Trial Title:
Patritumab Deruxtecan in Patients With Solid Tumor Harboring an NRG1 Fusion
NCT ID:
NCT06383884
Condition:
Solid Tumor, Adult
Conditions: Official terms:
Neoplasms
Patritumab deruxtecan
Conditions: Keywords:
Patritumab deruxtecan
NRG1 fusion
Study type:
Interventional
Study phase:
Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Patritumab Deruxtecan
Description:
Patritumab deruxtecan will be administered as an IV infusion Q3W on Day 1 of each 21-day
cycle as a fixed dose regimen of 5.6 mg/kg Q3W.
Arm group label:
Patritumab deruxtecan treatment arm
Other name:
U3-1402
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.
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 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.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
- Sign and date the tissue informed consent form (ICF) and the main ICF, prior to the
start of any study-specific qualification procedures.
- Male or female participants aged ≥18 years (follow local regulatory requirements if
the legal age of consent for study participation is >18 years old).
- Histologically or cytologically documented locally advanced or metastatic solid
tumor not amenable to curative surgery or radiation.
- Documentation of NRG1 fusion detected from tumor tissue or blood sample, including
but not limited to TruSightOncology-500, Guardant-360 or FoundationOne®CDx (F1CDx).
- At least 1 measurable lesion confirmed by investigator as per RECIST v1.1
- At least 1 measurable lesion confirmed per RECIST v1.1
- Consented and willing to provide required tumor tissue of sufficient quantity (as
defined in the Laboratory Manual) and of adequate tumor tissue content (as confirmed
by hematoxylin and eosin [H&E] staining). Required tumor tissue can be provided as
either:
1. Pretreatment tumor biopsy from at least 1 lesion not previously irradiated and
amenable to core biopsy OR
2. Archival tumor tissue collected from a biopsy performed within 3 months prior
to signing of the tissue consent and since progression while on or after
treatment with the most recent cancer therapy regimen.
- Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or 1 at
Screening.
- Has adequate bone marrow reserve and organ function based on local laboratory data
within 14 days prior to Cycle 1 Day
1. Platelet count: ≥100,000/mm^3 or ≥100 × 10^9/L (platelet transfusions are not
allowed up to 14 days prior to Cycle 1 Day 1 to meet eligibility)
2. Hemoglobin: ≥9.0 g/dL (transfusion and/or growth factor support is allowed)
3. Absolute neutrophil count: ≥1500/mm^3 or ≥1.5 × 10^9/L
4. Serum creatinine (SCr) or creatinine clearance (CrCl): SCr ≤1.5 × upper limit
of normal (ULN), OR CrCl ≥30 mL/min as calculated using the Cockcroft-Gault
equation or measured CrCl
5. Aspartate aminotransferase/alanine aminotransferase: ≤3 × ULN (if liver
metastases are present, ≤5 × ULN)
6. Total bilirubin: ≤1.5 × ULN if no liver metastases (<3 × ULN in the presence of
documented Gilbert's syndrome [unconjugated hyperbilirubinemia] or liver
metastases)
7. Serum albumin: ≥2.5 g/dL
8. Prothrombin time (PT) or PT-International normalized ratio (INR) and activated
partial thromboplastin time (aPTT)/PTT: ≤1.5 × ULN, except for subjects on
coumarin-derivative anticoagulants or other similar anticoagulant therapy, who
must have PT-INR within therapeutic range as deemed appropriate by the
Investigator
Exclusion Criteria:
- Any history of interstitial lung disease (including pulmonary fibrosis or radiation
pneumonitis) has current interstitial lung disease (ILD) or is suspected to have
such disease by imaging during screening.
- Clinically severe respiratory compromise (based on Investigator's assessment)
resulting from intercurrent pulmonary illnesses including, but not limited to:
1. Any underlying pulmonary disorder (eg, pulmonary emboli within 3 months prior
to the study enrollment, severe asthma, severe chronic obstructive pulmonary
disease [COPD]), restrictive lung disease, pleural effusion);
2. Any autoimmune, connective tissue or inflammatory disorders with pulmonary
involvement (eg, rheumatoid arthritis, Sjogren's syndrome, sarcoidosis); OR
prior complete pneumonectomy.
- Is receiving chronic systemic corticosteroids dosed at >10 mg prednisone or
equivalent anti-inflammatory or any form of immunosuppressive therapy prior to
enrollment. Participants who require use of bronchodilators, inhaled or topical
steroids, or local steroid injections may be included in the study.
- Evidence of any leptomeningeal disease.
- Evidence of clinically active spinal cord compression or brain metastases.
- Inadequate washout period prior to Cycle 1 Day 1, defined as:
1. Whole brain radiation therapy <14 days or stereotactic brain radiation therapy
<7 days;
2. Any cytotoxic chemotherapy, investigational agent or other anticancer drug(s)
from a previous cancer treatment regimen or clinical study (other than EGFR
TKI), <14 days or 5 half-lives, whichever is longer;
3. Monoclonal antibodies, other than immune checkpoint inhibitors, such as
bevacizumab (anti-VEGF) and cetuximab (anti-EGFR) <28 days;
4. Immune checkpoint inhibitor therapy <21 days;
5. Major surgery (excluding placement of vascular access) <28 days;
6. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field
of radiation <28 days or palliative radiation therapy <14 days; or
7. Chloroquine or hydroxychloroquine <14 days.
- Prior treatment with an anti-human epidermal growth factor receptor 3 (HER3)
antibody or single-agent topoisomerase I inhibitor.
- Prior treatment with an antibody drug conjugate (ADC) that consists of any
topoisomerase I inhibitor
- Has unresolved toxicities from previous anticancer therapy, defined as toxicities
(other than alopecia) not yet resolved to National Cancer Institute Common
Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, Grade ≤1 or baseline.
Participants with chronic Grade 2 toxicities may be eligible at the discretion of
the Investigator.
- Has history of other active malignancy within 3 years prior to enrollment, except:
1. Adequately treated non-melanoma skin cancer;
2. Superficial bladder tumors (Ta, Tis, T1);
3. Well-differentiated thyroid cancer
4. Adequately treated intraepithelial carcinoma of the cervix uteri;
5. Low risk non-metastatic prostate cancer (with Gleason score <7, and following
local treatment or ongoing active surveillance);
6. Any other curatively treated in situ disease.
- Uncontrolled or significant cardiovascular disease prior to Cycle 1 Day 1
- Active hepatitis B and/or hepatitis C infection, such as those with serologic
evidence of viral infection within 28 days of Cycle 1 Day 1.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Samsung Medical Center
Address:
City:
Seoul
Zip:
06351
Country:
Korea, Republic of
Contact:
Last name:
Se-Hoon Lee, MD, PhD
Phone:
+82-10-4579-7640
Email:
sehoon.lee@samsung.com
Start date:
May 30, 2024
Completion date:
April 30, 2029
Lead sponsor:
Agency:
Samsung Medical Center
Agency class:
Other
Source:
Samsung Medical Center
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06383884
