Dose-escalating, open-label
- Masking
- None (open label)
- Enrolment
- 32 participants (actual)
Sponsor and investigators
- Lead sponsor
- Synlogic
- Sponsor type
- Industry (pharma, biotech, devices)
- Collaborators
- IQVIA Biotech
- Responsible party
- Sponsor
- Investigators
- Aoife Brennan, MB, BCh, BAO, MMSc, Study director, Synlogic
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04167137
- Sponsor's protocol ID
- SYNB1891-CP-001
- Status last verified
- Nov 2023
- First submitted
- 12 Nov 2019
- Last updated
- 3 May 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
PubMed 19097774Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. doi: 10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2.
PubMed 28271869Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, Hoos A, Barrington SF, Armand P. Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy. Blood. 2016 Nov 24;128(21):2489-2496. doi: 10.1182/blood-2016-05-718528. Epub 2016 Aug 29.
PubMed 27574190Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013 May 10;31(14):1785-91. doi: 10.1200/JCO.2012.45.7903. Epub 2013 Apr 8.
PubMed 23569307Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, de Baere T, Robert C, Ascierto PA, Baurain JF, Imperiale M, Rahimian S, Tersago D, Klumper E, Hendriks M, Kumar R, Stern M, Ohrling K, Massacesi C, Tchakov I, Tse A, Douillard JY, Tabernero J, Haanen J, Brody J. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018 Nov 1;29(11):2163-2174. doi: 10.1093/annonc/mdy423.
PubMed 30295695Luke JJ, Piha-Paul SA, Medina T, Verschraegen CF, Varterasian M, Brennan AM, Riese RJ, Sokolovska A, Strauss J, Hava DL, Janku F. Phase I Study of SYNB1891, an Engineered E. coli Nissle Strain Expressing STING Agonist, with and without Atezolizumab in Advanced Malignancies. Clin Cancer Res. 2023 Jul 5;29(13):2435-2444. doi: 10.1158/1078-0432.CCR-23-0118.
PubMed 37227176
Study at a glance
From the registry record, last updated by the sponsor on 3 May 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT04167137
- Acronym / sponsor ID
- SYNB1891-CP-001
- Conditions
- Metastatic Solid Neoplasm, Lymphoma
- Keywords
- solid tumor
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Business reasons
- Enrolment
- 32 participants (actual)
- Lead sponsor
- SynlogicIndustry (pharma, biotech, devices)
- Collaborators
- IQVIA Biotech
- Study start
- 12 Dec 2019 (actual)
- Primary completion
- 9 Dec 2021 (actual)
- Study completion
- 9 Dec 2021 (actual)
- First posted
- 18 Nov 2019 (actual)
- Results
- Posted 3 May 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This Phase 1, open-label, multicenter, 2-arm study was designed to evaluate SYNB1891 when administered either as monotherapy (Arm 1) or in combination with atezolizumab (Arm 2) in participants with advanced/metastatic solid tumors or lymphoma. The primary objective was to evaluate the safety and tolerability of study treatment, with a secondary objective of assessing preliminary tumor response to treatment and exploratory objectives of evaluating the pharmacokinetics/pharmacodynamics (PK/PD) of study treatment.
Detailed description
Arm 1 comprised intratumoral (IT) injections of SYNB1891 monotherapy to determine the single-agent maximum tolerated dose (MTD). The starting dose of SYNB1891 in the first cohort was 1 × 10^6 live cells and was increased in approximately 3-fold increments in subsequent cohorts until MTD determination in accordance with the modified toxicity probability interval (mTPI) algorithm (Ji et al 2013). Dose escalation was to proceed until the target dose-limiting toxicity (DLT) range (approximately 30%) for SYNB1891 monotherapy was determined based on DLTs observed in Cycle 1. The dose selected as achieving the target DLT range was to be considered the MTD. DLTs were defined in the protocol as certain treatment-related Grade 3/4 laboratory values, sepsis, toxicity resulting in death, discontinuation of Cycle 1, or delay of Cycle 2.
Arm 2 comprised IT injections of SYNB1891 combined with standard dose atezolizumab (1200 mg intravenously [IV] every 3 weeks [Q3W]). Arm 2 dosing began after all participants in Arm 1 Cohort 4 completed their Cycle 1 DLT safety evaluation. The starting dose of IT SYNB1891 in the first cohort of Arm 2 was at the SYNB1891 Arm 1 Cohort 3 dose level. SYNB1891 dosing in the Arm 2 cohorts increased in approximately 3-fold increments in subsequent cohorts until recommended Phase 2 dose (RP2D) determination. SYNB1891 combination dosing in Arm 2 was always at least 1 dose level below the SYNB1891 monotherapy dose being evaluated in Arm 1, with combination doses not escalated above the SYNB1891 single-agent MTD established in Arm 1.
In both arms, after an initial 4 cycles (21 days per cycle) of study treatment, participants who did not have progressive disease may have received additional cycles of their assigned study treatment for up to 24 months (i.e., Cycles 5 to 35) after the initial dose.
The maximum time of study participation for a participant may have been up to 26 months, including the screening period (up to 28 days), treatment administration period (up to 24 months), and Safety Follow-up period (30 ± 5 days after the last dose).
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Sequential
- Masking
- None (open label)
- Number of arms
- 2
- Model description
- Dose-escalating, open-label
| Arm | Type | Receives |
|---|---|---|
| Arm 1: SYNB1891 Monotherapy | Experimental | Drug: SYNB1891SYNB1891 monotherapy was administered as an IT injection on Days 1, 8, and 15 of Cycle 1 and Day 1 of subsequent cycles for up to 24 months/35 cycles. The starting dose of SYNB1891 in the first cohort was 1 × 10^6 live cells and was increased in approximately 3-fold increments in subsequent cohorts. |
| Arm 2: SYNB1891 in Combination with Atezolizumab | Experimental | Drug: SYNB1891, Drug: AtezolizumabSYNB1891 was administered as an IT injection on Days 1, 8, and 15 of Cycle 1 and Day 1 of subsequent cycles for up to 24 months/35 cycles. The dose of SYNB1891 in the first cohort was 1 × 10^7 live cells and was increased in an approximately 3-fold increment to 3 × 10^7 live cells in the second cohort. Atezolizumab was administered in accordance with its recommended dose and schedule (1200 mg IV Q3W) on Day 1 of each cycle for up to 24 months/35 cycles. On days when atezolizumab and SYNB1891 were both administered, SYNB1891 was administered first, followed by at least 1 hour of observation prior to the atezolizumab infusion. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (23 listed)
- Able and willing to voluntarily complete the informed consent process (participant or participant'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 for which no therapeutic options were available to extend survival or for which the participant was 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 Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (Eisenhauer et al 2009), immune-related RECIST (iRECIST) (Seymour et al 2017), and/or Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) (Cheson et al 2016) and as assessed by the Investigator. Eligible lesions must not have been located in the thoracic cavity, spleen, pancreas, gastrointestinal tract (liver injection allowed), or cranium and must have been amenable to percutaneous injection and away from major blood vessels or neurological structures.
Key exclusion criteria (33 listed)
- Chemotherapy, radiation, or biological cancer therapy within 14 days prior to the first dose of study treatment, or failure of any adverse events (AEs) to recover to Baseline or NCI CTCAE version 5.0 Grade 1, except for any grade of alopecia caused by cancer therapeutics administered > 28 days earlier.
- Systemic immunostimulatory agents (including, but not limited to, interferon and interleukin-2) within 28 days or 5 drug elimination half-lives (whichever was longer) prior to initiation of study treatment. CPIs were not considered systemic immunostimulatory agents for this criterion and were subject to the washout period listed in exclusion criterion #1.
- Allogeneic hematopoietic stem cell transplantation that required 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 antibiotics within 7 days prior to the first dose of study treatment.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| SYNB1891SYNB1891 was administered as an IT injection over a dose range of 1 x 10^6 to 3 x 10^8 live cells in Arm 1 and 1 x 10^7 to 3 x 10^7 in Arm 2. | Drug | Arm 1: SYNB1891 Monotherapy, Arm 2: SYNB1891 in Combination with Atezolizumab |
| AtezolizumabAtezolizumab was administered in accordance with its recommended dose and schedule (1200 mg IV Q3W). | Drug | Arm 2: SYNB1891 in Combination with Atezolizumab |
Primary outcome
Number of Participants With Dose-limiting Toxicity
Time frame: 21 days (1 cycle)
The following adverse events (AEs) were DLTs if they occurred in Cycle 1 and were assessed by the Investigator as related to treatment: 1. Grade (Gr) 4 nonhematologic toxicity (not laboratory) 2. Gr 4 hematologic toxicity ≥ 7 days, any Gr 4 thrombocytopenia, or Gr 3 thrombocytopenia with significant bleeding 3. Gr ≥ 3 nonhematologic toxicity (exceptions: Gr 3 fatigue ≤ 3 days; Gr 3 diarrhea, nausea, or vomiting without treatment; Gr 3 rash without treatment) 4. Gr 3/4 nonhematologic laboratory value for > 1 week or resulting in significant medical intervention, hospitalization, or drug-induced liver injury (exceptions: clinically nonsignificant, treatable, or reversible laboratory abnormalities) 5. Gr 3/4 febrile neutropenia 6. Sepsis, severe abscesses and/or ulcerations requiring surgical management 7. Toxicity delaying Cycle 2 initiation >2 weeks 8. Toxicity causing treatment discontinuation 9. Gr 3 toxicity causing omission of > 33% of study doses 10. Gr 5 toxicity
2 secondary outcomes
Number of Participants With Treatment-Emergent Adverse Events
Time frame: Up to 13 months
Number of Participants With Best Tumor Response as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Time frame: Up to 13 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 May 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19097774Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
- Background: PubMed 28271869Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, Lin NU, Litiere S, Dancey J, Chen A, Hodi FS, Therasse P, Hoekstra OS, Shankar LK, Wolchok JD, Ballinger M, Caramella C, de Vries EGE; RECIST working group. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017 Mar;18(3):e143-e152. doi: 10.1016/S1470-2045(17)30074-8. Epub 2017 Mar 2.
- Background: PubMed 27574190Cheson BD, Ansell S, Schwartz L, Gordon LI, Advani R, Jacene HA, Hoos A, Barrington SF, Armand P. Refinement of the Lugano Classification lymphoma response criteria in the era of immunomodulatory therapy. Blood. 2016 Nov 24;128(21):2489-2496. doi: 10.1182/blood-2016-05-718528. Epub 2016 Aug 29.
- Background: PubMed 23569307Ji Y, Wang SJ. Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 design for practical phase I trials. J Clin Oncol. 2013 May 10;31(14):1785-91. doi: 10.1200/JCO.2012.45.7903. Epub 2013 Apr 8.
- Background: PubMed 30295695Marabelle A, Andtbacka R, Harrington K, Melero I, Leidner R, de Baere T, Robert C, Ascierto PA, Baurain JF, Imperiale M, Rahimian S, Tersago D, Klumper E, Hendriks M, Kumar R, Stern M, Ohrling K, Massacesi C, Tchakov I, Tse A, Douillard JY, Tabernero J, Haanen J, Brody J. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann Oncol. 2018 Nov 1;29(11):2163-2174. doi: 10.1093/annonc/mdy423.
- Derived from this study: PubMed 37227176Luke JJ, Piha-Paul SA, Medina T, Verschraegen CF, Varterasian M, Brennan AM, Riese RJ, Sokolovska A, Strauss J, Hava DL, Janku F. Phase I Study of SYNB1891, an Engineered E. coli Nissle Strain Expressing STING Agonist, with and without Atezolizumab in Advanced Malignancies. Clin Cancer Res. 2023 Jul 5;29(13):2435-2444. doi: 10.1158/1078-0432.CCR-23-0118.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Aoife Brennan, MB, BCh, BAO, MMSc study director
Synlogic
6 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing SYNB1891 and Atezolizumab in people with Metastatic Solid Neoplasm and Lymphoma, run by Synlogic at 6 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 23 inclusion and 33 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 3 May 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 6 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 3 May 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With Dose-limiting Toxicity (time frame: 21 days (1 cycle)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT04167137, which also lists 6 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 3 May 2024.