Safety, PK, and Preliminary Efficacy of MBRC-101 in Advanced Refractory Solid Tumors

Inclusion Criteria:

1. Provide written consent on an Informed Consent Form (ICF), approved by anInstitutional Review Board (IRB)/Independent Ethics Committee (IEC), prior to anystudy-specific evaluation. Patients should have the ability to read and understandthe ICF, ask for any clarifications from the study staff, and be able to comply withall planned study procedures.

2. 18 years of age or older at the time of informed consent.

3. Female patients must be at least 2 years postmenopausal (defined as 2 years withoutmenses), surgically sterile (at least 6 months prior to dosing; must be documented)or practicing effective contraception (must agree to use 2 forms of contraception, 1of which must be a barrier method) and willing to continue to use effectivecontraception for the duration of study participation and for 6 months after thefinal dose of study drug. Female patients must be nonlactating and have a negativeserum pregnancy test result at screening and baseline.

4. Male patients must agree to use effective contraception (must agree to use 2 formsof contraception, 1 of which must be a barrier method) for the duration of studyparticipation and for 6 months after the final dose of study drug.

5. Have a histologic or cytologic diagnosis of malignant solid tumor for which thereare no standard of care treatment options known to confer a clinical benefit or forwhich the patient is ineligible or declines. A. For Phase 1 dose escalation: histologic or cytologic diagnosis of malignant solidtumor of any type. The Sponsor may remove specific tumor indications based onemerging, real-time study data. B. For Phase 1b dose expansion: i. Cohort A: Histologic or cytologic diagnosis of NSLC (adenocarcinoma and SCC). ii. Cohort B: Histologic or cytologic diagnosis of TNBC or HR positive, HER2negative breast cancer. iii. Cohort C: Histologic or cytologic diagnosis of the following advancedmetastatic solid tumors refractory to standard treatment: pancreatic adenocarcinoma,gastric adenocarcinoma, hepatocellular carcinoma, ovarian adenocarcinoma, andsquamous cell carcinoma including, but not limited to, primary malignancies of thehead and neck, esophagus, cervix, and skin. The Sponsor may add or remove specifictumor indications based on emerging, real-time study results.

6. Availability of a tumor tissue sample (formalin-fixed paraffin embedded [FFPE]) mustbe confirmed for analysis of EphA5 expression based on IHC. Tumor biopsies are notrequired and should not be performed to assess eligibility. A. For Dose Escalation (Phase 1) and Dose Expansion (Phase 1b), tumor EphA5expression will not be required for enrollment.

7. For Dose Escalation (Phase 1), patients may have evaluable disease or measurabledisease according to RECIST v1.1). For Dose Expansion (Phase 1b) and Phase 2,patients must have measurable disease according to RECIST v1.1.

8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2.

9. Life expectancy ≥ 3 months as assessed by the investigator.

10. Hematologic function, as follows (no red blood cell [RBC] or platelet transfusionsare allowed within 14 days of the first dose of MBRC-101): A. Absolute neutrophil count (ANC) ≥ 1.0 × 109/L B. Platelet count ≥ 100 × 109/L C.Hemoglobin ≥ 9 g/dL

11. Estimated glomerular filtration rate (eGFR) ≥ 30 mL/min by the CKD-EPI or similarequation or as measured by 24-hour urine collection.

12. Total bilirubin ≤ 1.5 × upper limit normal (ULN).

13. AST ≤ 3.0 × ULN.

14. ALT ≤ 3.0 × ULN.

15. International normalised ratio (INR) < 1.5 (or ≤ 3.0 if on therapeuticanticoagulation).

16. Treatment with other agents for cancer, if received, must have been discontinued ≥ 2weeks prior to first dose of study drug.

Prior ADC therapy is allowed. Prior agents conjugated to MMAE are allowed for Phase 1 but not for Phase 1b or Phase 2. These exclusionary agents include brentuximab vedotin, polatuzumab vedotin, enfortumab vedotin, disitamab vedotin, tisotumab vedotin, and any MMAE-conjugated agents approved subsequent to the publication of this Protocol.

Exclusion Criteria:

1. Preexisting sensory neuropathy Grade ≥ 2.

2. Preexisting motor neuropathy Grade ≥ 2.

3. Uncontrolled central nervous system metastases.

4. Use of any investigational drug within 14 days prior to the first dose of studydrug.

5. Any anticancer therapy within 14 days prior to the first dose of study drug,including: small molecules, immunotherapy, chemotherapy, monoclonal antibodytherapy, radiotherapy, or any other agents to treat cancer (anti-hormonal therapygiven for advanced prostate cancer or as adjuvant therapy for early stage, hormonereceptor (HR) positive breast cancer is not considered cancer therapy for thepurpose of this Protocol).

6. Strong CYP3A or inducers within 14 days prior to the first dose of study drug.

8. Thromboembolic events and/or bleeding disorders 14 days (e.g., venousthromboembolism [VTE] or pulmonary embolism [or PE]) prior to the first dose ofstudy drug.

9. Documented history of a cerebral vascular event (stroke or transient ischemicattack), unstable angina, myocardial infarction, or cardiac symptoms (includingcongestive heart failure) consistent with New York Heart Association Class 3-4within 6 months prior to the first dose of MBRC-101.

10. A baseline QT (time from the beginning of the Q wave to the end of the T wave)interval as corrected by Fridericia's formula (QTcF) > 470 msec.

11. Human immunodeficiency virus (HIV) infection with 1 or more of the following: A.Acquired immunodeficiency syndrome (AIDs)-defining opportunistic infection within 6months of the start of screening; B. A change in antiretroviral therapy within 3months of the start of screening and viral load > 500 copies/mL; C. Receivingantiretroviral therapy that may interfere with study drug; D. CD4 count < 350 atscreening. 11. Active or symptomatic viral hepatitis. Patients who have beenproperly treated for hepatitis C infection can be included if they do not haveactive hepatitis C.

12. Known sensitivity to any of the ingredients of the investigational product MBRC-101.

13. Major surgery within 28 days prior to first dose of study drug. 14. History ofanother malignancy within 3 years before the first dose of study drug, or anyevidence of residual disease from a previously diagnosed malignancy. Allowedexceptions are patients with: A. Non-melanoma skin cancer considered completelycured; B. Localized prostate cancer treated with curative intent with no evidence ofprogression; C. Low-risk or very low-risk (per standard clinical guidelines)localized prostate cancer under active surveillance without immediate intent totreat; D. Malignancy that is otherwise considered cured with minimal risk ofrecurrence.

14. Currently receiving systemic antimicrobial treatment for active infection (bacterial, viral, or fungal) at the time of first dose of MBRC-101. Routineantimicrobial prophylaxis is permitted.

15. Condition or situation which, in the investigator's opinion, may put the patient atsignificant risk, may confound the study results, or may interfere significantlywith patient's participation in the study.

16. Any medical, psychiatric, addictive, or other kind of disorder which compromises theability of the patient to give written informed consent and/or to comply withprocedures.

17. Active ocular surface disease at baseline or any components of the ophthalmologichistory which, in the investigator's opinion, may place the patient at significantrisk.