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

This clinical trial is evaluating a drug called BT5528 alone and in combination with
nivolumab in participants with advanced solid tumors historically known for expression of
EphA2. The main goals of this study are to:

- Find the recommended dose(s) of BT5528 that can be given safely to participants alone
and in combination with nivolumab

- Learn more about the side effects of BT5528

- Learn about how effective BT5528 is for the treatment of ovarian cancer,
urothelial/bladder cancer, lung cancer (NSCLC), triple-negative breast cancer, head and
neck cancer (HNSCC), and gastric/upper gastrointestinal cancer.

- Learn more about BT5528 therapy alone and in combination with nivolumab.

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

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

Exclusion criteria (all participants):

- 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)

- 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 or vitiligo

- History of interstitial lung disease