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

NCT04167137 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: SYNB1891-CP-001
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 6

Brief 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. 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.

Conditions

Metastatic Solid Neoplasm; Lymphoma

Keywords

solid tumor

Outcome Measures

Primary Outcomes (1)

• 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: 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

  21 days (1 cycle)

Secondary Outcomes (2)

• Number of Participants With Treatment-Emergent Adverse Events

  Up to 13 months

• Number of Participants With Best Tumor Response as Measured by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1)

  Up to 13 months

Study Arms (2)

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.

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.

Drug: SYNB1891; Drug: Atezolizumab

Interventions

SYNB1891 DRUG

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.

Arm 1: SYNB1891 Monotherapy; Arm 2: SYNB1891 in Combination with Atezolizumab

Atezolizumab DRUG

Atezolizumab was administered in accordance with its recommended dose and schedule (1200 mg IV Q3W).

Arm 2: SYNB1891 in Combination with Atezolizumab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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)

You may not qualify if:

• 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.
• 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.
• 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.

Sponsors & Collaborators

• Synlogic: lead
• IQVIA Biotech: collaborator

Study Sites (6)

University of Colorado School of Medicine

Aurora, Colorado, 80045, United States

Location

Hackensack University John Theurer Cancer Center

Hackensack, New Jersey, 07601, United States

Location

Ohio State University College of Medicine

Columbus, Ohio, 43210, United States

Location

University of Pittsburgh Hillman Cancer Center

Pittsburgh, Pennsylvania, 15232, United States

Location

Mary Crowley Cancer Research

Dallas, Texas, 75230, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Related Publications (6)

• 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.

  PMID: 19097774 BACKGROUND

• Seymour 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.

  PMID: 28271869 BACKGROUND

• Cheson 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.

  PMID: 27574190 BACKGROUND

• Ji 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.

  PMID: 23569307 BACKGROUND

• Marabelle 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.

  PMID: 30295695 BACKGROUND

• Luke 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.

  PMID: 37227176 DERIVED

MeSH Terms

Conditions

Neoplasm Metastasis; Lymphoma

Interventions

atezolizumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Limitations and Caveats

The study was terminated prematurely by the Sponsor prior to enrollment completion.

Results Point of Contact

• Title: Aoife Brennan, MB, BCh, BAO, MMSc
• Organization: Synlogic

aoife@synlogictx.com

(857) 999-0767

Study Officials

• Aoife Brennan, MB, BCh, BAO, MMSc

  Synlogic

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: Dose-escalating, open-label

Study Record Dates

• First Submitted: November 12, 2019
• First Posted: November 18, 2019
• Study Start: December 12, 2019
• Primary Completion: December 9, 2021
• Study Completion: December 9, 2021
• Last Updated: May 3, 2024
• Results First Posted: May 3, 2024

Record last verified: 2023-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (6)