| Eligibility |
Inclusion Criteria:
1. Provision of fully informed consent prior to any study specific procedures.
2. Patients must be = 19 years of age
3. Has a pathologically documented advanced or metastatic adenocarcinoma of gastric or
gastroesophageal junction with at least one measurable lesion according to the
modified RECIST 1.1 are eligible
4. HER2-low (HER2 1+, HER2 2+ (SISH negative))
5. Patients are willing and able to comply with the protocol for the duration of the
study including undergoing treatment and scheduled visits and examinations.
6. ECOG performance status 0-1 with no deterioration between screening and the first dose
of study treatment.
7. Patients must have a life expectancy = 3 months from proposed first dose date.
8. Patients must have had a washout period of 2 weeks for any prior therapy prior to the
start of study drug. The following intervals between the end of the prior treatment
and first dose of study drug must be observed:
- Major surgery = 4 weeks
- Radiation Therapy including palliative stereotactic radiation therapy to chest =
4 weeks
- Palliative stereotactic radiation therapy to other anatomic areas including whole
brain radiation = 2 weeks
- Anti-Cancer chemotherapy [Immunotherapy (non-antibody based therapy)], retinoid
therapy, hormonal therapy = 3 weeks
- Antibody based anti-cancer therapy = 4 weeks
- Targeted agents and small molecules = 2 weeks or 5 half-lives, whichever is
longer
- Nitrosoureas or mitomycin C = 6 weeks
- TKIs approved for treatment of NSCLC =1 week (baseline CT scan must be completed
after discontinuation of TKI
- Chloroquine/Hydroxychloroquine = 14 days
- Cell-free and CART, peritoneal shunt or drainage of pleural effusion, ascites or
pericardial effusion = 2 weeks prior to screening assessment
9. Patients must have acceptable bone marrow, liver and renal function measured within 28
days prior to administration of study treatment as defined below:
- Hemoglobin =8.0 g/dL (Red blood cell transfusion is not allowed within 1 week
prior to the day)
- Absolute neutrophil count (ANC) = 1.5 x 109/L (G-CSF administration is not
allowed within 2 weeks prior to the day)
- Platelet count =100 x 109/L (Platelet transfusion is not allowed within 1 week
prior to the day)
- Total bilirubin = 1.5 x institutional upper limit of normal (ULN) or < 3×ULN in
the presence of documented Gilbert's syndrome (unconjugated hyperbilirubinemia)
or liver metastases at baseline
- AST (SGOT)/ALT (SGPT) = 2.5 x institutional upper limit of normal unless liver
metastases are present in which case it must be = 5x ULN
- Serum creatinine =1.5 x institutional ULN
- CrCl 30=mL/min as determined by Cockcroft Gault (using actual body weight)
- Serum albumin = 2.5 g/dL
- International normalised ratio or Prothrombin time and either partial
thromboplastin or activated partial thromboplastin time = 1.5 × ULN
10. Female patients must be using a highly effective method of contraception (refer to the
restrictions on P37) during the clinical trial and for 7 months after permanent
discontinuation of the study drug. There must be evidence that patients are not
breastfeeding, have a negative pregnancy test, or not of childbearing potential by
meeting one of the following criteria at screening:
1. Post-menopausal women defined as aged more than 50 years and amenorrhoeic for at
least 12 months following cessation of all exogenous hormonal treatment.
2. Documentation of irreversible surgical sterilisation by hysterectomy, bilateral
oophorectomy, or bilateral salpingectomy, but not tubal ligation.
3. Amenorrhoeic for 12 months and serum follicle-stimulating hormone (FSH),
lutenizing hormone (LH) and plasma oestradiol levels in the postmenopausal range
for the institution More detailed information is provided in Appendix F
(Definition and accepted contraception for women of childbearing age).
11. 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 IMP. Complete heterosexual abstinence for the duration of the
study and 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 at least one 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
randomisation/enrolment, throughout the study and for 4 months after the last dose of
IMP. Preservation of sperm should be considered prior to enrollment in this study.
12. Mandatory biopsy during the screening window prior to dosing and at progression
Exclusion Criteria:
1. Medical history of myocardial infarction within 6 months before registration,
symptomatic congestive heart failure (CHF) (New York Heart Association Class II to IV,
Section 17.4), troponin levels consistent with myocardial infarction as defined
according to American College of Cardiology (ACC) guidelines, unstable angina, or
serious cardiac arrhythmia requiring treatment.
2. History of (non-infectious) ILD / pneumonitis that required steroids, has current
ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at
screening.
3. Has 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)
4. Has uncontrolled infection requiring IV injection of antibiotics, antivirals, or
antifungals.
5. Active hepatitis B or C infection, such as those with serologic evidence of viral
infection within 28 days of Cycle 1 Day 1. Subjects with past or resolved hepatitis B
virus (HBV) infection who are anti-HBc positive (+) are eligible only if they are
HBsAg negative (-). Patients positive for hepatitis C (HCV) antibody are eligible only
if polymerase chain reaction is negative for HCV RNA.
6. Has clinically active brain metastases, defined as untreated and symptomatic, or
requiring therapy with steroids or anticonvulsants to control associated symptoms.
Subjects with treated brain metastases that are no longer symptomatic and who do not
require treatment with steroids for at least three weeks may be included in the study
if they have recovered from the acute toxic effect of radiotherapy. A minimum of 2
weeks must have elapsed between the end of whole brain radiotherapy and study
enrollment/randomization.
7. Has clinically significant corneal disease in the opinion of the investigator.
8. Prior treatment with an ADC which consists of an exatecan derivative that is a
topoisomerase I inhibitor.
Has unresolved toxicities from previous anticancer therapy, defined as toxicities
(other than chronic toxicities per the discretion of the investigator, eg, alopecia,
peripheral neuropathy, proteinuria, controllable hypertension, and controllable
diabetes) not yet resolved to National Cancer Institute's Common Terminology Criteria
for Adverse Events (NCI-CTCAE) version 5.0, Grade =1 or baseline. 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:
1. Hypothyroidism/hyperthyroidism
2. Type 1 diabetes
3. Hyperglycaemia
4. Adrenal insufficiency
5. Adrenalitis
6. Skin hypopigmentation (vitiligo)
9. Any gastrointestinal condition that would preclude adequate absorption of afatinib
including but not limited to inability to swallow oral medication, refractory nausea
and vomiting, chronic gastrointestinal diseases or previous significant bowel
resection, intestinal obstruction or CTCAE grade 3 or grade 4 upper GI bleeding within
4 weeks before the enrollment.
10. Active or prior documented autoimmune or inflammatory disorders (including IBD [e.g.
Chohn's disease, ulcerative colitis or diverticulitis], SLE, sarcoidosis syndrome,
tuberculosis, Wegener syndrome, myasthenia gravis, Graves' disease, rheumatoid
arthritis, hypophysitis, uveitis, at screening. Adjust wording as necessary and
consider evaluating at screening for studies with known hepatotoxicity or other
relevant requirements, history of organ transplant that requires use of
immunosuppressives, glomerulonephritis, nephritic syndrome, Fanconi Syndrome or renal
tubular acidosis within the past 2 years prior to the start of treatment. The
following are exceptions to this criterion:
- Subjects with vitiligo or alopecia, hypothyroidism (eg, following Hashimoto
syndrome) stable on hormone replacement or psoriasis not requiring systemic
treatment; patients with coeliac disease controlled by diet alone and patients
without active disease in the last 5 years may be included after consultation
with Chief Investigator.
- HbsAg carrier without active viral infection and under entecavir prophylaxis will
be allowed.
11. Known to have tested positive for human immunodeficiency virus (HIV) (positive HIV 1/2
antibodies) or active tuberculosis infection (clinical evaluation that may include
clinical history, physical examination and radiographic findings, or tuberculosis
testing in line with local practice). Active or prior documented history of primary
immunodeficiency or HIV infection, at screening.
12. Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or
cord compression. Note: Subjects previously treated for CNS metastases that are
asymptomatic, radiographically and neurologically stable for at least 4 weeks and do
not require corticosteroids (of any dose) for symptomatic management for at least 4
weeks prior to the first dose of treatment are not excluded.
13. Patients with second primary cancer, except: adequately treated non-melanoma skin
cancer, curatively treated in-situ cancer of the cervix, or other solid tumors
curatively treated with no evidence of disease for =3 years.
14. Patient was in receipt of any live attenuated vaccination within 30 days prior to
study entry or within 30 days of receiving study therapy.
15. Patients currently receiving (or unable to stop use at least 2 weeks) prior to
receiving the first dose of afatinib, medications known to be potent inhibitors of
CYP1A2 or strong inducers of CYP3A4 with a narrow therapeutic range
16. Patient with any of the following cardiac criteria:
- Mean QT interval corrected for heart rate (QTc) = 470 ms calculated from
electrogram (ECG) using Friderecia's correction
- Any clinicallly important abnormalities in rhythm, conduction or morphology of
resting ECG e.g. complete left bundle branch block, third degree heart block,
second degree heart block, PR Interval >250 msec.
- Any factors that increase the risk of QTc prolongation or risk of arrhythmic
events such as heart failure, uncorrectable chronic hypokalaemia, congenital long
QT syndrome, family history (first-degree relatives) of long QT syndrome or
unexplained sudden death under 40 years of age or concomitant medication known to
prolong the QT interval
- Uncontrolled hypotension: systolic BP < 90 mmHg and/or diastolic BP 60 mmHg or
clinically relevant orthostatic hypotension, including a fall in blood pressure
of > 20 mmHg
- Atrial fibrillation with a ventricular rate >100 bpm on ECG at rest
- Symptomatic heart failure (NYHA grade II-IV)
- Known reduced LVEF < 55%
- Prior or current cardiomyopathy
- Prior or current acute myocardial infarction
- Severe valvular heart disease
- Uncontrolled angina (Canadian Cardiovascular Society grade II-IV despite medical
therapy)
- Stroke or transient ischaemic attack in prior to screening
- Acute coronary syndrome within 6 months prior to starting treatment
17. Any evidence of severe or uncontrolled systemic disease, including active infection
(requiring antibiotics, antifungals or antivirals), diabetes type I and II,
uncontrolled seizures, bleeding diatheses, severe COPD, severe Parkinson's disease.
18. Any unresolved toxicity NCI CTCAE Grade =2 from previous anticancer therapy with the
exception of alopecia, vitiligo, Major surgical procedure (as defined by the
Investigator) within 28 days prior to the first dose of IP. Note: Local surgery of
isolated lesions for palliative intent is acceptable.
For unresolved toxicity, A.Patients with Grade =2 neuropathy will be evaluated on a
case-by-case basis after consultation with the PI.
B.Patients with irreversible toxicity not reasonably expected to be exacerbated by
treatment with Trastuzumab deruxtecan may be included only after consultation with the
PI
19. Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
situations that would limit compliance with study requirement, substantially increase
risk of incurring AEs or compromise the ability of the patient to give written
informed consent
20. History of active primary immunodeficiency
21. Female patients who are pregnant or breastfeeding or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 7 months after the last dose of Trastuzumab deruxtecan and Afatinib.
22. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.
23. History of allogenic organ transplantation.
24. 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 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. Full details of the disorder
should be recorded in the CRF for patients who are included in the study.
- Prior pneumonectomy (complete)
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