9  PRRT and CH

9.1 PRRT

  • Mechanism: Targeted delivery of β-emitting radionuclides (e.g., Lutetium-177 or Yttrium-90) linked to somatostatin analogs.

  • Also FDA approved for prostate cancer. Targeting PMSA

  • Indications: Treatment of metastatic or unresectable neuroendocrine tumors (NETs) expressing somatostatin receptors.

  • Standard Regimen: 4 cycles of 177Lu-DOTATATE given every 8 weeks.

9.2 Mayo Clinic data

  • (Kusne et al. 2024)
  • CHIP is present in 35.1% of NET patients before PRRT treatment (using a variant allele frequency ≥2% cutoff).
  • Patients with pre-existing CHIP who undergo PRRT appear to have an increased risk of developing thrombocytopenia and remaining in that condition longer than patients without CHIP.

9.3 PRRT and CH ECOG study planning

9.3.1 Goals and Objectives of retrospective analysis using ECOG sites

  • The primary mission of this group is to establish a comprehensive understanding of clonal hematopoiesis of indeterminate potential and clonal cytopenia of indeterminate significance (CHIP/CCUS) in patients receiving radioligand therapy, with the following objectives:
  • The frequency of CHIP/CCUS in patients prior to receiving radioligand therapy (baseline assessment of the population).
  • The evolutionary development of CHIP/CCUS as patients go through and then following treatment with radioligand therapy.
  • The impact of development of CHIP/CCUS on the ability of to treat patients with both full doses of radioligand therapy and then subsequent therapies as there may be limitations due to blood counts.
  • To understand if particular CH mutations are more or less likely to cause issues with cytopenias and/or progression to myeloproliferative neoplasms (MPNs).
  • To identify a patient subpopulation that would benefit from receiving protective intervention during radioligand therapy in an effort to prevent/slow the progression CHIP/CCUS/MNs.
  • To develop a clinical intervention that may serve as a protective measure in preventing the development/progression of CHIP/CCUS in patients receiving radioligand therapy.

To further investigate these objectives, we propose the following action items:

Query EA institutions to assess interest in and ability to contribute retrospective specimens and data for answering the above objectives: o Interest in participating? o Type and number of patient blood samples archived from patients receiving radioligand therapy?  Number of patients with samples before and after therapy?  Number of patients with samples before only?  Number of patients with samples after only? o Is associated clinical data available for these patients?  NET stage and extent of disease at time of treament?  Previous cancer therapies?  Subsequent cancer therapies?  Blood counts before and after radioligand therapy? (Blood counts at 8 weeks until 1 year post treatment if available)  Time to follow up? o Are bone marrow specimens available for any of these patients? o Has CH testing already been done on specimens and if so, using what assay? o Has germline testing already been for these specimens and if so, using what assay? o Are there institutional regulatory/legal requirements (MTAs) that are needed for contributing data to a central repository that will be housed at Mayo? • Work with EA statisticians to determine number of specimens requied to answer these questions. • Consider development of a prospective protocol to be opened across institutions that will allow for longitudinal biospecimen collection. o Explore grant options to pay for such an effort. • Development of Uniform CH Testing Assay o Establish a standardized next-generation sequencing panel focused on recurrent CH-associated mutations o Define minimum analytical sensitivity requirements (variant allele frequency detection thresholds)- error-corrected sequencing assay with UMIs o Create a centralized bioinformatics pipeline for consistent variant calling and classification

• Continue discussion with Novartis regarding a CDK4/6 trial in patients receiving radioligand therapy. o Pursue an initial phase I dose finding study with correlative biomarkers looking at CHIP/CCUS in this limited patient population. o Phase II endpoints to be determined pending data generated from the above objectives.

9.3.2 Assay development for uniform CH testing

9.3.3 Therapeutics

9.3.3.1 Novartis

  • CDK4/6 inhibitor (Ribociclib)
  • Dose escalation and expansion. Possibly randomized phase 2 clinical trial
  • What are the endpoints?
  • Should we do myelosuppression as an endpoint just as in PRESERVE-1 study(Lenz et al. 2024)

9.3.3.2 P53 activators

9.3.3.3 PPM1D inhibitors