Inclusion Criteria:
1. Capable of providing signed informed consent to participate in the study, and to
comply with the requirements and restrictions listed in the protocol.
2. ≥18 years of age at time of informed consent. 3. Histologically or cytologically confirmed metastatic or locally advanced
unresectable clear cell renal cell carcinoma (ccRCC), cutaneous melanoma, or EGFR/
ALK wildtype adenocarcinoma-type non-small cell lung carcinoma (NSCLC).
4. At least one measurable lesion per RECIST v 1.1 criteria. 5. Subjects must have progressed on treatment with a PD-1/PD-L1 inhibitor administered
either as monotherapy, or in combination with other checkpoint inhibitors or other
therapies. PD-1/PDL-1 inhibitor treatment progression is defined by meeting all of
the following criteria:
1. Has received at least 2 doses of a PD-1/PD-L1 inhibitor.
2. Has demonstrated disease progression after PD-1/PD-L1 therapy as defined by
RECIST v1.1, iRECIST or irRECIST. The initial evidence of disease progression
(PD) is to be confirmed by a second assessment no less than four weeks from the
date of the first documented PD, in the absence of rapid clinical progression.
3. Progressive disease has been documented within 12 weeks from the last dose of a
PD-1/PD-L1 inhibitor.
6. Subjects must have had prior response to anti-PD1/PDL-1 as single agent or in
combination with other cancer therapies, defined as at least stable disease per
iRECIST, as assessed by 2 consecutive imaging ≥ 4 weeks apart, with the first one
performed no earlier than 9 weeks from initiation of anti PD1/PDL-1 treatment.
7. Subjects must demonstrate adequate organ functions at Screening:
1. Absolute neutrophil count ≥1500/μL, platelet count ≥100,000/μL; hemoglobin ≥9.0
g/dL Note: Patients must not have received any growth factors or blood
transfusions within 28 days prior to the Screening hematologic laboratory tests. 2. Total bilirubin <1.5 × the upper limit of normal (ULN) (with the exception of
patients diagnosed with Gilbert syndrome), Alanine aminotransferase or
aspartate aminotransferase <1.5 × ULN. 3. Creatinine ≤ 1.5 ULN and/or estimated glomerular filtration rate ≥ 60. 4. Albumin >30 g/L (3.0 g/dL)
8. Eastern Cooperative Oncology Group (ECOG) performance status 0-1. 9. Female subjects of childbearing potential should have a negative urine pregnancy
test within 72 hours prior to enrolment (enrolment = start of depletion phase). If
urine pregnancy results cannot be confirmed as negative, a SERUM β-HCG pregnancy
test is required. Subjects of childbearing potential are those who have not been
surgically sterilized or those age < 60 y who have not been free from menses for ≥2
years.
10. Female subjects of childbearing potential must be willing to use 2 methods of birth
control starting from the start of the induction phase or be surgically sterile, or
abstain from heterosexual activity throughout the course of the study and 120 days
after the last dose of study medication. 11. Male subjects with female partners of childbearing potential should agree to use an
adequate method of contraception starting with the first dose of study therapy
through 120 days after the last dose of study therapy.
Exclusion Criteria:
1. History of partial or complete colon resection or colonic dissemination of tumor.
2. Active brain metastases or leptomeningeal disease. Subjects with asymptomatic
central nervous system (CNS) metastases which have been stable (defined as without
evidence of progression by magnetic resonance imaging (MRI) for at least 42 days
prior to enrolment (initiation of depletion phase) and any neurologic symptoms have
returned to baseline) following treatment with surgery or radiation therapy are
allowed.
3. Prior solid organ or hematologic transplant.
4. Prior treatment with PD1/ PDL-1 inhibitor in combination with an immune-modifying
microbiome agent.
5. History of treatment-related immune-mediated (or immune-related) adverse reactions
to immune-modulatory agents (including but not limited to anti-PD1/PD-L1 agents,
anti-CTLA4 monoclonal antibodies) that caused permanent discontinuation of the
agent, or that were grade 3 or 4 in severity. Subjects with grade 3-4
hypothyroidism, primary adrenal insufficiency or diabetes mellitus which are
asymptomatic following adequate supplementation, will be eligible.
6. Treatment with chemotherapy, immunotherapy, biologic therapy (except for denosumab
and bisphosphonates), or other investigational agents <21 days of enrolment
(initiation of depletion phase)
7. Palliative radiotherapy within 14 days or less from enrolment.
8. Comorbidity requiring corticosteroid therapy (>10mg prednisone/day or equivalent)
within 7 days of enrolment. Physiologic replacement doses are allowed if they are
≤10mg of prednisone/day or equivalent, as long as they are not being administered
for immunosuppressive intent. Inhaled, intranasal or topical steroids are permitted,
provided that they are not for treatment of an autoimmune disorder.
9. Significant cardiac disease; New York Heart Association classification for chronic
heart failure III-IV, symptomatic coronary artery disease, significant ventricular
arrhythmias, myocardial infarction within 6 months, unstable, poorly controlled
angina pectoris. 10. Active, known or suspected autoimmune disease that has required systemic treatment
within the past 2 years (i.e., with use of disease-modifying agents, corticosteroids
or immunosuppressive drugs), except for replacement therapy (e.g., thyroxine,
insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary
insufficiency, etc.).
Note: corticosteroids given within 24 hours of an imaging study for purposes of
pre-medication in subjects with hypersensitivity to radiologic contrast agents are
allowed. 11. Serious active infection requiring systemic therapy. 12. Subject has completed a course of antibiotics within the four weeks prior to
enrollment. 13. Subjects, who, in the opinion of the investigator, have predisposing risk factors
for recurrent infections requiring systemic antibiotic treatment (i.e., fistulae,
obstructing pulmonary mass, non-healing wound)
14. A known psychiatric or substance abuse disorder that would interfere with the
subject's ability to cooperate with the requirements of the trial. 15. Receipt of a live-virus vaccination within 28 days of enrolment. COVID-19 vaccine is
not mandatory. However, patients who have been vaccinated against COVID-19 prior to
study entry, should have completed the primary series of vaccination (initial two
doses of the vaccine) at least 3 days before enrolment.
16. Known HIV infection, or active infection with hepatitis B or C. 17. History of (non-infectious) pneumonitis that required steroids or has current active
pneumonitis. 18. Known additional malignancy either progressing or requiring active treatment (except
for non-melanoma skin cancer, in situ cervical cancer or prostate intraepithelial
neoplasia) within the last 2 years.
19. Female subjects who are breastfeeding. 20. Known intolerance or hypersensitivity to study drugs. 21. Known intolerance or hypersensitivity to oral vancomycin or neomycin. 22. History or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator. 23. Known inability to orally ingest capsules
