BC3195 in Combination With Pembrolizumab in Participants With Locally Advanced or Metastatic Solid Tumors

A Phase 1/2, Open-Label, Dose Escalation and Expansion Study to Evaluate the Safety, Tolerability, Pharmacokinetics (PK), and Preliminary Efficacy of BC3195 in Combination With Pembrolizumab in Participants With Locally Advanced or Metastatic Solid Tumors

This is a Phase 1/2, open-label, dose escalation and expansion study to assess the safety, pharmacokinetics, and preliminary efficacy of BC3195 in combination with pembrolizumab in participants with locally advanced or metastatic solid tumors.

This is a Phase 1/2, open-label, dose escalation and expansion study to assess the safety, pharmacokinetics, and preliminary efficacy of BC3195 in combination with pembrolizumab in participants with locally advanced or metastatic solid tumors. This study consists of two parts: A dose escalation part (Part 1) and a dose expansion part (Part 2). Each part will include a screening period, a treatment period, and follow-up period.

Inclusion Criteria:

1. Provide written informed consent.

2. Aged at least 18 years at the time of ICF signature.

3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 within 7 days prior to the first dose of study treatment.

4. Life expectancy of ≥ 3 months based on the Investigator's assessment.

5. Participants in Dose escalation part must meet the following criteria: Histologically or cytologically confirmed advanced/metastatic solid tumor by pathology report and have received, or been intolerant to, all treatment known to confer clinical benefit, including but not limited to: NSCLC, BC, HNSCC, ESCC, EMC, UC, CRC, OC, and prostate cancer. The sponsor or designee must approve eligibility for malignancies other than those specifically mentioned above.

6. Participants in Dose expansion part must meet one of the following criteria:

   1. For NSCLC (cohort 1):

      Participants have pathologically documented Stage IIIB, IIIC, or Stage IV NSCLC without actionable genomic alterations (AGA) based on the American Joint Committee on Cancer, Eighth Edition (Participants must have documented negative test results for EGFR and ALK genomic alterations and have no known genomic alterations in ROS1, NTRK, BRAF, MET exon 14 skipping, or RET) and meet one of the following criteria:

      1. Locally advanced or metastatic NSCLC participants relapsed or refractory to at least 1 prior line of therapy including platinum-based chemotherapy in combination with or without anti-PD(L)1 antibody; OR
      2. Locally advanced or metastatic NSCLC participants relapsed or refractory to at least 2 prior lines of therapy including anti-PD(L)1 antibody and platinum-based chemotherapy sequentially.

   2. For TNBC (cohort 2):

      Participants have histologically or cytologically confirmed TNBC per ASCO/CAP criteria based on the most recent analyzed biopsy or other pathology specimen and meets the following criteria: Relapsed or refractory to 2 or more prior systemic regimens for unresectable, locally advanced or metastatic disease (-For prior therapy, 1 could be in the (neo)adjuvant setting, provided progression occurred during treatment or within 12 months after treatment discontinuation;-Received taxane(s) in any setting).

   3. For HNSCC (cohort 3):

      Participants have histologically or cytologically confirmed locally advanced or metastatic HNSCC and meet one of the following criteria:

      1. Relapsed or refractory to at least 1 prior line of therapy including platinum-based chemotherapy with cetuximab, or platinum-based chemotherapy with or without anti-PD(L)1 antibody. OR
      2. Disease progression while on or after at least 2 prior lines of therapy including anti-PD(L)1 antibody and platinum-based chemotherapy sequentially.

   4. For Other solid tumors (cohort 4):

      Participants with other solid tumors and meets the following criteria:

      1. Histologically or cytologically confirmed locally advanced or metastatic solid tumors (e.g., ESCC, EMC, UC, CRC, OC, prostate cancer or tumors with observed efficacy signal during the dose escalation part).
      2. Participants refractory to, or intolerant of existing therapy(ies) known to provide clinical benefit for their condition.

7. Participants with at least one measurable lesion according to RECIST v1.1 as assessed by the local site investigator/radiology.

8. Participants with adequate organ function.

9. Agree to provide previously archived tumor tissue samples, or newly obtained biopsy of a previously unirradiated tumor lesion (optional for dose escalation part). Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. Details pertaining to tumor tissue collection can be found in the Laboratory Manual.

10. Males and females of child-bearing potential must agree to use effective contraception (e.g., oral contraceptives, intrauterine devices, abstinence, or barrier contraceptives combined with spermicides) from the time ICF signature until 6 months after the last dose. Females of childbearing potential include those who are premenopausal and those who are 2 years postmenopausal.

Exclusion Criteria:

1. Has received prior systemic anticancer treatment, including investigational agents, within 5 half-lives or 4 weeks prior to the first dose of study treatment (whichever is shorter). Has received Traditional Chinese Medication within 7 days prior to study treatment.

2. Participants who have received major surgery (defined as requiring general anesthesia and >24-hour inparticipant hospitalization) within 4 weeks prior to the first dose of study treatment. Participant must have recovered adequately from complications from the intervention prior to starting study treatment.

3. Has received prior radiotherapy within 2 weeks of start of study treatment or have had a history of radiation pneumonitis.

   Note: Participants must have recovered from all radiation-related toxicities and not require corticosteroids. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.

4. Has had an allogeneic tissue/solid organ transplant.

5. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.

6. Has known active CNS metastases and/or carcinomatous meningitis. Participants with previously treated brain metastases may participate provided they are radiologically stable (ie, without evidence of progression) for at least 4 weeks as confirmed by repeat imaging performed during the study screening, are clinically stable and have not required steroid treatment for at least 14 days before the first dose of study treatment.

7. Has clinically uncontrolled pericardial effusion, pleural effusion, or ascites at screening.

8. Has a history of (non-infectious) pneumonitis / interstitial lung disease that required steroids or has current pneumonitis / interstitial lung disease.

9. Active viral infection requiring systemic therapy during the screening period.

10. Hypertension that cannot be well-controlled with medical treatment. Not well-controlled is defined as systolic blood pressure >150 mmHg or diastolic blood pressure >95 mmHg (adjustment of hypertensive medication prior to study initiation is permitted, but the mean of the most recent three consecutive blood pressure records prior to study entry must be ≤150/95 mmHg [with at least 2- minute interval between each measurement]).

11. Cardiovascular disease of clinical significance: Including New York Heart Association [NYHA] Class II-IV, congestive heart failure, second-degree or higher heart block, myocardial infarction within the past 3 months, unstable arrhythmia or unstable angina, marked QT interval prolongation (12-lead ECG showing baseline-corrected QTc interval >480 ms), cerebral infarction within 3 months, or having received PTCA or CABG within 6 months.

12. Participants with active or chronic corneal disorders, with other active ocular conditions requiring ongoing therapy or with any clinically significant corneal disease that prevents adequate monitoring of drug-induced keratopathy.

13. Participants with any active infection that requires systemic anti-infective therapy judged by the investigators.

14. Has a known additional malignancy that is progressing or has required active treatment within the past 3 years.

    Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or carcinoma in situ, excluding carcinoma in situ of the bladder, that have undergone potentially curative therapy are not excluded. Participants with low-risk early-stage prostate cancer (T1-T2a, Gleason score ≤6, and PSA <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease are not excluded.

15. Grade 2 or higher peripheral neuropathy. Other toxicities caused by prior anti-tumor therapy has not recovered to ≤ grade 1 (per CTCAE 5.0) (except for alopecia, pigmentation, and other events judged by the Investigator to be tolerable) or the level specified by the inclusion/exclusion criteria in this study.

    Note: Participants with endocrine-related AEs Grade ≤2 requiring treatment or hormone replacement may be eligible.

16. Received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher irAE (except endocrine disorders that can be treated with replacement therapy) or was discontinued from that treatment due to Grade 2 myocarditis or recurrent Grade 2 pneumonitis.

17. Known severe hypersensitivity or delayed hypersensitivity (≥Grade 3) reactions to the same class and/or any components of BC3195 or pembrolizumab.

18. Participants who received strong CYP3A4 inhibitors or strong CYP3A4 inducers within 14 days, before the first dose of the study treatment (refer to Appendix 7 for a list of strong CYP3A4 inhibitors and inducers).

19. Has received a live or live-attenuated vaccine within 30 days prior to the first dose of study intervention, or planned to receive live or live-attenuated vaccine during the screening. Administration of killed vaccines are allowed.

20. Has a history or current evidence of any condition, therapy, or laboratory abnormality, or other circumstance that might confound the results of the study or interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator.

21. Pregnant or breastfeeding or planning to become pregnant; a positive blood pregnancy test within 7 days prior to the first dose of study treatment.

22. Participants with poor compliance, who are unwilling to or unable to follow study procedures.

23. Has received radiation therapy to the lung that is >30 Gy within 6 months of the first dose of study treatment for participants with NSCLC.