Trastuzumab Deruxtecan Before Surgery for the Treatment of Patients with Brain Cancer, WONDER-BT Trial
This phase II trial tests how well trastuzumab deruxtecan (T-DXd) works in treating patients with HER2-expressing/mutant brain cancer or cancer that has spread from where it first started (primary site) to other places in the body (metastatic). Trastuzumab deruxtecan is a monoclonal antibody called trastuzumab, linked to a chemotherapy drug called deruxtecan. Trastuzumab is a form of targeted therapy because it attaches to specific molecules (receptors) on the surface of cancer cells, known as HER2 receptors and delivers deruxtecan to kill them. Researchers want to find out if T-DXd, may help patients with HER2-expressing brain cancer because the drug targets different parts of tumor cells to slow or stop the growth. This study may find out how much T-DXd can get into the tumor (penetrates the tumor) when injected into the body, and whether T-DXd may be an effective treatment for brain cancers that express the HER2 protein.
Inclusion Criteria
- Adult patients >= 18 years of age with one or more brain tumors planned for neurosurgical resection/biopsy
- Pathologically-documented glioblastoma; or
- Metastatic cancer that: * Has a history of Her2 expression or activating Her2-mutation ** Her2+ defined as 3+ on IHC ** Her2-low defined as IHC1+ or 2+ and ISH- according to American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) 2018 Her2 testing guidelines ** Her2 mutations must be described to be activating, occur at a known hotspot (e.g. exon 20 insertions, S310, G660, R678, L755, D769, L777), or involve the transmembrane, juxtamembrane or tyrosine kinase domains ** Other untreated brain tumors (and prior radiation, including whole-brain and/or stereotactic radiation) are allowed ** Patients with concomitant leptomeningeal metastasis are eligible provided they have parenchymal brain neoplastic disease requiring resection/biopsy
- Prior treatments: * Cohort A: Brain parenchymal metastases in patients with Her2-expressing/ERBB2- activating-mutant cancer with no prior T-DXd exposure (T-DXd naïve) * Cohort B: Brain parenchymal metastases in patients with Her2-expressing/ERBB2- activating-mutant cancer with prior T-DXd exposure * Cohort C: Recurrent glioblastoma * For all cohorts: no limit on prior CNS radiation or systemic therapy, including Her2- targeting antibody therapy (including trastuzumab, pertuzumab, trastuzumab emtansine)
- Karnofsky performance scale >= 60 or Eastern Cooperative Oncology Group (ECOG) < 2
- Life expectancy > 12 weeks
- Left ventricular ejection fraction >= 50%
- Absolute neutrophil count (ANC) >= 1.5 x 10^3/uL (granulocyte-colony stimulating factor administration is not allowed within 1 week prior to cycle 1 day 1 [C1D1]) (obtained >= 7 days prior to the first day of study treatment)
- Platelet count >= 10.0 x 10^4/uL. Note: Participants requiring ongoing transfusions or growth factor support to maintain platelet count >= 10.0 x 10^4/uL are not eligible. (Platelet transfusion is not allowed within 1 week prior to C1D1) (obtained >= 7 days prior to the first day of study treatment)
- Hemoglobin >= 8.0 g/dL. Note: Participants requiring ongoing transfusions or growth factor support to maintain hemoglobin >= 8.0 g/dL are not eligible (> 8 g/dL in gastric cancer / gastroesophageal cancer indications). (Red blood cell transfusion is not allowed within 1 week prior to C1D1) (obtained >= 7 days prior to the first day of study treatment)
- Serum albumin >= 2.5 g/dL (obtained >= 7 days prior to the first day of study treatment)
- Creatinine clearance >= 30 mL/min, as calculated using the Cockcroft-Gault equation (obtained >= 7 days prior to the first day of study treatment)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x upper limit of normal (ULN) (< 5x ULN in participants with liver metastases) (obtained >= 7 days prior to the first day of study treatment)
- Total bilirubin >= 1.5 x ULN) if no liver metastases or < 3 x ULN in the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia) or liver metastases at baseline (obtained > 7 days prior to the first day of study treatment)
- International normalized ratio (INR) and activated partial thromboplastin time (aPTT) =< 1.0 x ULN unless on medication known to reversibly alter INR and/or aPTT (obtained >= 7 days prior to the first day of study treatment)
- Evidence of post-menopausal status or negative serum pregnancy test for females of childbearing potential who are sexually active with a non-sterilized male partner. For women of childbearing potential, a negative result for serum pregnancy test (test must have a sensitivity of at least 25 mIU/mL) must be available within 7 days of the screening visit and urine beta-human chorionic gonadotropin (beta-human chorionic gonadotropi [HCG]) pregnancy test prior to each administration of T-DXd
- Women of childbearing potential are defined as those who are not surgically sterile (i.e. underwent bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy). Women will be considered post-menopausal if they have been amenorrheic for 12 months without an alternative medical cause
- Female patients of childbearing potential who are sexually active with a non-sterilized male partner must use at least one highly effective method of contraception, presented in Table 1 from the time of screening and must agree to continue using such precautions for 7 months after the last dose of T-DXd. Note: estrogen/progesterone is contraindicated in ER+ breast cancer, and in other cancers could increase the risk of deep vein thrombosis (DVT). Female patients must refrain from breastfeeding while on study and for 7 months after the last dose of T-DXd
- Non-sterilized male patients who are sexually active with a female partner of childbearing potential must use a condom with spermicide from screening to 4 months after the final dose of T-DXd. Complete heterosexual abstinence for the drug washout period is an acceptable contraceptive method if it is in line with the patient's usual lifestyle (consideration must be made to the duration of the clinical trial); however, periodic or occasional abstinence, the rhythm method, and the withdrawal method are not acceptable. It is strongly recommended for the female partners of a male patient to also use .1 highly effective method of contraception throughout this period. In addition, male patients should refrain from fathering a child, or freezing or donating sperm from the time of enrollment until 4 months after the last dose of T-DXd; sperm preservation 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 enrollment through at least 7 months after the final study drug administration. Preservation of ova may be considered prior to enrollment in this study
- Adequate treatment washout period from prior therapies to allow recovery from any prior treatment-related toxicities before enrollment in the judgment of the investigator
Exclusion Criteria
- Contraindication or history of allergic reaction to T-DXd
- Significant comorbidities as per investigator evaluation
- Inability to comply with protocol and/or unwilling or not available for follow up assessments or any condition which in the investigator’s opinion makes the patient unsuitable for study participation
- Ferrous or other contraindication to MR imaging
- History of myocardial infarction within 6 months before enrollment
- History of symptomatic congestive heart failure (New York Heart Association Class II to IV)
- Corrected QT interval (QTc) prolongation to > 470 ms (females) or > 450 ms (male) based on 12- lead electrocardiogram (ECG)
- Subjects with troponin levels above ULN at screening (as defined by the manufacturer), and without any myocardial related symptoms, should have a cardiologic consultation before enrollment to rule out myocardial infarction (MI)
- History of (noninfectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis can not be ruled out by baseline chest CT at screening
- Lung criteria: * Lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder (e.g. pulmonary emboli within three months of the study enrollment, severe asthma, severe chronic obstructive pulmonary disease (COPD), restrictive lung disease, pleural effusion etc.) * Any autoimmune, connective tissue or inflammatory disorders (e.g. rheumatoid arthritis, Sjogren's, sarcoidosis etc.) where there is documented, or a suspicion of pulmonary involvement at the time of screening * Prior pneumonectomy (complete)
- Uncontrolled infection requiring IV antibiotics, antivirals, or antifungals
- Active primary immunodeficiency, known human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA)
- Receipt of live, attenuated vaccine (mRNA and replication deficient adenoviral vaccines are not considered attenuated live vaccines) within 30 days prior to the first dose of trastuzumab deruxtecan. Note: Patients, if enrolled, should not receive live vaccine during the study and up to 30 days after the last dose of T-DXd
- Has unresolved toxicities from previous anticancer therapy, defined as toxicities (other than alopecia) not yet resolved to grade =< 1 or baseline. Note: Subjects may be enrolled with chronic, stable grade 2 toxicities (defined as no worsening to > grade 2 for at least 3 months prior to [randomization/enrollment/cycle 1 day 1] and managed with standard of care treatment) that the investigator deems related to previous anticancer therapy, such as: * Chemotherapy-induced neuropathy * Fatigue * Residual toxicities from prior IO treatment: grade 1 or grade 2 endocrinopathies which may include: ** Hypothyroidism/hyperthyroidism ** Type 1 diabetes **. Hyperglycemia ** Adrenal insufficiency ** Adrenalitis ** Skin hypopigmentation (vitiligo)
- Known allergy or hypersensitivity to study treatment or any of the study drug excipients. For patients who are allergic to gadolinium-based agents may receive premedication as per institutional protocol or imaged without contrast at the discretion of the principal investigator; reactions will be managed per standard institutional protocol
- History of severe hypersensitivity reactions to other monoclonal antibodies
- Pregnant or breastfeeding female patients, or patients who are planning to become pregnant
- 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
- Multiple primary malignancies within 3 years, with the exception of: * Adequately resected non-melanoma skin cancer * Carcinoma in situ of the cervix * Smoldering pre-malignant or malignant conditions with minimal concern for CNS or extracranial progression during treatment such as chronic lymphocytic leukemia (CLL) or monoclonal gammopathy of unknown significance (MGUS) based on the assessment of the treating provider * Curatively treated in-situ disease * Other solid tumors curatively treated * Contralateral breast cancer (patients with metastatic breast cancer)
- A pleural effusion, ascites or pericardial effusion that requires drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy (CART)
Additional locations may be listed on ClinicalTrials.gov for NCT06058988.
Locations matching your search criteria
United States
New Jersey
Basking Ridge
Middletown
Montvale
New York
Commack
New York
Uniondale
West Harrison
PRIMARY OBJECTIVE:
I. To evaluate the brain tumor penetration of trastuzumab deruxtecan (T-DXd) and its payload (DXd) in Her2+/Her2-low/Her2-mutant brain metastases and of Her2-expressing glioblastoma.
EXPLORATORY OBJECTIVES:
I. To explore correlations between Her2 expression and drug penetration.
II. To describe the rates of surgical site progression, untreated-site, and de novo central nervous system (CNS) parenchymal progression, leptomeningeal carcinomatosis development, and overall survival (OS) in patients who are treated with a single dose and those who remain on the drug.
III. To explore correlations between preoperative 89Zr-trastuzumab positivity on positron emission tomography (PET) and tissue drug penetration and autoradiography.
IV. To describe extracranial overall response rate (ORR), progression-free survival (PFS), duration of response (DoR), and disease control rate (DCR) for patients with brain metastases treated in this study.
V. To explore correlations of plasma and cerebrospinal fluid (CSF)-derived cell free deoxyribonucleic acid (cfDNA) genomic profiles with those of resected/biopsied tumors for patients treated in this study.
VI. To spatially describe Her2 expression and IgG1 (an ADC surrogate) distribution via immunohistochemistry.
VII. To explore correlations between intra-metastasis drug levels and surrogates of cytotoxicity (e.g. cleaved PARP).
VIII. To describe resistance mechanisms to trastuzumab-based antibody binding (in resected/biopsied brain tumors and any available primary/untreated metastases accumulation of cleaved, constitutively active p95 Her2 via WB using pTyr1248 Her2-directed antibody; and over expression of CD44 and MUC4, which have been implicated as epitope masks to trastuzumab).
IX. To examine the immune microenvironment of TDXd-exposed brain metastases as compared to available primary and untreated brain metastasis controls using multiplexed immunohistochemistry and/or single-cell sequencing.
X. To evaluate efflux pump expression (P-glycoprotein, MRP1, BCRP) in resected/biopsied metastasis brain tumor endothelium using immunohistochemistry.
XII. To evaluate the correlation of ex vivo labeled T-DXd uptake in dissociated brain tumors with drug levels in resected/biopsied metastases.
OUTLINE: Patients are assigned to 1 of 3 groups.
GROUP I: Patients with brain metastases who have never received T-DXd receive T-DXd intravenously (IV) between days -5 to -1, and undergo standard of care (SOC) resection on study. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may optionally receive 89Zr-trastuzumab IV and undergo PET prior to T-DXd infusion. Patients undergo an echocardiography (ECHO) or multigated acquisition (MUGA) scan and computed tomography (CT) or magnetic resonance imaging (MRI) during screening and on study. Patients also undergo blood sample collection and tissue biopsy and may undergo lumbar puncture (LP) for cerebrospinal fluid (CSF) sample collection on the trial.
GROUP II: Patients with brain metastases whose disease has gotten worse (progressed) while receiving T-DXd receive T-DXd IV between days -5 to -1, and undergo SOC resection on study. Patients may optionally receive 89Zr-trastuzumab IV and undergo PET prior to T-DXd infusion. Patients undergo an ECHO or MUGA scan during screening. Patients also undergo blood sample collection and tissue biopsy and may undergo LP for CSF sample collection on the trial. Additionally, patient undergo MRI throughout the trial.
GROUP III: Patients with glioblastoma receive T-DXd IV between days -5 to -1, and undergo SOC resection on study. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients may optionally receive 89Zr-trastuzumab IV and undergo PET prior to T-DXd infusion. Patients undergo an ECHO or MUGA scan during screening and on study. Patients also undergo blood sample collection and tissue biopsy and may undergo LP for CSF sample collection on the trial. Additionally, patient undergo MRI throughout the trial.
After completion of study treatment, patients are followed up at least every 3 months the first year and then at least every 6 months the second year.
Trial PhasePhase II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorNelson Moss
- Primary ID22-208
- Secondary IDsNCI-2023-08419
- ClinicalTrials.gov IDNCT06058988