177Lu-BetaBart in Patients With Relapsed/Refractory, Locally Advanced Inoperable, or Metastatic Solid Tumors

Inclusion Criteria:

1. Willing and able to provide informed consent prior to start of any study proceduresand assessments and must be willing to comply with all study procedures.

2. Participants ≥ 18 years of age.

3. Participants with a documented history of histopathologically confirmed CRPC*, CRC,NSCLC, SCLC, HNSCC, ovarian cancer, cervical cancer, endometrial cancer, TNBC, orESCC. (Note: inclusion or exclusion criteria below marked with * refer to CRPC only,criteria without * refer to all tumor indications including CRPC) a. *Progressive CRPC defined as castrate levels of testosterone and progressing byat least one of the following criteria: i. Serum PSA progression consisting of twoconsecutive increases in PSA measured at least 1 week apart. The minimal baselinevalue is 2.0 ng/mL. ii. Soft tissue progression defined as a ≥20% increase in the sum of the diameter (short axis for nodal lesions and long axis for non-nodal lesions) of all targetlesions based on the smallest sum of the diameter since the previous treatment wasstarted or the appearance of one or more new lesions by computed tomography (CT)/magnetic resonance imaging (MRI). iii. Progression of bone disease defined by Prostate Cancer Working Group 3 (PCWG3)as evaluable disease or new bone lesions by bone scan. iv. Identification of new soft tissue or bone lesions on prostate-specific membraneantigen (PSMA) positron emission tomography (PET) imaging. b. *Metastatic disease defined as either or both of the following: i. Documented M1disease on conventional imaging (CT/MRI of the chest/abdomen/pelvis and/orTechnetium 99m [99mTc] whole-body bone scan) ii. Identification of bone lesion(s),extra-pelvic soft tissue lesion(s), or visceral metastases on PSMA PET imaging withan FDA-approved imaging agent (e.g., 68Ga-PSMA-11, 18F-DCFPyL, or 18F-rhPSMA-7.3) c. *Progression following treatment with ADT and at least one ARSI (e.g., enzalutamide,apalutamide, darolutamide, and/or abiraterone acetate). If a participant iscurrently on ADT, they should continue ADT for the duration of their participationin the study but will not be permitted to start a new therapy or ADT regimen. If aparticipant has progressed on an ARSI, they will have the option to remain on thesame ARSI or discontinue therapy. If they discontinue the ARSI, a 28-day washoutperiod will be required prior to initiating study intervention. d. Prior definitive and palliative external beam radiation therapy and stereotacticbody radiation therapy is allowed. Note: Participants with extended external beam radiation therapy to the axialskeleton, which in the opinion of the Investigator may pose a risk for increasedmyelotoxicity, will be discussed with the Sponsor to determine eligibility. e. Participants with liver metastases are eligible if they meet the followingcriteria: i. ≤3 lesions i. All lesions must be ≤2 cm in the short axis ii. SUVmean ≥2 x that of liver parenchyma f. *Prior treatment with one taxane-based chemotherapyis allowed but not required. A taxane-based chemotherapy is defined as a minimumexposure of two cycles of a taxane chemotherapy.

4. Participants must have documented disease progression during or after their mostrecent line of anticancer therapy. Participants must be refractory to or intolerantof standard of care therapy or have no standard of care therapy available that islikely to provide clinical benefit. Any number of prior treatment lines are allowed.

5. Must have at least 1 measurable target lesion according to RECIST v1.1. (Note: thisdoes not apply for CRPC)

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

7. Participants must have a life expectancy of ≥ 4 months in the opinion of theInvestigator.

8. Participants of child-bearing potential (CBP) must have a negative β-hCG test andmust not be breastfeeding. Participants of CBP are defined as those who are notsurgically sterile or post-menopausal. Participants will be consideredpost-menopausal if they have been amenorrheic for 12 months without an alternativemedical cause. Participants < 50 years of age who meet the criteria forpost-menopausal status without previous surgical sterilization should be consideredfor further investigation with luteinizing hormone (LH) and follicle stimulatinghormone (FSH) levels to confirm serological post-menopausal status.

9. Participants of CBP must agree to use a highly effective method of contraceptionduring the study and for 6 months after the last dose of 177Lu-BetaBart, asdescribed in Appendix 4.

10. Male participants who are able to father a child must agree to avoid impregnating apartner and to adhere to a highly effective method of contraception during the studyand for 6 months after the last dose of 177Lu-BetaBart, as described in Appendix 4.All male participants must agree to not donate sperm during the study and for 6months after the last dose of 177Lu-BetaBart.

11. Participants who have received prior radiation therapy >28 days before the firstdose of 177Lu-BetaBart are permitted. Documentation of the dates the radiotherapywas received, the cumulative dose, and the absorbed dose to critical organs, ifavailable, should be provided.

12. Participants with previously treated brain metastases are eligible to participateif:

• they are neurologically and radiologically stable (no evidence of progressionby imaging; same imaging modality [MRI or CT scan] must be used for eachassessment) for at least 28 days prior to the first dose of 177Lu-BetaBart; and

• do not require corticosteroids to treat associated neurological symptoms or ifrequired, are on a stable dose of corticosteroids not exceeding 10 mg/day ofprednisone (or equivalent), and

• have no history of leptomeningeal disease or spinal cord compression.

Exclusion Criteria:

1. History of prior organ transplant.

2. Any other known, active malignancy, except for treated cervical intraepithelialneoplasia, or non-melanoma skin cancer. Participants with a history of malignanciesof low recurrence potential who have received curative-intent therapy may beapproved on a case-by-case basis in discussion with the Sponsor, if it is determinednot to put the participant at an increased risk of adverse drug effects and/orinterfere with the integrity of the study outcome.

3. Have any medical condition that would, in the Investigator's judgment, prevent theparticipant's full participation in the clinical study due to safety concerns orcompliance with clinical study procedures such as participants with severeclaustrophobia who are unresponsive to oral anxiolytics, participants with low backpain who cannot lie comfortably on an imaging table, participants who arehyperactive or hyperkinetic such that they cannot tolerate lying still for multipletime point imaging procedures, etc.

4. Residual toxicity ≥ Grade 2 from prior anti-cancer therapy (except alopecia andperipheral sensory neuropathy).

5. History of uncontrolled allergic reactions and/or known or expected hypersensitivityto protein therapeutics, 177Lu-BetaBart, or any of its excipients.

6. Inadequate organ functions as reflected in laboratory parameters:

• Estimated glomerular filtration rate (eGFR) < 50 mL/min adjusted forparticipant's body surface area using the Chronic Kidney Disease EpidemiologyCollaboration (CKD-EPI 2021) formula

• Platelet count of < 100 x 109/L

• Absolute neutrophil count (ANC) < 1.5 x 109/L

• Hemoglobin < 9 g/dL

• Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x upperlimit of normal (ULN), or > 5 x ULN for participants with known livermetastases

• Total bilirubin > 1.5 x ULN, except for participants with documented Gilbert'ssyndrome who are eligible if total bilirubin ≤ 3 x ULN

• For participants not taking warfarin or other anticoagulants: INR ≤1.5 or PT ≤1.5 x ULN; and either PTT or aPTT ≤1.5 x ULN. Participants taking warfarinmust be on a stable dose that results in a stable INR <3.5. Among participantsreceiving other anticoagulant therapy, PT or aPTT must be within the intendedtherapeutic range of the anticoagulant.

7. Participants requiring blood product transfusion within 2 weeks of first dose of 177Lu-BetaBart are not eligible to participate.

8. *Participants with CRPC who have received prior Lu-177-PSMA radioligand therapy.

9. Clinically significant cardiovascular disease including but not limited to:

• Unstable angina

• Acute myocardial infarction within 6 months prior to screening

• New York Heart Association (NYHA) Class II or greater congestive heart failure

• Clinically significant abnormalities in rhythm, conduction or morphology onresting ECG (e.g., complete left bundle branch block, third degree heart block)

• Known left ventricular ejection fraction < 50%

• QTcF > 480 msec on screening electrocardiogram (ECG), or congenital long QTsyndrome.

10. Participation in any other interventional investigational trial for treatment ofunderlying malignancy at the time of informed consent signature.

11. Participants who are pregnant or breastfeeding.

12. Major surgery within 4 weeks prior to first dose of 177Lu-BetaBart.

13. Received anti-cancer therapy, including chemotherapy, immunotherapy, radiationtherapy, biologic, herbal therapy, or any investigational therapy or investigationaldevice, ≤ 28 days (or 5 half-lives for biologic/non-cytotoxic agents, whichever isshorter), prior to the first dose of 177Lu-BetaBart.

14. Known active hepatitis B (defined as hepatitis B surface antigen [HBsAg] reactive)or known active hepatitis C virus (defined as HCV RNA [qualitative] is detected)infection.

• Active viral (any etiology) hepatitis participants are excluded.

• Participants with serologic evidence of chronic hepatitis B virus (HBV)infection (defined by a positive hepatitis B surface antigen test and apositive anti hepatitis core antigen antibody test) who have a viral load belowthe limit quantification (HBV DNA titer < 1000 cps/mL or 200 IU/mL) and are notcurrently on viral suppressive therapy may be eligible and should be discussedwith the Sponsor's Medical Monitor (or designee).

• Note, participants with a history of HCV infection should have completedcurative antiviral treatment and have a viral load below the limit ofquantification to be eligible to enroll into the study.

• No testing for HBV or HCV is required unless mandated by local healthauthority.

15. Any uncontrolled intercurrent illness or clinically significant uncontrolledcondition(s), including but not limited to active bacterial, fungal, or viralinfections requiring systemic therapy.

16. Untreated moderate to severe hydronephrosis. If hydronephrosis is corrected viastent or nephrostomy, hydronephrosis will be considered resolved.

17. *Prescence of a superscan by nuclear medicine/99mTc bone scan.

18. Active autoimmune disease that has required systemic treatment within 90 days (i.e.,with the use of disease modifying agents, corticosteroids or immunosuppressivedrugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid [stable / low doses of ≤10 mg/day prednisone or equivalent dose]) for adrenal orpituitary insufficiency is allowed.

19. Any other clinically significant comorbidities, such as uncontrolled pulmonarydisease, active infection, or any other condition, which in the judgment of theinvestigator could compromise compliance with the protocol, interfere with theinterpretation of study results, or predispose the subject to safety risks.