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Testare la sicurezza e la tollerabilità dei farmaci antitumorali Trastuzumab Deruxtecan e Neratinib per i tumori con alterazioni del gene HER2

1 ottobre 2026 aggiornato da: National Cancer Institute (NCI)

Studio di fase I di DS-8201a (Trastuzumab Deruxtecan) in combinazione con Neratinib nei tumori solidi con alterazioni di HER2

This phase I trial tests the safety, side effects, and best dose of neratinib in combination with trastuzumab deruxtecan in treating patients with solid tumors that have spread from where it first started (primary site) to other places in the body (metastatic) or that cannot be removed by surgery (unresectable), and have changes in a gene called human epidermal growth factor receptor 2 (HER2). Neratinib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals tumor cells to multiply. This helps slow or stop the spread of tumor cells. Trastuzumab deruxtecan is in a class of medications called antibody-drug conjugates. It is composed of a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug, called deruxtecan. Trastuzumab attaches to HER2 positive tumor cells in a targeted way and delivers deruxtecan to kill them. Adding neratinib to trastuzumab deruxtecan may be able to shrink cancer with a change in the HER2 gene.

Panoramica dello studio

Stato

Reclutamento

Condizioni

Intervento / Trattamento

Descrizione dettagliata

PRIMARY OBJECTIVE:

I. To assess dose limiting toxicities and determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of neratinib maleate (neratinib) and trastuzumab deruxtecan (DS-8201a) in patients with advanced solid tumors harboring alterations in HER2 (including HER2 overexpression/amplification and selected HER2-activating mutations).

II. To evaluate the objective response rate (ORR) in patients with advanced pancreas cancer with HER2 activating mutations, amplification, and/or HER2 overexpression. (Part 2, Pancreatic Cohort ONLY)

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity of neratinib and DS-8201a, as measured by objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by investigator assessment, and overall survival (OS).

II. To assess the safety and tolerability for the combination neratinib and DS-8201a.

III. To assess the effect of neratinib on DS-8201a payload (DXd/MAAA-1181a) tissue concentration in Part 2 pharmacodynamic (PD) Cohort at the RP2D chosen in part 1 (and potentially at a lower dose[s] of neratinib) before and after addition of neratinib to DS-8201a.

IV. To assess the pharmacokinetics of DS-8201a and neratinib in combination.

EXPLORATORY OBJECTIVES:

I. To assess the pharmacodynamic response to neratinib and DS-8201a as measured by markers of DS-8201a-induced deoxyribonucleic acid (DNA) damage using gammaH2AX, phosphorylated (p) NBS1 and pKAP1 immunofluorescence assay (IFA), multiplex multiple reaction monitoring mass spectrometry (MRM)- based proteomic assay panel of DNA repair response pathway biomarkers, induction of apoptosis, and HER2 signaling along with other PD biomarkers such as cleaved caspase3 (apoptosis) and TOP1CC (target engagement) pending National Clinical Laboratory Network (NCLN) assay availability. (Part 1 Dose Escalation and Part 2 PD Cohorts) II. To assess quantifiable HER2 protein expression of pre-treatment or archival tumor biopsies, and at disease progression in correlation with treatment response.

III. To assess tumor tissue mutation profile pre-treatment and at progression in correlation with treatment response.

IV. To assess circulating cell-free DNA (cfDNA) mutation profiles pre-treatment, cycle 2 day 1 (C2D1), and at progression in correlation with treatment response.

OUTLINE: This is a dose-escalation study of neratinib followed by a dose-expansion (PD and Pancreatic Cohorts) study.

Patients receive neratinib orally (PO) once daily (QD) on days 1-21 of each cycle (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD cohort) and trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, computed tomography (CT) scan and echocardiography or multigated acquisition (MUGA) scan throughout study. Additionally, patients may undergo a tissue biopsy at baseline if no archival sample available (dose-escalation cohort only), optionally at baseline (pancreatic cohort only), on study (PD cohort only), and optionally at disease progression (all cohorts).

After completion of study treatment, patients are followed up every 3 months for at least one year or until death.

Tipo di studio

Interventistico

Iscrizione (Stimato)

58

Fase

  • Fase 1

Contatti e Sedi

Questa sezione fornisce i recapiti di coloro che conducono lo studio e informazioni su dove viene condotto lo studio.

Luoghi di studio

  • Stati Uniti
    • California
      • Duarte, California, Stati Uniti, 91010
        • Reclutamento
        • City of Hope Comprehensive Cancer Center
        • Contatto:
        • Investigatore principale:
          • Dani R. Castillo
      • Irvine, California, Stati Uniti, 92618
        • Reclutamento
        • City of Hope at Irvine Lennar
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 877-467-3411
        • Investigatore principale:
          • Dani R. Castillo
      • Irvine, California, Stati Uniti, 92612
        • Reclutamento
        • UCI Health - Chao Family Comprehensive Cancer Center and Ambulatory Care
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 877-827-8839
          • Email: ucstudy@uci.edu
        • Investigatore principale:
          • Farshid Dayyani
      • Lancaster, California, Stati Uniti, 93534
        • Sospeso
        • City of Hope Antelope Valley
      • Orange, California, Stati Uniti, 92868
        • Reclutamento
        • UC Irvine Health/Chao Family Comprehensive Cancer Center
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 877-827-8839
          • Email: ucstudy@uci.edu
        • Investigatore principale:
          • Farshid Dayyani
      • Sacramento, California, Stati Uniti, 95817
        • Reclutamento
        • University of California Davis Comprehensive Cancer Center
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 916-734-3089
        • Investigatore principale:
          • Mili Arora
      • South Pasadena, California, Stati Uniti, 91030
        • Sospeso
        • City of Hope South Pasadena
      • Upland, California, Stati Uniti, 91786
        • Sospeso
        • City of Hope Upland
    • Florida
      • Gainesville, Florida, Stati Uniti, 32610
        • Reclutamento
        • UF Health Cancer Institute - Gainesville
        • Investigatore principale:
          • Thomas J. George
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 352-273-8010
    • Illinois
      • Chicago, Illinois, Stati Uniti, 60611
        • Reclutamento
        • Northwestern University
        • Contatto:
        • Investigatore principale:
          • Aparna Kalyan
    • Kentucky
      • Lexington, Kentucky, Stati Uniti, 40536
        • Reclutamento
        • University of Kentucky/Markey Cancer Center
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 859-257-3379
        • Investigatore principale:
          • Reema A. Patel
    • Massachusetts
      • Boston, Massachusetts, Stati Uniti, 02215
        • Reclutamento
        • Dana-Farber Cancer Institute
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 877-442-3324
        • Investigatore principale:
          • Geoffrey I. Shapiro
    • Missouri
      • St Louis, Missouri, Stati Uniti, 63110
        • Reclutamento
        • Washington University School of Medicine
        • Investigatore principale:
          • Andrew Davis
        • Contatto:
    • Ohio
      • Columbus, Ohio, Stati Uniti, 43210
        • Reclutamento
        • Ohio State University Comprehensive Cancer Center
        • Contatto:
        • Investigatore principale:
          • Floor Backes
    • Pennsylvania
      • Pittsburgh, Pennsylvania, Stati Uniti, 15232
        • Reclutamento
        • UPMC Hillman Cancer Center
        • Contatto:
          • Site Public Contact
          • Numero di telefono: 412-647-8073
        • Investigatore principale:
          • Sarah E. Taylor
    • Texas
      • Houston, Texas, Stati Uniti, 77030
        • Reclutamento
        • UT MD Anderson Cancer Center
        • Contatto:
        • Investigatore principale:
          • Ecaterina E. Ileana Dumbrava
    • Wisconsin
      • Madison, Wisconsin, Stati Uniti, 53792
        • Reclutamento
        • University of Wisconsin Carbone Cancer Center - University Hospital
        • Investigatore principale:
          • Nataliya V. Uboha
        • Contatto:
      • Madison, Wisconsin, Stati Uniti, 53718
        • Reclutamento
        • University of Wisconsin Carbone Cancer Center - Eastpark Medical Center
        • Investigatore principale:
          • Nataliya V. Uboha
        • Contatto:

Criteri di partecipazione

I ricercatori cercano persone che corrispondano a una certa descrizione, chiamata criteri di ammissibilità. Alcuni esempi di questi criteri sono le condizioni generali di salute di una persona o trattamenti precedenti.

Criteri di ammissibilità

Età idonea allo studio

18 anni e precedenti (Adulto, Adulto più anziano)

Accetta volontari sani

No

Sessi ammissibili allo studio

Tutto

Descrizione

Inclusion Criteria:

  • Patients must have histologically confirmed malignancy that is metastatic or unresectable with participation in this clinical trial determined to be the best option for next treatment in the opinion of the investigator, and meet the following specific criteria:

    • Patients enrolling in Part 1 (Dose Escalation) may have a diagnosis of any solid tumor
    • Patients enrolling in the Part 2 Pharmacodynamic Cohort may have a diagnosis of any solid tumor except pancreas cancer (NOTE: pancreatic cancer excluded from this cohort after Revision 11 activation due to the addition of the pancreatic specific cohort)
    • Patients enrolling in the Part 2 Pancreatic Cohort must have a diagnosis of pancreatic adenocarcinoma (PDAC) and meet the HER2 positivity guidance

  • Patients must have a solid tumor with HER2-positivity as determined by any one or more of the following:

    • HER2 overexpression defined by immunohistochemistry (IHC) 3+

    • ERBB2 amplification by in situ hybridization (ISH) or next-generation sequencing as determined by any Clinical Laboratory Improvement Act (CLIA) certified lab

    • A known HER2 activating mutation

    • HER2 overexpression by IHC/ISH will follow histology specific American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines for breast and gastric cancers. HER2 overexpression by IHC/ISH for the Pancreatic Cohort will follow ASCO-CAP guidelines for gastric cancers. For tumor histologies without specific guidelines the following criteria will apply:

      • HER2 IHC should be performed first, followed by ISH methods in cases showing 2+ (equivocal) expression by IHC. Positive (IHC 3+) or negative (IHC 0 or 1+) do not require further ISH testing. Cases with HER2:CEP17 ratio ≥ 2 or an average HER2 copy number ≥ 6.0 signals per cell are considered positive by ISH

    • Known HER2 activating mutations:

      • G309A/E

      • S310F/Y

      • S653C

      • V659E

      • G660D

      • R678Q

      • E693K

      • Q709L

      • L755S/P

      • Del. 755-759

      • D769Y/H

      • G776V/C

      • V777L

      • V842I

      • T862A

      • L869R

      • H878Y

      • All exon 20 insertions, including:

        • A771_Y772insYVMA
        • A775_G776insYVMA
        • Y772_A775dup
        • P780_Y781insGSP
        • G778_P780dup

      • V697L

      • T733I

      • D769N

      • L841V

      • L866M

      • R896C

    • If a different mutation is identified, contact the study chair for conferral. Synonymous mutations are not eligible

  • Patients must have received at least 1 prior line of therapy in the advanced/metastatic setting. No limitation on number of prior therapies; however, patients may not have received neratinib or DS-8201a previously. Prior HER2-targeted therapy other than neratinib or DS-8201a is allowed (e.g., trastuzumab, pertuzumab, TDM-1, lapatinib, etc.)

  • Age >= 18 years. Because no dosing or adverse event data are currently available on the use of neratinib in combination with DS-8201a in patients < 18 years of age, children are excluded from this study

  • Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

  • Hemoglobin >= 9.0 g/dL (>= 8.0 g/dL for gastric cancer [GC] only) (within 14 days of enrollment)

    • No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment

  • Leukocytes >= 3.0 K/cumm (within 14 days of enrollment)

  • Absolute neutrophil count >= 1.5 K/cumm (within 14 days of enrollment)

    • No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment

  • Platelets >= 100 K/cumm (within 14 days of enrollment)

    • No transfusions with red blood cells or platelets are allowed within 1 week prior to screening assessment

  • Serum albumin >= 2.5 g/dL (within 14 days of enrollment)

  • Total bilirubin =< 1.5 × institutional upper limit of normal (ULN), (< 3 × ULN in the presence of documented Gilbert's syndrome or liver metastases at baseline) (within 14 days of enrollment)

  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN (if liver metastases are present =< 5 x ULN) (within 14 days of enrollment)

  • International normalized ratio (INR)/prothrombin time (PT) and activated partial thromboplastin time (aPTT) =< 1.5 x institutional ULN (within 14 days of enrollment)

    • This applies only to patients who are not receiving therapeutic anticoagulation that may affect INR. Those who are on therapeutic anticoagulation, should be on a stable dose for 4 weeks and should be considered within therapeutic range

  • Creatinine =< 1.5 x institutional ULN OR Glomerular filtration rate (GFR) >= 30 mL/min/1.73 m^2 (using the Cockcroft-Gault equation) (within 14 days of enrollment)

  • Patients who are human immunodeficiency virus (HIV)-positive may participate IF they meet the following eligibility requirements:

    • They must be stable on their anti-retroviral regimen, and they must be healthy from an HIV perspective

    • They must have a CD4 count of greater than 250 cells/mcL over the past 6 months on this same anti-retroviral regimen and must not have had a CD4 count < 200 cells/ul over the past 2 years, unless it was deemed related to THE CANCER AND/OR CHEMOTHERAPY-induced bone marrow suppression

      • For patients who have received chemotherapy in the past 6 months, a CD4 count < 250 cells/ul during chemotherapy is permitted as long as viral loads were undetectable during this same chemotherapy

    • They must have an undetectable viral load and a CD4 count >= 250 cells/uL within 7 days of enrollment

    • They must not be currently receiving prophylactic therapy for an opportunistic infection and must not have had an opportunistic infection within the past 6 months.

HIV-infected patients should be monitored every 12 weeks for viral load and CD4 counts

  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Patients with treated brain metastases are eligible if the following criteria are met: 1) follow-up brain imaging done at least in 4 weeks after central nervous system (CNS)-directed therapy shows no evidence of progression and 2) the patient no longer requires steroids, or is on a stable steroid dose > 4 weeks
  • Patients with radiographically new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible only if has no progressive clinical symptoms and if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy
  • Patients should be New York Heart Association functional classification of class 2B or better
  • Patients must have left ventricular ejection fraction (LVEF) >= 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before randomization/enrollment
  • Part 2, Pancreatic cohort ONLY: Patients must have disease that is measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
  • Part 2, PD cohort ONLY: Patients must have disease that is evaluable or measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • Part 2, PD cohort ONLY: Patients must have at least one lesion suitable for biopsy without significant risk to the patient. The biopsiable lesion can be the same as the evaluable lesion for response by RECIST 1.1
  • HER2 antibody conjugated to a topoisomerase 1 inhibitor agents as well as other therapeutic agents used in this trial are known to be teratogenic; thus, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for at least 1 month after the last dose of neratinib, or at least 7 months after the last dose of DS-8201a, whichever is longer (women of childbearing potential [WOCBP] only). Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after the last dose of neratinib, or 4 months after completion of DS-8021a administration, whichever is longer
  • Women of non-child-bearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L] is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods outlined for women of child-bearing potential if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method
  • Male subjects must not freeze or donate sperm starting at screening and throughout the study period, and at least 4 months after the final study drug administration. Preservation of sperm should be considered prior to enrollment in this study
  • Female subjects must not donate, or retrieve for their own use, ova from the time of screening and throughout the study treatment period, and for at least 7 months after the final study drug administration
  • Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity who have a legally-authorized representative (LAR) and/or family member available will also be eligible

Exclusion Criteria:

  • With the exception of medications that are under investigation in the study (e.g., standard of care, comparators, or combination therapies), the following medications, treatment, and procedures will be prohibited during the treatment period:

    • Other anticancer therapy, including small-molecule targeted agents within 2 weeks or five half-lives, whichever is longer; chemotherapy otherwise not specified (including, but not limited to cytotoxic chemotherapy, antibody drug conjugates, retinoid therapy, hormonal therapy) within 3 weeks; immunotherapy or monoclonal antibody within 4 weeks; and nitrosoureas or mitomycin C within 6 weeks (concurrent use of hormones for noncancer-related conditions [e.g., insulin for diabetes and hormone replacement therapy] is acceptable)
    • Other investigational therapeutic agents
    • Patients who have had major surgery or radiation within 4 weeks; palliative stereotactic radiation within 2 weeks (except for palliative radiation to known metastatic sites as long as it does not affect assessment of response or interrupt treatment for more than the maximum time specified in dose modification section)
    • Radiotherapy to the thorax (palliative radiation to known metastatic sites in the thoracic spine is permitted in this study)
    • Concomitant use of chronic systemic (IV or oral) corticosteroids or other immunosuppressive medications except for managing adverse events (inhaled steroids or intra-articular steroid injections are permitted in this study); chronic replacement dose steroids (e.g., for those with adrenal insufficiency) are permitted in this study
    • Subjects with bronchopulmonary disorders who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study
    • Concomitant treatment with chloroquine or hydroxychloroquine is not allowed during the study treatment due to concern for overlapping toxicities. If treatment with chloroquine and hydroxychloroquine treatment is absolutely required, study treatment must be interrupted. If chloroquine or hydroxychloroquine is administered, then a wash-out period of more than 14 days is required before restarting study treatment
    • Receipt of live, attenuated vaccine (messenger ribonucleic acid [mRNA] and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of study drug

  • Patients with a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening

  • Patients with clinically severe pulmonary compromise resulting from intercurrent pulmonary illnesses including, but not limited to, any underlying pulmonary disorder (i.e. pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with potential pulmonary involvement (i.e. rheumatoid arthritis, Sjogren's, sarcoidosis, etc.), or prior pneumonectomy

  • Patients with history of allergic reactions attributed to compounds of similar chemical or biologic composition to DS-8201a, the inactive ingredients in the drug product, or neratinib

  • Patients who have a history of severe hypersensitivity reactions to other monoclonal antibodies

  • Patients receiving any medications or substances that are moderate or strong inhibitors or inducers of CYP3A4 and P-glycoprotein are ineligible. Avoid concomitant use with proton pump inhibitors and P-glycoprotein substrates. Because the lists of these agents are constantly changing, it is important to regularly consult a frequently-updated medical reference. As part of the enrollment/informed consent procedures, the patient will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product

  • Patients with a medical history of myocardial infarction within 6 months before enrollment, or symptomatic congestive heart failure (CHF) (New York Heart Association class II to IV)

  • Patients with a corrected QT interval (QTc) prolongation to > 470 ms (females) or > 450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram (ECG)

  • Patients with clinically significant corneal disease in the opinion of the investigator

  • Patients with a pleural effusion, ascites, or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART). (Drainage and CART are not allowed within 2 weeks prior to screening assessment) (GC indication)

  • Patients with spinal cord compression

  • Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or antifungals

  • Patients with unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade =< 1 or baseline. Subjects with chronic grade 2 toxicities may be eligible per the discretion of the investigator after consultation with the sponsor medical monitor or designee (e.g., grade 2 chemotherapy-induced neuropathy)

  • Patients with substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may, in the opinion of the investigator, interfere with the subject's participation in the clinical study or evaluation of the clinical study results

  • Pregnant women are excluded from this study because DS-8201a is a HER2 antibody conjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with DS-8201a, breastfeeding should be discontinued if the mother is treated with DS-8201a. These potential risks may also apply to other agents used in this study

  • Prior treatment with neratinib or DS-8201a

  • Clinically significant chronic gastrointestinal disorder with diarrhea as a major symptom; grade 2 (G2) or greater diarrhea at baseline. Please contact the study principal investigator (PI) for any patient with more than two episodes of diarrhea per day averaged over at least a 7 day period at time of screening to determine whether the diarrhea would be considered clinically significant

  • Inability to swallow tablets

  • Patients with active additional malignancy or a personal history of additional malignancy that may affect outcome of disease under treatment (patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen at the discretion of the treating investigator are allowed)

  • Patients with prior allogeneic organ transplantation including allogeneic stem cell transplantation

Piano di studio

Questa sezione fornisce i dettagli del piano di studio, compreso il modo in cui lo studio è progettato e ciò che lo studio sta misurando.

Come è strutturato lo studio?

Dettagli di progettazione

  • Scopo principale: Trattamento
  • Assegnazione: N / A
  • Modello interventistico: Assegnazione di gruppo singolo
  • Mascheramento: Nessuno (etichetta aperta)

Armi e interventi

Gruppo di partecipanti / Arm
Intervento / Trattamento
Sperimentale: Treatment (neratinib, trastuzumab deruxtecan)

Patients receive neratinib PO QD on days 1-21 of each cycle (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD cohort) and trastuzumab deruxtecan IV over 30-90 minutes on day 1 of each cycle. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection, CT scan and echocardiography or MUGA scan throughout study. Additionally, patients may undergo a tissue biopsy at baseline if no archival sample available (dose-escalation cohort only), optionally at baseline (pancreatic cohort only), on study (PD cohort only), and optionally at disease progression (all cohorts).
Procedura: Biospecimen Collection

Undergo blood sample collection

Altri nomi:
  • Raccolta di campioni biologici
  • Biocampione raccolto
  • Raccolta di campioni
  • Raccolta campione
Procedura: Biopsy Procedure

Undergo biopsy

Altri nomi:
  • Bx
  • BIOPSY_TYPE
  • Biopsia
Procedura: Multigated Acquisition Scan

Undergo MUGA scan

Altri nomi:
  • Scansione della pozza di sangue
  • Angiografia con radionuclidi di equilibrio
  • Imaging del pool di sangue recintato
  • MUGA
  • Ventricolografia con radionuclidi
  • RNVG
  • Scansione SIMA
  • Scansione di acquisizione multigate sincronizzata
  • Scansione MUGA
  • Scansione di acquisizione multi-gate
  • Scansione del ventricologramma con radionuclidi
  • Scansione del pool cardiaco recintato
  • Scansione RNV
Procedura: Computed Tomography

Undergo CT scan

Altri nomi:
  • CT
  • GATTO
  • TAC
  • Tomografia assiale computerizzata
  • Tomografia computerizzata
  • tomografia
  • Tomografia assiale computerizzata (procedura)
  • Scansione tomografia computerizzata (CT).
  • Scansione CAT diagnostica
  • Tipo di servizio di scansione CAT diagnostica
Procedura: Echocardiography Test

Undergo echocardiography

Altri nomi:
  • Ecocardiografia
  • CE
Droga: Neratinib Maleate

Given PO

Altri nomi:
  • Nerlynx
  • 2-butenammide, N-(4-((3-cloro-4-(2-piridinilmetossi)fenil)ammino)-3-ciano-7-etossi-6-chinolinil)-4-(dimetilammino)-, (2E) -, (2Z)-2-butenedioato (1:1)
  • HKI-272 Maleato
  • NERATINIB MALEATO ANIDRO
Biologico: Trastuzumab Deruxtecan

Given IV

Altri nomi:
  • Enhertu
  • DS-8201a
  • T-DXd
  • DS-8201
  • Fam-trastuzumab Deruxtecan-nxki
  • OMS 10516

Cosa sta misurando lo studio?

Misure di risultato primarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Incidence of dose limiting toxicities (Part 1, Dose Escalation)
Lasso di tempo: In the first 2 cycles in dose escalation of combination of neratinib and trastuzumab deruxtecan (DS-8201a) (cycle length = 21 days)

Safety endpoints will be listed for each dose level.
In the first 2 cycles in dose escalation of combination of neratinib and trastuzumab deruxtecan (DS-8201a) (cycle length = 21 days)
Incidence of treatment-emergent adverse events (Part 1, Dose Escalation)
Lasso di tempo: In the first 2 cycles of combination of neratinib and DS-8201a (cycle length = 21 days)

Safety endpoints will be listed for each dose level and the tabulations of adverse events will also be produced by severity and by relationship to study drug.
In the first 2 cycles of combination of neratinib and DS-8201a (cycle length = 21 days)
Objective response rate (ORR) (Part 2, Pancreatic Cohort)
Lasso di tempo: Up to 1 year

ORR will be determined as the proportion of subjects with a confirmed partial response (PR) or complete response (CR). The ORR and 90% confidence intervals (CIs) will be constructed using the Clopper-Pearson method for ORR to form repeated CIs according to Jennison and Turnbull at the interim analysis and primary analysis, respectively. The nominal p-value from the exact binomial test will also be reported.
Up to 1 year

Misure di risultato secondarie

Misura del risultato
Misura Descrizione
Lasso di tempo
Incidence of adverse events
Lasso di tempo: Up to 1 year

Graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.
Up to 1 year
Objective response rate
Lasso di tempo: Up to 1 year

Defined as the percentage of patients who achieve CR or PR per Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1.
Up to 1 year
Duration of response (Pancreatic Expansion Cohort)
Lasso di tempo: Time from first documentation of response (CR or PR) until the time of first documentation of disease progression, assessed up to 1 year

By RECIST v 1.1. Summary statistics of DOR will be calculated for responders.
Time from first documentation of response (CR or PR) until the time of first documentation of disease progression, assessed up to 1 year
Progression free survival (Pancreatic Expansion Cohort)
Lasso di tempo: Time from first dose to the earlier date of assessment of progression or death by any cause in the absence of progression, assessed up to 1 year

By RECIST v 1.1. Described using Kaplan-Meier product limit methods.
Time from first dose to the earlier date of assessment of progression or death by any cause in the absence of progression, assessed up to 1 year
Overall survival (Pancreatic Expansion Cohort)
Lasso di tempo: From date of first dose to the date of death by any cause, assessed up to 1 year

Described using Kaplan-Meier product limit methods.
From date of first dose to the date of death by any cause, assessed up to 1 year
DXd (MAAA-1181a) tissue concentration (Pharmacodynamic [PD] Expansion Cohort)
Lasso di tempo: Up to 1 year

Summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point and the change will be compared by paired t-test or Wilcoxon rank-sum test as appropriate.
Up to 1 year
Pharmacokinetic (PK) profiles of DS-8201a and its metabolites (PD Expansion Cohort)
Lasso di tempo: Up to 1 year

PK will be analyzed using descriptive statistics. Analysis of variance (ANOVA) and regression model may be used to investigate any possible relationship of PK biomarker levels with anti-tumor efficacy. Endpoint data will be analyzed, reporting the mean, standard deviation, median, minimum, and maximum values.
Up to 1 year
PK profiles of neratinib and its metabolites (PD Expansion Cohort)
Lasso di tempo: Up to 1 year

PK will be analyzed using descriptive statistics. ANOVA and regression model may be used to investigate any possible relationship of PK biomarker levels with anti-tumor efficacy. Endpoint data will be analyzed, reporting the mean, standard deviation, median, minimum, and maximum values.
Up to 1 year

Altre misure di risultato

Misura del risultato
Misura Descrizione
Lasso di tempo
Circulating cell-free DNA (Dose Escalation and PD Cohorts)
Lasso di tempo: At pre-treatment, cycle 2 day 1, and at progression, assessed up to 1 year (cycle length = 21 days)
At pre-treatment, cycle 2 day 1, and at progression, assessed up to 1 year (cycle length = 21 days)
Deoxyribonucleic acid (DNA) damage
Lasso di tempo: Up to 1 year

Measured by gammaH2AX and pNBS1 and pKAP1 immunofluorescence assay at cycle 1 days 3-5 and cycle 2 days 3-5 biopsies. Other pharmacodynamic biomarkers include cleaved PARP, Caspase 3, p-HER2, downstream signaling. Summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point.
Up to 1 year
Quantitative HER2 protein
Lasso di tempo: At cycle 1 days 3-5 and cycle 2 days 3-5, and at progression, assessed up to 1 year (cycle length = 21 days)

Summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point.
At cycle 1 days 3-5 and cycle 2 days 3-5, and at progression, assessed up to 1 year (cycle length = 21 days)
Tumor mutation profile (Dose Escalation and PD Cohorts)
Lasso di tempo: Before treatment and at progression, assessed up to 1 year

As measured by whole exome sequencing. Summarized using descriptive statistics (means, median, and standard deviations) at each measurement time point.
Before treatment and at progression, assessed up to 1 year

Collaboratori e investigatori

Qui è dove troverai le persone e le organizzazioni coinvolte in questo studio.

Sponsor

National Cancer Institute (NCI)

Investigatori

  • Investigatore principale: Andrew Davis, Yale University Cancer Center LAO

Pubblicazioni e link utili

La persona responsabile dell'inserimento delle informazioni sullo studio fornisce volontariamente queste pubblicazioni. Questi possono riguardare qualsiasi cosa relativa allo studio.

Pubblicazioni generali

Studiare le date dei record

Queste date tengono traccia dell'avanzamento della registrazione dello studio e dell'invio dei risultati di sintesi a ClinicalTrials.gov. I record degli studi e i risultati riportati vengono esaminati dalla National Library of Medicine (NLM) per assicurarsi che soddisfino specifici standard di controllo della qualità prima di essere pubblicati sul sito Web pubblico.

Studia le date principali

Inizio studio (Effettivo)

5 ottobre 2022

Completamento primario (Stimato)

17 luglio 2028

Completamento dello studio (Stimato)

17 luglio 2028

Date di iscrizione allo studio

Primo inviato

12 maggio 2022

Primo inviato che soddisfa i criteri di controllo qualità

12 maggio 2022

Primo Inserito (Effettivo)

13 maggio 2022

Aggiornamenti dei record di studio

Ultimo aggiornamento pubblicato (Effettivo)

2 ottobre 2026

Ultimo aggiornamento inviato che soddisfa i criteri QC

1 ottobre 2026

Ultimo verificato

1 settembre 2026

Maggiori informazioni

Termini relativi a questo studio

Termini MeSH pertinenti aggiuntivi

Altri numeri di identificazione dello studio

  • NCI-2022-04099
  • UM1CA186689 (Sovvenzione/contratto NIH degli Stati Uniti)
  • NCI-2022-04099 (Identificatore di registro: CTRP (Clinical Trial Reporting Program))
  • 10495 (Altro identificatore: CTEP)
  • 202207020
  • 10495 (Altro identificatore: Yale University Cancer Center LAO)

Piano per i dati dei singoli partecipanti (IPD)

Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?

SÌ

Descrizione del piano IPD

"NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page."

Informazioni su farmaci e dispositivi, documenti di studio

Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti

Sì

Studia un dispositivo regolamentato dalla FDA degli Stati Uniti

No

prodotto fabbricato ed esportato dagli Stati Uniti

No

Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .

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