Neuroendocrine

Drug(s)/Mechanism:
Belzutifan

Eligiblity information:
Cohort B1 specific inclusion criteria:

1. Have a diagnosis of VHL disease as determined by a germline test (documented germline VHL gene alteration) locally and/or clinical diagnosis, which can be made in the
following instances:
a. in a participant with a family history of VHL disease and at least one of the characteristic VHL-related tumors (eg, retinal HBs, CNS HBs, clear cell RCCs, pNETs, and endolymphatic sac tumors).
b. in the presence of 2 or more retinal or CNS HBs.
c. in the presence of 1 retinal or CNS HB, plus at least 1 of the characteristic VHLrelated visceral tumors, excluding renal and epididymal cysts.

2. Have at least 1 measurable PPGL or pNET per RECIST 1.1 by CT or MRI as assessed by local site investigator/radiology assessment and verified by BICR. BICR must verify the
presence of radiologically measurable disease per RECIST 1.1 for either PPGL or pNET for the participant to be eligible for the study.

3. For Cohort B1 participants with PPGL:
a. No pheochromocytoma >5 cm or paraganglioma >4 cm that requires immediate surgery.
b. Participants should have adequately controlled BP defined as BP 150/90 mm Hg and with no change in antihypertensive medications (for participants with concomitant hypertension) for at least 2 weeks prior to start of study treatment.
c. Metastatic or locally advanced, unresectable PPGL will be exclusionary.
d. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

4. For Cohort B1 participants with pNET:
a. No lesion(s) located in the head of the pancreas must be >2 cm that requires immediate surgery.
b. No lesion(s) located in the body or tail of the pancreas must be >3 cm that requires immediate surgery.
c. Locally advanced, unresectable or metastatic pNET will be exclusionary.
d. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

5. For Cohort B1 participants with RCC:
a. No lesion(s) must be >3 cm that requires immediate surgery.
b. Metastatic RCC will be exclusionary.
c. Presence of concomitant VHL disease associated tumors is permitted as long as they do not require immediate surgery or intervention as applicable (see exclusion criteria #2d-2g).

6. For Cohort D participants with advanced solid tumors with HIF-2A related genetic alterations:
a. Local test report documenting germline or somatic mutations in at least one of the HIF-2A related genes (HIF-2A/EPAS1, FH, SDHA, SDHB, SDHC, SDHD, SDHAF2, EGLN1, EGLN2, MDH2, ELOC/TCEB1).
b. Has locally advanced or metastatic solid tumor that is not amenable to surgery or curative intent treatment.
c. Participants must have progressed on/after standard therapy for advanced/metastatic disease. More than 3 prior therapies will not be allowed for this cohort in the advanced/metastatic setting.

For pre-screening, please contact: Message Basket: VICC RESEARCH REFERRALS/ELIGIBILITY

Key Eligibility Criteria:

Inclusion Criteria:
1. Adult PRRT-naïve subjects with NETs or meningioma by local pathology
2. Disease described clinically as:
(a) Locally advanced/unresectable or metastatic NETs for dose-finding part of the study
(b) Locally advanced/unresectable or metastatic GEP-NETs, bronchial NETs, pheochromocytoma, or paragangliomas for the dose-expansion part of the study
(c) Requiring at least 1 prior surgery (resection/biopsy) and a maximum of 1 line of EBRT, if technically feasible, for meningioma.
3. For meningioma: histologically confirmed diagnosis of meningioma, i.e., all grades (1 to 3)
4. Radiological evidence of measurable disease by: (a) For NETs: RECIST v1.1 criteria on CT with contrast or MRI of the areas of tumor involvement within 60 days of enrollment.
5. Lesions must have shown radiological evidence of disease progression in the 12 months prior to enrollment. (b) For meningioma: RANO meningioma criteria on contrast-enhanced skull MRI for meningioma within 3 weeks prior to enrollment.
6. Demonstration of lesional SSTR expression:
(a) For NETs: using an FDA-approved somatostatin receptor PET imaging agent, e.g. [68Ga]DOTATATE, [64Cu]DOTATATE, or [68Ga]DOTATOC (b) For meningioma: using a standard-of-care SSTR PET imaging agent within 45 days of enrollment

Exclusion Criteria:
1. Known hypersensitivity to SSA, SSTR imaging agents or any of the excipients of [212Pb]VMT-a-NET.
2. Known additional malignancy that is progressing or requires active treatment.
3. Prior treatment with systemic PRRT based therapies (i.e., [90Y] DOTATATE/DOTATOC or [177Lu] DOTATATE)
4. Prior treatment with 90-Yttrium radioembolization must be completed at least 6 months prior to enrollment.
5. For Subjects with NETs: Known brain metastases; unless these metastases have been treated and stabilized 6 months prior to enrollment and the subject has been off steroid support for at least 14 days prior to enrollment.
6. QTc > 450 milliseconds for males and females.

For internal pre-screening, please contact: Epic message basket- VICC RESEARCH PHASE 1