Safety and Efficacy of RX-af01 Combined With PD-1 Antibody

Inclusion Criteria:

• Advanced (not amenable to curative surgery or radiation therapy) or metastatic (American Joint Committee on Cancer [AJCC] stage IV) solid tumors, including melanoma,nasopharyngeal squamous carcinoma, esophageal squamous cell carcinoma, gastricadenocarcinoma, renal cell carcinoma, et al.
• Fail to or could not tolerate standard treatment.
• Receive at least 2 cycles of PD-1/PD-L1/CTLA4 inhibitors and the response is completeresponse (CR) or partial response (PR) or stable disease (SD).
• Measurable disease as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
• Recovery to baseline or =< grade 1 CTCAE v5 from toxicities related to any priortreatments unless adverse events (AE[s]) are clinically nonsignificant and/or stableon supportive therapy
• ECOG performance status score: 0-1
• Males and females, ages >= 18
• Absolute neutrophil count (ANC) >= 1500/uL without granulocyte colony-stimulatingfactor support (within 14 days before first dose of study treatment)
• Platelets >= 90,000/uL without transfusion (within 14 days before first dose of studytreatment)
• Hemoglobin >= 8 g/dL (>= 80 g/L) (within 14 days before first dose of study treatment)
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkalinephosphatase (ALP) =< 3 x upper limit of normal (ULN). ALP =< 5 x ULN with documentedbone metastases (within 14 days before first dose of study treatment) Total bilirubin =< 1.5 x ULN (for subjects with Gilbert's disease =< 3 x ULN) (within 14 days beforefirst dose of study treatment)
• Serum albumin >= 3.0 g/dl (within 14 days before first dose of study treatment)
• Prothrombin time (PT)/international normalized ratio (INR) or partial thromboplastintime (PTT) test < 1.3 x the laboratory ULN (within 14 days before first dose of studytreatment)
• Serum creatinine =< 1.5 x ULN or calculated creatinine clearance >= 40mL/min (>= 0.675mL/sec) using the Cockcroft-Gault equation (within 14 days before first dose of studytreatment)
• Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-hour (h)urine protein =< 1 g (within 14 days before first dose of study treatment)
• Capable of understanding and complying with the protocol requirements and must havesigned the informed consent document
• Sexually active fertile subjects and their partners must agree to use medicallyaccepted methods of contraception (e.g., barrier methods, including male condom,female condom, or diaphragm with spermicidal gel) during the course of the study andfor 4 months after the last dose of treatment, 5 months after the last dose of PD-1inhibitor for women with childbearing potential, and 7 months after the last dose ofPD-1 inhibitor for men
• Female subjects of childbearing potential must not be pregnant at screening. Femalesubjects are considered to be of childbearing potential unless one of the followingcriteria is met: documented permanent sterilization (hysterectomy, bilateralsalpingectomy, or bilateral oophorectomy) or documented postmenopausal status (definedas 12 months of amenorrhea in a woman > 45 years-of-age in the absence of otherbiological or physiological causes. In addition, females < 55 years-of-age must have aserum follicle stimulating [FSH] level > 40 mIU/mL to confirm menopause).

Exclusion Criteria:

• Current use, or intent to use, probiotics, yogurt, or bacterial fortified foods duringthe period of treatment
• Active interstitial lung disease (ILD)/pneumonitis or history of ILD/pneumonitisrequiring treatment with systemic steroids. History of idiopathic pulmonary fibrosis,organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest CT scan.
• Known medical condition (e.g., a condition associated with diarrhea or acutediverticulitis) that, in the investigator's opinion, would increase the riskassociated with study participation or study drug administration or interfere with theinterpretation of safety results
• Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment
• Radiation therapy for bone metastasis within 2 weeks or any other radiation therapywithin 4 weeks before first dose of study treatment. Systemic treatment withradionuclides within 6 weeks before first dose of study treatment. Subjects withclinically relevant ongoing complications from prior radiation therapy are noteligible
• Known brain metastases or cranial epidural disease unless adequately treated withradiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeksprior to first dose of study treatment after radiotherapy or at least 4 weeks prior tofirst dose of study treatment after major surgery (e.g., removal or biopsy of brainmetastasis). Subjects must have complete wound healing from major surgery or minorsurgery before first dose of study treatment. Eligible subjects must be neurologicallyasymptomatic and without corticosteroid treatment at the time of first dose of studytreatment
• Administration of a live, attenuated vaccine within 30 days before first dose of studytreatment
• The subject has uncontrolled, significant intercurrent or recent illness including,but not limited to, the following conditions:

1. Cardiovascular disorders: Congestive heart failure New York Heart Association class 3 or 4, unstable anginapectoris, serious cardiac arrhythmias Uncontrolled hypertension defined assustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolicdespite optimal antihypertensive treatment Stroke (including transient ischemicattack [TIA]), myocardial infarction (MI), or other ischemic event, orthromboembolic event (e.g., deep venous thrombosis, pulmonary embolism) within 6months before first dose of study treatment.
2. Subjects with a diagnosis of incidental, subsegmental pulmonary embolism (PE) ordeep vein thrombosis (DVT) within 6 months are allowed if stable, asymptomatic,and treated with a stable dose of permitted anticoagulation for at least 1 weekbefore first dose of study treatment.
3. Gastrointestinal (GI) disorders including those associated with a high risk ofperforation or fistula formation: The subject has evidence of tumor invading the GI tract, active peptic ulcer disease,inflammatory bowel disease (e.g., Crohn's disease), diverticulitis, cholecystitis,symptomatic cholangitis or appendicitis, acute pancreatitis, acute obstruction of thepancreatic duct or common bile duct, or gastric outlet obstruction. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6months before first dose of study treatment. Note: Complete healing of an intra-abdominalabscess must be confirmed before first dose of study treatment Clinically significanthematuria, hematemesis, or hemoptysis of > 0.5 teaspoon (2.5 ml) of red blood, or otherhistory of significant bleeding (e.g., pulmonary hemorrhage) within 12 weeks before firstdose of study treatment

• Other clinically significant disorders that would preclude safe study participation: Any active, known, or suspected autoimmune disease will be excluded, with the followingexceptions: Type 1 diabetes mellitus; hypothyroidism only requiring hormone replacement;skin disorders (e.g., vitiligo, psoriasis, or alopecia) not requiring systemic treatment;conditions not expected to recur in the absence of an external trigger.
• Any condition requiring systemic treatment with either corticosteroids (> 10 mg dailyprednisone equivalent) or other immunosuppressive medications within 14 days beforefirst dose of study treatment. Note: Inhaled, intranasal, intra-articular, or topicalsteroids are permitted. Adrenal replacement steroid doses > 10 mg daily prednisoneequivalent are permitted. Transient short-term use of systemic corticosteroids forallergic conditions (e.g., contrast allergy) is also allowed.
• Active infection requiring systemic treatment. Acute or chronic hepatitis B or Cinfection (with the DNA copy number >1000 copies/ml), known human immunodeficiencyvirus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness, or knownpositive test for tuberculosis infection where there is clinical or radiographicevidence of active mycobacterial infection.
• Serious non-healing wound/ulcer/bone fracture.
• Malabsorption syndrome.
• Uncompensated/symptomatic hypothyroidism.
• Moderate to severe hepatic impairment (Child-Pugh B or C).
• Requirement for hemodialysis or peritoneal dialysis.
• History of solid organ or allogenic stem cell transplant.
• Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal, or biopsy of brainmetastasis) within 2 weeks before first dose of study treatment. Minor surgerieswithin 10 days before first dose of study treatment. Subjects must have complete woundhealing from major surgery or minor surgery before first dose of study treatment.Subjects with clinically relevant ongoing complications from prior surgery are noteligible.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms perelectrocardiogram (ECG) within 14 days before first dose of study treatment.Furthermore, subjects with a history of additional risk factors for torsades depointes (e.g., long QT syndrome) are also excluded.
• Pregnant or lactating females
• Inability to swallow tablets or unwillingness or inability to receive IVadministration
• Previously identified allergy or hypersensitivity to components of the study treatmentformulations or history of severe infusion-related reactions to monoclonal antibodies.
• Any other active malignancy at time of first dose of study treatment or diagnosis ofanother malignancy within 5 years prior to first dose of study treatment that requiresactive treatment, except for locally curable cancers that have been apparently cured,such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinomain situ of the prostate, cervix, or breast.