| Eligibility |
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
- Patients must have a solid tumor with HER2-positivity as determined by any one or more
of the following:
- HER2 overexpression defined by IHC 3+
- ERBB2 amplification by ISH or next-generation sequencing as determined by any
CLIA certified lab
- A known HER2 activating mutation
- HER2 overexpression by IHC/ISH will follow histology specific 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
- 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
- Serum albumin >= 2.5 g/dL (within 14 days of enrollment)
- 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
- 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 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; G2 or greater diarrhea at baseline. Please contact the study 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
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