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.
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.
