PRIMARY OBJECTIVE:
I. To assess the effects of trastuzumab deruxtecan (DS-8201a) on total Top1 levels in biopsy
specimens from patients with HER2-expressing advanced solid tumors, at early and late
post-treatment time points, thereby establishing the degree and duration of DS-8201 target
engagement.
SECONDARY OBJECTIVES:
I. To assess any associations between serum concentrations of DS-8201a and the effects of
DS-8201a on total Top1 levels in tumor biopsy specimens.
II. To determine the safety and tolerability of DS-8201a administered intravenously every 3
weeks, in 21-day cycles, at a dose of 5.4 mg/kg.
III. To determine the overall response rate (complete response [CR] + partial response [PR])
for patients administered intravenously with DS-8201a every 3 weeks, in 21-day cycles, at a
dose of 5.4 mg/kg.
EXPLORATORY OBJECTIVES:
I. To evaluate the effects of DS-8201a on CD8+ T cell infiltration and activation in tumor,
tumor PD-L1 and HER2 expression, and DDR signaling (gamma H2AX, RAD51, and phosphorylated
[p]NBS1) in biopsy specimens.
II. To examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated
with DS-8201a response or resistance.
III. To examine any associations between baseline tumor HER2 amplification or HER2 expression
level and response to DS-8201a.
IV. To evaluate the effects of DS-8201a on tumor levels of HER2 and DDR-associated proteins.
V. To examine any tumor genomic alterations that may be associated with resistance to
DS-8201a.
VI. To evaluate anti-drug antibodies following administration of DS-8201a.
OUTLINE:
Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1.
Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 40 days.
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 measurable or evaluable disease
- Patients must have HER2-positive or HER2-expressing tumors as defined by Clinical
Laboratory Improvement Act (CLIA)-certified labs. Patients must have either:
- A tumor HER2 immunohistochemistry (IHC) score of 1+ or greater (as determined by
a CLIA-certified IHC test, per criteria specified) or
- A tumor with HER2 amplification (as determined by CLIA-certified in situ
hybridization (ISH) or a CLIA-certified next-generation sequencing assay)
- Patients with HER2 mutations are eligible, as are patients with HER2-positive breast
cancer
- Patients must have Eastern Cooperative Oncology Group (ECOG) performance status =< 1
(Karnofsky >= 70%)
- Absolute neutrophil count >= 1,500/mcL (within 8 days of enrollment)
- Platelets >= 100,000/mcL (within 8 days of enrollment)
- Leukocytes >= 3,000/mcL (within 8 days of enrollment)
- Hemoglobin >= 9 g/dL (>= 8.0 g/dL for gastric cancer [GC] only) (within 8 days of
enrollment)
- Serum albumin >= 2.5 g/dL (GC only) (within 8 days of enrollment)
- Total bilirubin =< 1.5 x institutional upper limit of normal (=< 3 x upper limit of
normal in the presence of documented Gilbert's syndrome or liver metastases at
baseline) (within 8 days of enrollment)
- Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 3 x institutional upper limit of normal OR =< 5 x institutional upper limit of
normal for patients with liver metastases at baseline (within 8 days of enrollment)
- Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional normal
(within 8 days of enrollment)
- No transfusions with red blood cells or platelets are allowed within 1 week prior to
screening assessment
- No administration of granulocyte colony-stimulating factor (G-CSF) is allowed within 1
week prior to screening assessment
- International normalized ratio (INR)/prothrombin time (PT) and either partial
thromboplastin or activated partial thromboplastin time (aPTT) =< 1.5 x upper limit of
normal (ULN)
- Ability to understand and the willingness to sign a written informed consent document
- Willingness to provide blood samples for research purposes
- Patients must have a lesion or lesions amenable to biopsy and must be willing to
undergo 3 core needle biopsy procedures for research purposes
- Patients must have left ventricular ejection fraction (LVEF) >= 50% by either an
echocardiogram (ECHO), multigated acquisition (MUGA), or cardiac magnetic resonance
imaging (MRI) scan within 28 days prior to 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
immunotherapy-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
8 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 follow-up brain imaging after
central nervous system (CNS)-directed therapy shows no evidence of progression for >=
1 month after treatment of the brain metastases
- 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 are eligible for this trial
- The effects of DS-8201a on the developing human fetus are unknown. For this reason and
because HER2 antibodies conjugated to topoisomerase 1 inhibitor agents are known to be
teratogenic, women of child-bearing potential and men must agree to use adequate
contraception (hormonal or barrier method of birth control or abstinence) prior to
study entry and for the duration of study participation and for at least 7 months
after the last dose of study drug. 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 4 months after completion of DS-8201a administration
- 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
- Subjects must not freeze, donate, or retrieve for their own use ova or sperm starting
at screening, throughout the study period, and for at least 4.5 months after the final
study drug administration. Preservation of sperm or ova should be considered prior to
enrollment in this study
- 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
Exclusion Criteria:
- Patients who have had:
- Chemotherapy (including antibody drug therapy, retinoid therapy, hormonal therapy
for cancer) within:
- 4 weeks or five half-lives, whichever is shorter, for small-molecule
targeted agents such as 5-fluorouracil-based agents, folinate agents, weekly
paclitaxel or
- 6 weeks for nitrosoureas or mitomycin C or
- Immunotherapy, including monoclonal antibody therapy, within 4 weeks
- Patients with any of the following pulmonary-related illnesses:
- A history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that
required steroids, current ILD/pneumonitis, or for whom suspected ILD/pneumonitis
cannot be ruled out by imaging at screening
- 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] grade 3-4 per Global
Initiative for Obstructive Lung Disease [GOLD] criteria, 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 who have had radiation therapy within 4 weeks (or palliative stereotactic
radiation therapy within 2 weeks)
- Patients who have had a major surgery within 4 weeks
- Patients who are receiving any other investigational agents
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to DS-8201a (e.g., other topoisomerase I inhibitors) or the inactive
ingredients in the drug product
- Patients who have a history of severe hypersensitivity reactions to other monoclonal
antibodies
- Patients with a medical history of myocardial infarction within 6 months before
enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association
class II to IV), or with troponin levels consistent with myocardial infarction (as
defined according to the assay manufacturer) 28 days prior to enrollment
- Patients with a Fridericia's formula-corrected QT interval (QTcF) prolongation to >
470 ms (females) or > 450 ms (males) based on average of the screening triplicate
12-lead electrocardiogram (ECG)
- Patients with spinal cord compression or clinically active central nervous system
metastases, defined as untreated and symptomatic, or requiring therapy with
corticosteroids or anticonvulsants to control associated symptoms
- 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 (e.g., grade 2 chemotherapy-induced neuropathy) may be
eligible per the discretion of the investigator after consultation with the sponsor
medical monitor or designee. Subjects should no longer be symptomatic nor require
treatment with corticosteroids or anticonvulsants and must have recovered from the
acute toxic effect of radiotherapy
- Patients with substance abuse or any other medical conditions that would increase the
safety risk to the subject or interfere with participation of the subject or
evaluation of the clinical study in the opinion of the investigator
- Patients with uncontrolled intercurrent illness
- Patients with psychiatric illness/social situations that would limit compliance with
study requirements
- 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
- Patients are not allowed to receive chloroquine/hydroxychloroquine. Patients receiving
chloroquine/hydroxychloroquine require a washout of > 14 days
