Ignite Creation Date:
2024-05-06 @ 8:27 PM
Last Modification Date:
2024-10-26 @ 3:27 PM
Study NCT ID:
NCT06383884
Status:
NOT_YET_RECRUITING
Last Update Posted:
2024-05-14
First Post:
2024-04-16
Brief Title:
Patritumab Deruxtecan in Patients With Solid Tumor Harboring an NRG1 Fusion
Sponsor:
Samsung Medical Center
Organization:
Samsung Medical Center
Study Overview
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
Status Verified Date:
2024-05
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief 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 02 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
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 02 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
Detailed 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 56mgkg 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 Simons 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
Patritumab deruxtecan will be dosed at 56mgkg 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 Simons 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None