Testing the Safety and Tolerability of the Anti-cancer Drugs Trastuzumab Deruxtecan and Neratinib for Cancers With Changes in the HER2 Gene

Phase I Trial of DS-8201a (Trastuzumab Deruxtecan) in Combination With Neratinib in Solid Tumors With HER2 Alterations


Lead Sponsor: National Cancer Institute (NCI)

Source National Cancer Institute (NCI)
Brief Summary

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 to other parts of 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.

Detailed Description

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). 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 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 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 pharmacodynamic (PD) biomarkers such as cleaved caspase3 (apoptosis) and TOP1CC (target engagement) pending National Clinical Laboratory Network (NCLN) assay availability. 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, C2D1, and at progression in correlation with treatment response. OUTLINE: This is a dose-escalation study of neratinib followed by a dose-expansion (PD) study. Patients receive neratinib orally (PO) once daily (QD) on days 1-21 (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD study) of each cycle 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. After completion of study treatment, patients are followed up every 3 months for at least one year or until death.

Overall Status Not yet recruiting
Start Date 2022-06-20
Completion Date 2023-08-31
Primary Completion Date 2023-08-31
Phase Phase 1
Study Type Interventional
Primary Outcome
Measure Time Frame
Incidence of dose limiting toxicities In the first 42 days of combination of neratinib and trastuzumab deruxtecan (DS-8201a)
Incidence of treatment-emergent adverse events In the first 42 days of combination of neratinib and DS-8201a
Secondary Outcome
Measure Time Frame
Incidence of adverse events Up to 1 year
Objective response rate Up to 1 year
Duration of response 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 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 From date of first dose to the date of death by any cause, assessed up to 1 year
DXd (MAAA-1181a) tissue concentration Up to 1 year
Pharmacokinetic (PK) profiles of DS-8201a and its metabolites Up to 1 year
PK profiles of neratinib and its metabolites Up to 1 year
Enrollment 18

Intervention Type: Procedure

Intervention Name: Biopsy

Description: Correlative studies

Arm Group Label: Treatment (neratinib, trastuzumab deruxtecan)

Intervention Type: Drug

Intervention Name: Neratinib Maleate

Description: Given PO

Arm Group Label: Treatment (neratinib, trastuzumab deruxtecan)

Intervention Type: Biological

Intervention Name: Trastuzumab Deruxtecan

Description: Given IV

Arm Group Label: Treatment (neratinib, trastuzumab deruxtecan)



Inclusion Criteria: - Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective - Patients must have HER2-positive or HER2-overexpressing tumors as defined by Clinical Laboratory Improvement Act (CLIA)-certified laboratories (labs). Specific requirement of HER2 status is outlined below - Solid tumor with HER2 overexpression by immunohistochemistry (IHC) or amplification by in situ hybridization (ISH)/sequencing or activating mutation (see below) by sequencing from a CLIA certified lab (both local HER2 IHC and sequencing data required even if enrollment is based on one of the criteria) - HER2 overexpression by IHC/ISH will follow histology specific American Society of Clinical Oncology-College of American Pathologists (ASCO-CAP) guidelines for breast and 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 - L755S - L755P; T862A - Del. 755-759; D769Y/H; V842I - V777L - L869R - H878Y - G776V/C - All exon 20 insertions, including: - A771_Y772insYVMA - A775_G776insYVMA - P780_Y781insGSP - G660D, R678Q, E693K, and Q709L - V659E - G660D - V697L - T733I - I767M - D769N - Y772_A775dup - G778_P780dup - L841V - L866M - H878Y - R896C - If a different mutation is identified, contact the study chair for conferral - No limitation on number of prior therapies; however, 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 >= 3,000/mcL (within 14 days of enrollment) - Absolute neutrophil count >= 1,500/mcL (within 14 days of enrollment) - No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1 week prior to screening assessment - Platelets >= 100,000/mcL (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 - Dose expansion phase (PD cohort): Patients must have disease that is evaluable or measurable by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 - Dose expansion phase (PD cohort): 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 - Patients who had clinically significant side effects from prior cancer therapy must have recovered to grade 1 or below - 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. The sponsor must be notified if a subject receives any of these during the study: - 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 nitrosureas 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 - 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 mo



Minimum Age:

18 Years

Maximum Age:


Healthy Volunteers:


Overall Official
Last Name Role Affiliation
Haeseong Park Principal Investigator Yale University Cancer Center LAO
Overall Contact Contact information is only displayed when the study is recruiting subjects.
Verification Date


Responsible Party

Type: Sponsor

Has Expanded Access No
Condition Browse
Number Of Arms 1
Arm Group

Label: Treatment (neratinib, trastuzumab deruxtecan)

Type: Experimental

Description: Patients receive neratinib PO QD on days 1-21 (days 8-21 of cycle 1, then days 1-21 in cycles thereafter for PD study) of each cycle 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.

Patient Data Yes
Study Design Info

Allocation: N/A

Intervention Model: Single Group Assignment

Primary Purpose: Treatment

Masking: None (Open Label)

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