Lung Cancer Clinical Trials

• 1\. Male or female subject age ≥18 years at the time of informed consent. 2. Phase 1a and dose escalation part of Phase 1b: Subjects with histologically or cytologically diagnosed unresectable locally advanced/metastatic solid tumors, mainly but not limited to CRC, HCC, melanoma, NSCLC.

‣ Dose expansion part of Phase 1b:

• Cohort 1: Subjects with histologically or cytologically diagnosed unresectable locally advanced and/or metastatic CRC.

• Cohort 2: Subjects with histologically or cytologically diagnosed unresectable locally advanced and/or metastatic melanoma.

• Cohort 3: Subjects with histologically or cytologically diagnosed unresectable locally advanced and/or metastatic NSCLC.

• Cohort 4: Subjects with other histologically or cytologically diagnosed unresectable locally advanced/metastatic solid tumors.

• 3\. Subjects should have documented progression of disease despite all standard therapy or are intolerant of all standard therapy, or for whom no effective standard therapy exists. (Standard therapies are defined as treatments recommended by local guidelines, including but not limited to, chemotherapy, radiation, target therapies based on mutation status, immunotherapy, and surgery in general).

‣ Dose expansion part of Phase 1b:

• Cohort 1: Subjects with unresectable locally advanced and/or metastatic CRC o At least 2 prior standard chemotherapy/therapy regimens are required with documented progression or intolerability to the treatment.

‣ Standard chemotherapy regimens include all the following ones (if eligible and no contraindication): Fluoropyrimidine-containing regimen, and/or oxaliplatin-containing regimen, and/or irinotecan-containing regimen (treatment with a FOLFIRINOX regimen will count as 2 regimens).

⁃ With or without an anti-VEGF therapy (e.g., bevacizumab).

⁃ At least one of the anti-EGFR monoclonal antibodies (cetuximab or panitumumab) for KRAS wild-type subjects if clinically indicated.

⁃ For subjects with a known microsatellite instability high (MSI-H):

⁃ Prior treatment with an at least 2 doses of approved or investigational immune checkpoint inhibitor is required with documented progression or intolerability to the treatment.

• Demonstrated disease progression after immune checkpoint inhibitor treatment as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix 5). The initial evidence of disease progression is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.

• Progressive disease that has been documented within 12 weeks from the last dose of immune checkpoint inhibitor.

⁃ Note: a line of therapy is generally considered \>2 cycles of exposure to the same regimen followed by radiographically documented progression. Agents that are mechanistically similar (e.g., 5-fluorouracil and capecitabine) and are used interchangeably due to tolerability but not progression may be considered as components of the same regimen upon discussion with the medical monitor.

⁃ Subjects must have progressed while receiving or after of the last administration of their last line of standard therapy or be unable to tolerate any of these standard treatments.

⁃ Subjects who progressed on/within 3 months of adjuvant therapy with anti-PD-1 antibody will be allowed; subjects who received adjuvant chemotherapy and had recurrence/progression with development of unresectable or metastatic disease during or within 6 months of completion of the adjuvant chemotherapy can count this as a line of therapy.

• Cohort 2: Subjects with anti-PD-(L)1 antibody PD-1 relapsed/refractory melanoma

‣ PD-1 refractory disease as defined as progression on treatment with anti-PD-1 antibody administered either as monotherapy or in combination with other checkpoint inhibitors (anti-CTLA4 antibody or anti-LAG-3 antibody) or other therapies. Anti-PD-1 treatment progression is defined by meeting all of the following criteria:

‣ 1\) Has received at least 2 doses of an approved or investigational anti-PD-1 antibody with documented progression or intolerability to the treatment.

‣ 2\) Demonstrated disease progression after anti-PD-1 treatment as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 (Appendix 5). The initial evidence of disease progression is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.

‣ 3\) Progressive disease that has been documented within 12 weeks from the last dose of anti-PD-1 antibody.

⁃ Subjects who progressed on/within 3 months of adjuvant therapy with anti-PD-1 antibody will be allowed; an adjuvant therapy will count as 1 prior line of therapy if received within the prior 6 months.

⁃ For patients with BRAF V600 mutations, treatment with BRAF and MEK inhibitors prior to initiation on trial is required, unless patients are intolerant of BRAF targeted therapy.

⁃ Treatment must have been discontinued for disease progression or intolerance to therapy.

• Cohort 3: Subjects with anti-PD-(L)1 antibody relapsed/refractory NSCLC

• o Anti-PD-(L)1 antibody refractory disease as defined as progression on treatment with anti-PD-(L)1 inhibitor administered either as monotherapy or in combination with platinum-based chemotherapy or other therapies. Anti PD (L)1 treatment progression is defined by meeting all of the following criteria:

‣ Has received at least 2 doses of an approved or investigational anti-PD-(L)1 inhibitor with documented progression or intolerability to the treatment.

‣ Has demonstrated disease progression after anti-PD-(L)1 inhibitor as defined by RECIST v1.1 (Appendix 5). The initial evidence of disease progression is to be confirmed by a second assessment no less than 4 weeks from the date of the first documented disease progression, in the absence of rapid clinical progression. Once disease progression is confirmed, the initial date of disease progression documentation will be considered the date of disease progression.

‣ Progressive disease has been documented within 12 weeks from the last dose of anti-PD-(L)1 inhibitor.

∙ o Subjects who progressed on/within 3 months of adjuvant therapy with anti PD (L)1 inhibitor will be allowed; an adjuvant therapy will count as 1 prior line of therapy if received within the prior 6 months.

∙ o Documented disease progression during or after platinum-based chemotherapy alone or intolerability to the treatment for subjects with contraindications to anti PD (L)1 inhibitors.

• Patients with NSCLC with known oncogenic driver (including but not limited to EGFR, ALK, ROS, MET alterations) must have received and progressed past driver-specific therapy.

• Treatment must have been discontinued for disease progression or intolerance to therapy.

• Cohort 4: Subjects with other histologically or cytologically diagnosed unresectable locally advanced/metastatic solid tumors All subject in Phase 1b must meet PD-L1 expression ≥1%. 4. Subjects must have at least one evaluable lesion in Phase 1a or at least one measurable lesion in Phase 1b as defined by RECIST v1.1 (Appendix 5) which has not received radiotherapy (or progressive disease after radiotherapy).

• 5\. ECOG PS (Appendix 6) of 0\

⁃ 6. Life expectancy ≥3 months. 7. Subjects have sufficient baseline organ function and laboratory data meet the following criteria at enrollment:

• Hematological (without need for hematopoietic growth factor or transfusion support within 2 weeks prior to enrollment):

• 1\) ANC ≥1.5×109/L. 2) Hemoglobin (HGB) ≥90 g/L. 3) Platelet (PLT) ≥75×109/L.

• Hepatic:

• 1\) AST and ALT ≤2.5×ULN (≤5×ULN for subjects with liver metastases). 2) Total bilirubin (TBil) ≤1.5×ULN, or TBil ≤3.0×ULN for subjects with liver cancer or liver metastases. Subjects with Gilbert's syndrome may enroll if direct bilirubin ≤1.5×ULN.

• Renal:

• 1\) Creatinine apparent clearance (CL) \>50 mL/min according to modification Cockcroft-Gault equation (140-age \[year\])×body weight \[kg\]×1.23×(0.85 if female)/serum creatinine \[μmol/L\]).

• Coagulation:

• 1\) International normalized ratio (INR) ≤1.5. 2) Activated partial thromboplastin time (APTT) ≤1.5×ULN. 8. Woman of child-bearing potential must have a negative serum pregnancy test within 7 days prior to treatment. A female subject of nonchildbearing potential will have had at least 12 continuous months of natural (spontaneous) amenorrhea, follicle stimulating hormone level ≥40 mIU/mL at screening, and an appropriate clinical profile (e.g., age appropriate, history of vasomotor symptoms), or have had surgical bilateral oophorectomy, hysterectomy, or tubal ligation ≥6 weeks prior to screening.

• 9\. Female subjects of childbearing potential or male subjects with a partner of childbearing potential must agree to use effective contraception at the time of informed consent and continuing through the study until 6 months after the last dose of study treatment (Appendix 4).