Phase 2b Imaging Study of RAD101 in Participants with Suspected Recurrent Brain Metastases

This is an open-label, single dose, single arm, multicenter Phase 2b study to establish the imaging performance of RAD101 PET in participants who are ≥ 18 years of age and with suspected recurrent brain metastases from solid tumors.

The study consists of a 4-week Screening Period, a 3-day Imaging and Safety Follow-Up Period, and a Data Collection Period of up to 6 months. Participant eligibility will be determined during the Screening Period and eligible participants will be enrolled in the study. On Day 1, the enrolled participants will receive a single dose of the investigational medicinal product (IMP), RAD101. Participants will then proceed with a whole brain PET scan. A high-resolution Magnetic Resonance Imaging (MRI) will be performed in joint acquisition with PET or separately on the same day. A phone follow-up will be performed on Day 3 (+ 1 day). Participants will have follow-up (longitudinal) MRI scans (longitudinal imaging) and/ or a biopsy according to their Standard of Care (SoC). The longitudinal MRI results, and details of the biopsy if performed as part of SoC (i.e., location and histopathology results), will be collected during the 6- month Data Collection Period.

This is an open-label, single dose, single arm, multicenter Phase 2b study to establish the imaging performance of RAD101 PET in participants who are ≥ 18 years of age and with suspected recurrent brain metastases from solid tumors. Approximately 30 participants will be enrolled in the study. To avoid overrepresentation of a specific tumor type, a maximum of 15 participants per tumor type will be enrolled: lung, breast, colon, kidney, or melanoma.

The study consists of a 4-week Screening Period, a 3-day Imaging and Safety Follow-Up Period, and a Data Collection Period of up to 6 months. Participant eligibility will be determined during the Screening Period and eligible participants will be enrolled in the study. All participants will have an MRI (otherwise CT) performed as their SoC within 6 weeks before Day 1. For enrolled participants, the screening MRI images will be collected and submitted for central imaging review. On Day 1, the enrolled participants will receive a single dose of the investigational medicinal product (IMP), RAD101, at a target dose of 370 Megabecquerel (MBq) (10 millicurie (mCi)) ± 10% through a slow intravenous (IV) bolus injection over a maximum of 30 seconds, followed by a saline flush. Participants will then proceed with a whole brain PET scan at 60 ± 10 min post-dose. A high-resolution MRI will be performed in joint acquisition with PET or separately on the same day. Safety assessments, such as physical examination, vital signs, Electrocardiogram (ECG), and laboratory tests, will be conducted on Day 1 before RAD101 administration. Vital signs and ECG will be repeated 30 ± 5 min following RAD101 administration on Day 1. A phone follow-up will be performed on Day 3 (+ 1 day).

Participants will have follow-up (longitudinal) MRI scans (longitudinal imaging) and/ or a biopsy according to their SoC. If a biopsy is performed as part of their SoC during follow-up, the location of the biopsied lesion(s) and results of histopathology assessments on the lesion(s) will be collected. The longitudinal MRI results will be collected for central reading until a SoC biopsy is performed and the histopathology results are available, or up to 6 months following RAD101 administration, whichever comes first. The longitudinal MRI results, and details of the biopsy if performed as part of SoC (i.e., location and histopathology results), will be collected during the 6- month Data Collection Period.

To limit the number of participants being exposed to a dose-ranging study, the minimum effective dose (MBq) of RAD101 will be assessed on a subset of 6 to 10 participants using images obtained by simulated count reduction.

The duration of study participation for each participant is approximately 211 days (7 months), including 28 days of the Screening Period, 3 days of the Imaging and Safety Follow-Up Period, and up to 180 days of the Data Collection Period. The duration of the entire study is planned to be approximately 15 months.

Eligibility Criteria:
Inclusion Criteria:

1. Must be ≥ 18 years of age at the time of signing the informed consent.
2. Participant has one of the following histopathologically confirmed advanced solid tumors with known history of brain metastases: lung, breast, colon, kidney, or melanoma, and with known history of brain metastases.
3. Participant has undergone SRS for their brain metastases prior to study screening with pre-planning images available for submission to the centralized imaging reader as reference.
4. Participant has suspected but not confirmed recurrent brain metastases in at least 1 but not more than 5 lesions previously treated with SRS, based on gadolinium-enhanced volumetric MRI (MRI preferred, otherwise CT) within 6 weeks prior to Day 1, with post-SRS images available for submission to the centralized imaging reader as reference. In addition, each suspected lesion must meet the following criteria:

   1. Size must be at least 5 mm in longest diameter seen on 2 slices on the volumetric MRI analyzed at 2.5 mm slice thickness, AND
   2. Lesion does not meet complete response criteria or unequivocal progressive disease criteria as outlined in Appendix 5 (Section 10.5).

   Note: New brain metastases or new leptomeningeal disease based on macrocyclic gadolinium-enhanced MRI within 6 weeks prior to Day 1, in addition to the above findings, are permitted.
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
6. Creatinine clearance ≥ 60 mL/min according to the Cockroft-Gault formula
7. Life expectancy ≥4 months
8. Participant is not scheduled to undergo a confirmatory biopsy to characterize MRI findings until after the Day 1 study procedures have been completed.
9. Female participants must meet either of the following criteria:

   1. Women of childbearing potential (WOCBP) must have a negative beta human chorionic gonadotropin (β-hCG) test within 72 hours before administration of IMP and must not be breastfeeding. WOCBP, defined as all women physiologically capable of becoming pregnant, should agree to use highly effective methods of contraception during dosing and for 12 hours after administration of RAD101.
   2. Women who are not of childbearing potential are those who are surgically sterile or post-menopausal. Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause.
10. Male participants who are able to father a child must agree to avoid impregnating a partner and to adhere to a highly effective method of contraception during dosing and for 12 hours after administration of IMP. All male participants must agree to not donate sperm for 12 hours after administration of IMP.

    Highly effective contraception methods include:
    1. Total abstinence (when this is in line with the preferred and usual lifestyle of the participant. Periodic abstinence (i.e., calendar, ovulation, symptothermal, post ovulation methods) and withdrawal are not acceptable methods of contraception.
    2. Female sterilization (have had bilateral surgical oophorectomy with or without hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow-up hormone level assessment.
    3. Male sterilization (at least 6 months prior to Screening). The vasectomized male partner should be the sole partner for that participant and the absence of sperm should be confirmed.
    4. Use of oral, injected, or implanted hormonal methods of contraception, or placement of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal contraception that inhibit ovulation and have comparable efficacy (failure rate \<1%), for example hormone vaginal ring or transdermal hormone contraception. In case of use of oral contraception, women should have been stable on the same pill for a minimum of 3 months before taking IMP. Acceptable contraception methods are further described in the protocol.
11. Willing and capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the Informed Consent Form (ICF), and willing to comply with all study procedures.

Exclusion Criteria:

1. History of known additional malignancy that is progressing or requires treatment.
2. Brain surgery within 4 weeks before the screening MRI.
3. Whole brain Radiation Therapy (RT) or SRS within 6 weeks of Day 1
4. Baseline Fridericia-corrected QT interval (QTcF) \> 470 msec or history of congenital long QT syndrome
5. Any medical condition that would, in the Investigator's judgment, prevent the participant's full participation in the clinical study due to safety concerns or compliance with clinical study procedures, such as participants with severe claustrophobia who are unresponsive to oral anxiolytics, participants with low back pain who cannot lie comfortably on an imaging table, and participants who are hyperactive or hyperkinetic such that they cannot tolerate lying still for multiple time point imaging procedures.
6. Participation in any other investigational trial from the time of informed consent signature to the end of the Imaging and Safety Follow-Up Period.
7. History of uncontrolled allergic reactions and/or known or expected hypersensitivity to RAD101, or any of its excipients, and/or macrocyclic gadolinium-based contrast agents.