[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).