Patritumab Deruxtecan in Patients With Solid Tumor Harboring an NRG1 Fusion

Solid Tumor, Adult Clinical Trial

Official title: An Open Label, Phase 2 Basket Study of Patritumab Deruxtecan in Patients With Solid Tumor Harboring an NRG1 Fusion

Status Not yet recruiting

Clinical Trial Summary

The NRG1 gene is located on chromosome 8 (8p12 region) and encode NRG1. NRG1 gene is translated to generate six different proteins (I-VI) and at least 31 isoforms. NRG1 proteins are structurally related to EGF and contain an EGF-like motif that binds and activates ErbB3 and ErbB4. Upon ligand binding, these receptors form homodimers or heterodimers, which results in phosphorylation of the intrinsic kinase domain, and activation of the PI3K-AKT, MAPK, and other pathways.

The overall incidence of NRG1 fusions is very rare. In many tumor types, only limited numbers of NRG1 fusion variant have been identified. By percentage, there is no organ dominance of the presence of NRG1 fusions. In an analysis of 21, 858 tumor specimens that underwent anchored multiplex PCR for targeted RNA sequencing, the prevalence of NRG1 fusions was 0.2%. Of these, CD74 was the most common partner (29%), followed by ATP1B1 (10%), SDC4 (7%), and RBPMS (5%), and most CD74-NRG1 fusions have been reported in patients with lung IMA. NRG1 fusions result in aberrant expression of the epidermal growth factor (EGF)-like domain of neuregulin-1 (NRG1) on the cell surface binds primarily to ErbB3 and ErbB4, leading to heterodimerization or oligomerization with other ERBB family members. NRG1-mediated activation of ErbB3 promotes dimerization with EGFR, ErbB2, and ErbB4. These partners phosphorylate ErbB3, forming docking sites for SH2-domain proteins, leading to pathologic activation of multiple signal transduction pathways, including the phosphoinositide 3-kinase (PI3K) pathway. Subsequently, ErbB3 expression was noted at high levels, and the proteins were phosphorylated, in fusion-positive cases. Targeting ErbB3 signaling therefore represents a promising therapeutic approach for patients with NRG1 fusion-positive malignancies.

Clinical Trial Description

This is a global, multicenter, open-label, Phase 2 study exploring the efficacy and safety of patritumab deruxtecan in patients with NRG1 fusion solid tumor. Patients with tumor harboring NRG1 fusion will be identified through previously documented mutation testing performed prior to screening. The presence of NRG1 fusion will be retrospectively confirmed by central testing via next generation sequencing (NGS) or FISH or Anchored multiplex PCR for targeted RNA sequencing (AMP). The study has a basket design and includes several cohorts, either defined by an actionable somatic mutation and tumor histology.

Patritumab deruxtecan will be dosed at 5.6mg/kg as an itravenous (IV) infusion administered on Day 1 of each 21-day cycle. Dose reductions or interruptions, and initiation of supportive care, are allowed as deemed appropriate by the investigator.

The study start date is the date when the first subject has signed the main informed consent. A subject is eligible to be enrolled into the interventional phase of the study when the Investigator or designee has obtained written consent, has confirmed all eligibility criteria have been met by the subject, and all Screening procedures have been completed.

A Simon's optimal 2-stage design (with significance level 5%, power of 80%) will be used to determine whether patritumab deruxtecan has sufficient activity to warrant further development. The null hypothesis is carried through into the second stage before it is rejected or not. Early study termination will be permitted if data at the first stage indicate that the treatment is ineffective.

As the range of ORR in NRG1 fusion patients treated with chemotherapy or chemoimmunotherapy was found to be 0% to 13%, the investigators considered the average 6% will be considered unacceptable, whereas the ORR of patients who treated with afatinib was 25%, the investigators hypothesized the average of ORR 25% will merit further study (alternative hypothesis).

In the first stage, enrollment will continue until 7 patients received at least one dose of study treatment and completed the first tumor assessment by the investigator (response evaluable). If no responses are observed, the second stage for the cohort must be discontinued. Otherwise, 23 additional response evaluable patients will be accrued for a total of 30 patients in the cohort, considering 15% of dropout rate. The null hypothesis will be rejected if at least 4 responses are observed in Stage 2.

The study will be divided into 3 periods: a Screening Period, Treatment Period, and Follow-up Period.

The primary analysis of ORR will be conducted after all enrolled subjects have either a minimum of 9 months of follow-up or have discontinued from the study earlier. The final analysis will occur after all subjects have discontinued from the study. ;

Related Conditions & MeSH terms

• Neoplasms
• Solid Tumor, Adult

• NCT number: NCT06383884
• Study type: Interventional
• Source: Samsung Medical Center
• Contact: Se-Hoon Lee, MD, PhD
• Phone: +82-10-4579-7640
• Email: sehoon.lee@samsung.com
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: May 30, 2024
• Completion date: April 30, 2029