Phase I/II Study of the Safety, Pharmacokinetics, and Preliminary Clinical Activity of BT5528 in Patients with Advanced Malignancies Associated with EphA2 Expression

General Inclusion:

• Written informed consent, according to local guidelines, signed and dated by the patient or by a legal guardian prior to the performance of any study-specific procedures, sampling or analyses
• At least 18 years-of-age at the time of signature of the informed consent form
• Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1
• Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1
• Acceptable renal, hepatic, hematologic and coagulation functions
• Negative pregnancy test for women of childbearing potential
• Male participants with female partners of childbearing potential and female participants of childbearing potential are required to follow highly effective contraception
• All patients must have tumor tissue (fresh or archived) available for analysis of EphA2 tumor expression and other biomarkers. In the absence of available tumor tissue, patients must be willing to undergo a biopsy to provide fresh tumor samples
• Life expectancy ≥12 weeks after the start of BT5528 treatment according to the Investigator's judgment.
• Must be willing and able to comply with the protocol and study procedures.

Additional inclusion criteria for Phase I (dose escalation phase, with BT5528 alone or in combination with nivolumab):

• Metastatic recurrent histologically confirmed malignant solid tumors historically known for high EphA2 tumor expression. Confirmation of EphA2 expression prior to enrollment is not required for participants with ovarian cancer and specific other individual tumor types.
• Exhausted all appropriate treatment options per local guidelines
• Participants with urothelial cancer who have at least 1 (but no more than 3) prior lines of systemic therapy.

Additional inclusion criteria for Phase II (dose expansion phase, with BT5528 alone):

• Participants with metastatic recurrent disease histologically confirmed to be non-small cell lung cancer, ovarian cancer, triple-negative breast cancer (TNBC), gastric/upper gastrointestinal (GI) cancer, head and neck (H&N) cancer, urothelial cancer are eligible and must have failed or are ineligible for all appropriate treatment options per local guidelines and must have evidence of radiographic progression on the most recent line of therapy
• Patients with urothelial cancer who have previously received treatment with enfortumab vedotin (EV) are eligible to the study. Patients who received EV and showed disease progression within 6 months of treatment start are planned for less than 50% of total patients enrolled in the cohort

• Chemotherapy treatments within 14 days prior to first dose of study treatment, other anticancer treatments, treatment within 28 days or 5 half-lives, whichever is the shorter
• Experimental treatments within 4 weeks of first dose of BT5528
• Prior toxicities must have resolved to Grade 1 per Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 (except alopecia which can be Grade 2), or well-controlled Grade 2 hypothyroidism or Grade 2 adrenal insufficiency on appropriate therapy
• Current treatment with strong inhibitors or inducers of CYP3A4 or strong inhibitors of P-gp
• Known sensitivity to any of the ingredients of the investigational product or monomethyl auristatin E (MMAE)
• Any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient's participation, or is not in the best interest of the patient to participate in the opinion of the investigator including but not limited to specific cardiovascular criteria
• Major surgery (excluding placement of vascular access) within 4 weeks of first dose of BT5528 study treatment and must have recovered adequately prior to starting study therapy
• Receipt of live vaccine within 30 days of study treatment
• Untreated CNS metastases or leptomeningeal disease
• Uncontrolled hypertension (systolic BP ≥160 mmHg or diastolic BP ≥100 mmHg that is not responsive to intervention) at screening or prior to initiation of study drug.
• History or current evidence of any condition, therapy or laboratory abnormality that might confound the results of the study, interfere with the patient's participation, or is not in the best interest of the patient to participate in the opinion of the Investigator including but not limited to:

(a) Patients with history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, congestive heart failure or symptoms of New York Heart Association Class III-IV documented within 6 months prior to first dose of BT5528 or: (i) Mean resting corrected QT interval (QTcF) >470 msec (ii) Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years-of-age, or any concomitant medication known to prolong the QT interval (iii) Any clinically important abnormalities (as assessed by the Investigator) in rhythm, conduction, or morphology of resting electrocardiograms (ECGs), e.g., complete left bundle branch block, third degree heart block

• Known human immunodeficiency virus (HIV) or acquired immune deficiency syndrome (AIDS). Note: Well controlled HIV will be allowed if the patient meets all the following criteria at inclusion:
1. CD4+ T-cell (CD4+) counts ≥350 cells/uL;
2. HIV viral load <400 copies/mL
3. Without a history of opportunistic infection within the last 12 months.
4. On established antiretroviral therapy (ART) for at least 4 weeks. Use of anti-retroviral therapy is permitted, but should be discussed with the Medical Monitor on a case-by-case basis.
• Patients with a positive hepatitis B surface antigen and/or anti-hepatitis B core antibody. Patients with a negative polymerase chain reaction (PCR) assay are permitted with appropriate antiviral therapy
• Active hepatitis C infection with positive viral load if hepatitis C virus (HCV) antibody positive (if antibody is negative then viral load not applicable). Patients who have been treated for hepatitis C infection can be included if they have documented sustained virologic response of ≥12 weeks.
• Thromboembolic events and/or bleeding disorders 3 months (e.g., deep vein thrombosis [DVT] or pulmonary embolism [PE]) prior to first dose
• Prior history of pneumonitis with presence of residual symptoms
• History of another malignancy within 3 years before the first dose of BT5528, or any evidence of residual disease from a previously diagnosed malignancy (excluding adequately treated with curative intent basal cell carcinoma, squamous cell of the skin, cervical intraepithelial neoplasia/cervical carcinoma in situ or melanoma in situ or ductal carcinoma in situ of the breast).
• Systemic anti-infective treatment or fever within the last 14 days prior to first dose of BT5528 study treatment
• Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol and/or follow-up procedures outlined in the protocol.

Additional Exclusion Criteria (BT5528 in combination with nivolumab):

• Prior intolerance to immune checkpoint inhibitor
• Known hypersensitivity to checkpoint inhibitor therapy
• Prior organ transplant (including allogeneic)
• Diagnosis of clinically relevant immunodeficiency
• Active systemic infection requiring therapy
• More than 10 mg daily prednisone equivalent or other strong immunosuppressant
• History of autoimmune disease except alopecia, vitiligo, hypothyroidism, or adrenal insufficiency