Pedi-STAR: Surface Target Antibody-drug Conjugate (ADC) Antigen Expression in Relapsed/Refractory Pediatric Solid and CNS Tumors

This is a non-therapeutic feasibility study evaluating the prospective measurement of antibody-drug conjugate (ADC) target antigen expression in pediatric patients with relapsed or refractory solid or CNS tumors. The study aims to characterize ADC antigen expression patterns, compare expression at diagnosis and relapse, and describe real-world utilization and outcomes of ADCs in pediatric tumors.

Participants will be enrolled into two cohorts: a prospective cohort and a retrospective cohort.

The prospective cohort will undergo eligibility screening, enrollment, specimen submission, bulk RNA sequencing screening, followed by immunohistochemistry (IHC) of highly expressed targets, and clinical return of IHC results to their enrolling provider.The retrospective cohort will include participants who have received ADC therapy as part of routine clinical care and will undergo specimen submission, targeted IHC testing, and clinical data collection.

It is expected that about 130 people will take part in this research.

B+ Foundation is helping to support this research by providing study funding.

• Bulk RNA Sequencing (Diagnostic test): Test performed on tumor tissue to measure antibody-drug conjugate (ADC) target expression
• Immunohistochemistry (IHC) (Diagnostic test): Test performed on tumor tissue to confirm protein expression of antibody-drug conjugate (ADC) target antigens identified by bulk RNA sequencing

Primary outcomes

• Antibody-Drug Conjugate (ADC) Target Expression Screening Success Rate [Prospective Cohort] [Week 6]: ADC target expression screening success rate is defined as the proportion of participants who successfully complete bulk RNA sequencing with interpretable results. If immunohistochemistry (IHC) testing is indicated based on the bulk RNA sequencing results, the participant must also successfully complete IHC testing with interpretable results. If IHC testing is not indicated, no further testing is required. Participants who submit a tissue specimen but do not meet these criteria will be classified as screening failures.

Secondary outcomes

• ADC Target Antigen Expression Rate by Bulk RNA Sequencing [Prospective Cohort] [Week 4]: Bulk RNA sequencing is performed on one tumor sample collected from participants with relapsed/refractory CNS or solid tumors. Expression is defined using a predefined threshold of transcripts per million (TPM) ≥3. The ADC target antigen expression rate is the proportion of participants with expression of at least one evaluated ADC target antigen.
• ADC Target Antigen Expression Rate by Immunohistochemistry (IHC) [Prospective Cohort] [Week 6]: IHC is performed on one tumor sample collected from participants with relapsed/refractory CNS or solid tumors. Candidate ADC target antigens identified by screening bulk RNA sequencing are evaluated by IHC. Protein expression is assessed using semi-quantitative staining intensity scores (0-3+) and H-scores. The ADC target antigen expression rate is the proportion of participants with expression of at least one evaluated ADC target antigen by IHC.
• ADC Target Antigen Transcript Expression Levels by Histologic Diagnosis [Prospective Cohort] [Week 4]: All potential ADC target antigens are evaluated regardless of histologic diagnosis, and transcript expression is quantified using TPM.
• ADC Target Antigen Protein Expression Levels by Histologic Diagnosis [Prospective Cohort] [Week 6]: Candidate ADC target antigens identified by screening bulk RNA sequencing are evaluated by IHC. Protein expression is assessed using semi-quantitative staining intensity scores (0-3+) and H-scores, with higher scores indicating greater protein expression
• Change in ADC Target Antigen Transcript Expression Level from Diagnosis to Relapse [Prospective Cohort] [48 months]: ADC target antigen transcript expression is measured by bulk RNA sequencing. Transcript expression is quantified as TPM.
• Change in ADC Target Antigen Protein Expression Level from Diagnosis to Relapse [Prospective Cohort] [48 months]: ADC target antigen protein expression is measured by IHC. Protein expression is assessed using semi-quantitative staining intensity scores (0-3+) and H-scores, with higher scores indicating greater protein expression.
• ADC Treatment Rate [Prospective Cohort] [48 months]: ADC treatment rate is defined as the proportion of participants who receive an ADC as part of their clinical care following return of study results.
• ADC Therapy Response Rate [Prospective Cohort] [48 months]: ADC therapy response rate is defined as the proportion of participants classified as responders according to tumor-specific response criteria. Response is assessed using the International Neuroblastoma Response Criteria (INRC) for neuroblastoma, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 for extracranial solid tumors, and Response Assessment in Neuro-Oncology (RANO) criteria for primary central nervous system (CNS) tumors.
• ADC Therapy Response Rate [Retrospective Cohort] [48 months]: ADC therapy response rate is defined as the proportion of participants who are classified as responders according to tumor-specific response criteria following ADC therapy.

Sex: All, ages: any to 30 Years

Inclusion Criteria:

Inclusion Criteria for Prospective Cohort

* Age 0 - 30 years at time of initial diagnosis of the solid or CNS tumor
* Diagnosis of relapsed or refractory solid or CNS tumor, without a limit on the number of prior episodes of relapse. Refractory disease is defined as disease that progresses on standard-of-care upfront therapy or requires salvage therapy due to inadequate response, e.g. bridging chemoimmunotherapy in a patient with high-risk neuroblastoma and poor end-induction response (PEIR).
* Life expectancy of at least 12 weeks at the time of enrollment
* Available specimens Tissue block or unstained slides available expected to yield a minimum of 30 total slides., OR other specimens expected to result in adequate (1) RNA quantity and quality for sequencing and (2) IHC testing may substitute for tissue requirement above with the approval of the PI or study staff designee approval prior to submission enrollment. Tumor tissue from relapse/progression is preferred, but tumor tissue from diagnosis if obtained prior to neoadjuvant chemotherapy is acceptable if no relapse/progression sample available.Note that this requirement may be reduced to 15 total slides for patients who have already had RNA sequencing performed on their tumor material.
* Informed consent for participation for adult participants or parental permission for minor participants (with assent as appropriate based on age of participant).

Inclusion Criteria for Retrospective Cohort

* Age 0 - 30 years at time of initial diagnosis of the solid or CNS tumor
* Diagnosis of relapsed or refractory solid or CNS tumor, without a limit on the number of prior episodes of relapse. Refractory disease is defined as disease that progresses on standard-of-care upfront therapy or requires salvage therapy due to inadequate response, e.g. bridging chemoimmunotherapy in a patient with high-risk neuroblastoma and poor end-induction response (PEIR).
* Available specimens Tissue block or unstained slides available expected to yield a minimum of 15 total slides OR other specimens expected to result in adequate IHC testing may substitute for tissue above with the approval of the PI or study staff approval designee prior to submission.. Tumor tissue from relapse/progression is preferred, but tumor tissue from diagnosis if obtained prior to neoadjuvant chemotherapy is acceptable if no relapse/progression sample available.
* Prior receipt of an antibody-drug conjugate (ADC). The ADC may have been received via either commercial supply or as a participant on a clinical trial. The ADC may have been received at any time during a patient's treatment course for relapsed or refractory disease and on or after January 1st, 2011 up to the time of enrollment of the final prospective participant.

Exclusion Criteria:

Exclusion Criteria for Prospective Cohort

* adults who are unable to consent
* pregnant women
* incarcerated individuals

• Steven Dubois, MD,MS, Principal investigator, Dana-Farber Cancer Institute