[177Lu]-NeoB in Patients With Advanced Solid Tumors and With [68Ga]-NeoB Lesion Uptake

Inclusion Criteria:

1. Signed informed consent must be obtained prior to participation in the study.

2. Adult patients (age ≥ 18 years old) with any of the following advanced or metastatic
solid tumors:

- For Phase I: breast cancer, lung cancer, prostate cancer, GIST, GBM

- For Phase IIa:

1. Cohort A: Breast cancer with histology as follows: HR positive with ER >
10% of nuclei stain, HER-2 negative including HER-2 low based on current
practice and medical history

2. Cohort B: Prostate cancer

3. Cohort C: GIST

4. Cohort D: Patients affected by any advanced/metastatic solid tumor type
known to overexpress GRPR including recurrent GBM, and with moderate
impaired renal function defined as creatinine clearance (calculated using
the Cockcroft-Gault formula, or measured) ≥ 30 mL/min and < 60 mL/min

** Enrollment in cohort D will no longer be allowed with implementation of
protocol version 07. **

5. Cohort E: Breast cancer with histology as follows: HR positive with ER >
10% of nuclei stain, HER-2 negative including HER-2 low as assessed on the
primary diagnosis, or prostate cancer, or GIST

3. At least one measurable lesion as per RECIST 1.1, RANO (applicable for GBM only)
criteria detected on the low-dose CT or on the MRI (for GBM MRI only) acquired
together with the [68Ga]-NeoB PET.

The same identified measurable lesion shows [68Ga]-NeoB uptake on PET/CT or PET/MRI.
If the only matching lesion is located in the bone, the patient will still be
eligible.

4. Patients for whom no standard therapy is available, tolerated or appropriate in both
Phase I and Phase IIa. Specifically in the Phase IIa breast cancer Cohort A,
patients need to have completed at least one prior treatment of endocrine therapy
(including CDk4/6i) and at least one prior chemotherapy (unless contraindicated) in
the metastatic setting. Patients with prior treatment with trastuzumab deruxtecan,
alpelisib or elascestrant are also eligible. In case of confirmed presence of
deleterious or suspected deleterious germline BRCA1 or BRCA2 mutation, the patient
must also have already received a PARP inhibitor-based therapy.

5. Patient Eastern Cooperative Oncology Group (ECOG) performance status:

- For Phase I: =< 2

- For Phase IIa: =< 1

Exclusion Criteria:

1. Patients who have not had resolution, except where otherwise stated in the
inclusion/ exclusion criteria, of all clinically significant toxic effects of prior
systemic cancer therapy, surgery, or radiotherapy to Grade =< 1 (except for
alopecia)*.

2. Creatinine clearance (calculated using Cockcroft-Gault formula, or measured)

1. For Phase I and Phase IIa (Cohort A, B, C, and E): < 60 mL/min or serum
creatinine > 1.5 x ULN*

2. For Phase IIa (Cohort D): < 30 mL/min or >= 60 mL/min

3. Platelet count of < 75 x 109/L*†

4. Absolute neutrophil count (ANC) < 1.0 x 109/L*†

5. Hemoglobin < 9 g/dL*†

6. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x upper limit
of normal (ULN) if no demonstrable liver metastases or > 5 x ULN in the presence of
liver metastases*

7. Total bilirubin > 1.5 x ULN, except for patients with documented Gilbert's syndrome
who are eligible if total bilirubin ≤ 3 x ULN*

8. Serum amylase and/or lipase > 1.5 x ULN*

9. Known or expected hypersensitivity to [177Lu]-NeoB, [68Ga]-NeoB or any of their
excipients.

10. Impaired cardiac function or clinically significant cardiac disease, including any
of the following:

- Clinically significant and/or uncontrolled heart disease such as congestive
heart failure requiring treatment (NYHA grade >= 2), uncontrolled arterial
hypertension or clinically significant arrhythmia

- LVEF < 50% as determined by echocardiogram (ECHO)*

- QTcF >470 msec for females and QTcF >450 msec for males on screening
electrocardiogram (ECG) or congenital long QT syndrome

- Acute myocardial infarction or unstable angina pectoris < 3 months prior to
[177Lu]-NeoB (IMP1) administration

11. Patients with diabetes mellitus not stable under current treatment as judged by the
investigator or with hyperglycemia ≥ CTCAE version 5.0 Grade 2*.

12. Patients with history of or ongoing acute or chronic pancreatitis.

13. Concurrent bladder outflow obstruction or unmanageable urinary incontinence.

14. Administration of a radiopharmaceutical with therapeutic intent within a period
corresponding to 10 half-lives of the radionuclide used prior to injection of
[68Ga]-NeoB (IMP2).

15. Prior External Beam Radiation Therapy (EBRT) to more than 25% of the bone marrow.

16. [223Ra]-therapy within the context of diffuse bone or bone-marrow involvement (i.e.,
"superscan" defined as bone scintigraphy in which there is excessive skeletal
radioisotope uptake [>20 bone lesions] in relation to soft tissues along with absent
or faint activity in the genitourinary tract due to diffuse bone/ bone marrow
metastases).

17. [Removed]

18. Patients who have received prior systemic anti-cancer treatment within the following
time frames:

- Cyclical chemotherapy within a period that is shorter than the cycle length
used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) prior to
starting [177Lu]-NeoB treatment

- Biologic therapy (e.g., antibodies), continuous or intermittent small molecule
therapeutics, or any other investigational agents within a period which is ≤ 5
T1/2 or ≤ 14 days (whichever is shorter) prior to starting [177Lu]-NeoB
treatment

19. History of somatic or psychiatric disease/condition that may interfere with the
objectives and assessments of the study.

20. Malignant disease, other than that being treated in this study. Exceptions to this
exclusion include the following: malignancies that were treated curatively and have
not recurred within 2 years prior to [177Lu]-NeoB treatment; completely resected
basal cell and squamous cell skin cancers; any malignancy considered to be indolent
and that has never required therapy; and completely resected carcinoma in situ of
any type.

21. Pregnant or breast-feeding women

22. Women of child-bearing potential, defined as all women physiologically capable of
becoming pregnant, are not allowed to participate in this study UNLESS they are
using highly effective methods of contraception throughout the study and for 7
months after study drug discontinuation. Highly effective contraception methods
include:

- True abstinence, when this is in line with the preferred and usual lifestyle of
the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal,
post-ovulation methods), declaration of abstinence for the duration of exposure
to IMPs, and withdrawal are not acceptable methods of contraception.

- Male or female sterilization. Vasectomised partner is a highly effective birth
control method if the partner is the sole sexual partner of the study
participant and the vasectomised partner has received medical assessment of the
surgical success.

- Women tubal ligation is an acceptable highly effective contraception method,
but surgical sterility is defined as bilateral salpingectomy (or bilateral
oophorectomy or hysterectomy).

- Combination of any two of the following (a+b or a+c or b+c):

1. Use of oral, injected, or implanted hormonal methods of contraception. In
case of use of oral contraception, women should be stable on the same pill
for a minimum of 3 months before taking [177Lu]-NeoB treatment. This is
not applicable for patients with breast cancer.

2. Placement of an intrauterine device (IUD) or intrauterine system (IUS).
IUS is not applicable for patients with breast cancer.

3. Barrier methods of contraception: condom or occlusive cap (diaphragm or
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal
suppository Post-menopausal women are allowed to participate in this
study. Women are considered post-menopausal and not of child bearing
potential if they have had 12 months of natural (spontaneous) amenorrhea
with an appropriate clinical profile (e.g. age appropriate, history of
vasomotor symptoms) or six months of spontaneous amenorrhea with serum
Follicle-Stimulating Hormone (FSH) levels > 40 mIU/mL [for US only: and
estradiol < 20 pg/mL] or have had surgical bilateral oophorectomy or
bilateral salpingectomy or hysterectomy or tubal ligation at least six
weeks prior to screening. In the case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up hormone
level assessment is she considered not of childbearing potential.

Sexually active males must use a condom during intercourse while taking the drug and
for 4 months after stopping treatment and should not father a child in this period.
A condom is required to be used also by vasectomized men in order to prevent
delivery of the drug via seminal fluid. Female partners of childbearing potential
should use highly effective contraceptive methods during and up to 4 months after
stopping treatment.

23. Use of other investigational drugs within 30 days prior to informed consent
signature.

24. Cohorts A, B, and C: Patient currently receiving NEP inhibitors (e.g., Entresto,
racecadotril) and for whom images for dosimetry assessments cannot be acquired.

25. Cohort E only: Patient meeting at least one of the following conditions

- Currently receiving NEP inhibitors (e.g., Entresto, racecadotril)

- Known history of angioedema related to previous angiotensin-converting enzyme
(ACE) inhibitor or angiotensin receptor blocker (ARB) therapy or hereditary or
idiopathic angioedema

- Hypersensitivity to the LCZ696 active substances or to any of the excipients

- Diabetes mellitus and receiving aliskiren-containing medicinal products

- Receiving ACE inhibitors or has discontinued ACE inhibitor therapy within 36
hours before receiving the first dose of LCZ696 in the study

- Systolic blood pressure < 100 mmHg¥

- Serum potassium level > 5.5 mEq/L¥

- To be considered as valid to determine the eligibility of a patient, exam
results of exclusion criteria #2, #3, #4, #5, #6, #7, #8, #10 (except
LVEF) and #11 must be collected on or after date of patient's informed
consent and must be available in the source documents for monitoring. LVEF
evaluation is permitted within 6 weeks prior to IMP1 administration, even
if performed outside the screening period as part of standard routine
clinical practice of care, before ICF signature.

- No platelet transfusion, packed red cell transfusion, or G-CSF will
be allowed during the selection phase after ICF signature.
Transfusion for the sole purpose of making a patient eligible for the
study inclusion is not allowed.

- Blood pressure and serum potassium level must be evaluated at
screening and again at time of LCZ696 collection, within 7 days
prior to [177Lu]-NeoB first administration (C1D1).