| Eligibility |
Inclusion Criteria:
1. Signed written informed consent obtained prior to performing any study procedure,
including screening procedures
2. Men and women =18 years of age
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1
4. Histologically or cytologically confirmed gastric or GEJ adenocarcinoma
5. Arm 1: Has received no more than two prior treatment regimens for advanced disease,
including a platinum, a fluoropyrimidine, and HER2-directed therapy such as
trastuzumab Arm 2: Has received at least one prior treatment regimen for advanced
disease
6. Arm 1: Demonstration of HER2 positivity assessed by a test with appropriate regulatory
validation in a current tissue specimen and following guidelines for assessment in
gastric or GEJ adenocarcinoma described in Section 4.3 after receiving no more than
two prior treatment regimens, including a platinum, a fluoropyrimidine, and
HER2-directed therapy such as trastuzumab Arm 2: Demonstration of HER2 IHC 1+ or IHC
2+ without HER2/neu amplification assessed by a test with appropriate regulatory
validation in a current tissue specimen and following guidelines for assessment in
gastric or GEJ adenocarcinoma described in Section 4.3 after completion of the most
recent prior treatment regimen
7. Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST)
1.1
8. Adequate organ and hematologic function as defined below:
- Serum AST and ALT =2.5 × upper limit of normal (ULN) or =5 × ULN in the presence
of liver metastases
- Total serum bilirubin =1.5 × ULN
- Serum albumin = 3g/dL
- Serum creatinine =1.5 × ULN OR creatinine clearance measured via 24-hour urine
collection =40 mL/min if serum creatinine is > 1.5X ULN
- Arm 1 only: Urinary protein is = 1+ on dipstick or routine urine analysis; if
urine dipstick or urinalysis is = 2+, a 24-hour urine collection for protein must
demonstrate < 1000 mg of protein in 24 hours
- Hemoglobin = 9 g/dL; packed red blood cell transfusions are not allowed in the
week preceding screening evaluation
- ANC = 1500/mm3
- Platelet count = 100,000/mm3
- INR =1.5 and PT =1.5 × ULN and PTT =1.5 × ULN. Arm 1 only: Patients receiving
oral anti-coagulants must be switched to low molecular weight anti-coagulants and
have achieved stable coagulation profile prior to first dose of protocol therapy.
Arm 2 only: Patients receiving oral anti-coagulants must be switched to low
molecular weight heparin and have achieved stable coagulation profile prior to
first dose of protocol therapy.
9. Left ventricular ejection fraction (LVEF) of = 50% as determined by echocardiogram or
multigated acquisition scan
10. Resolution to Grade =1 by NCI CTCAE v5.0 of all clinically significant toxicities
associated with prior therapy or procedures
11. If sexually active, the patient must be post-menopausal, surgically sterile or using
highly effective contraception. Highly effective contraception for women of
child-bearing potential and males with female partners of child-bearing potential is
defined as 1 barrier method (e.g., condom) and 1 additional method (e.g., hormonal) of
contraception during the study and for at least three months from the last study
treatment or recommended contraceptive period according to the local label of the
concomitant drug if greater than 3 months
12. Women of child-bearing potential may not be breastfeeding and must have a negative
serum pregnancy test within 96 hours prior to start of study treatment
Exclusion Criteria:
1. Disease of squamous or undifferentiated histology
2. History or evidence of known active CNS metastases or carcinomatous meningitis.
Patients with brain metastases are eligible provided they have shown clinical and
radiographic stable disease for at least 4 weeks after definitive therapy and have not
used steroids (> 10 mg/day of prednisone or equivalent) for at least 2 weeks prior to
the first dose of study treatment
3. Arm 1 only: Receipt of any previous systemic therapy (including investigational
agents) targeting the VEGF or the VEGFR signaling pathways
4. Intolerance to trastuzumab or other HER2-directed agent in prior treatment regimen
5. History of deep vein thrombosis (DVT), pulmonary embolism (PE) or any other
significant thromboembolism during the three months prior to first dose of study
treatment; venous port or catheter thrombosis or superficial venous thrombosis are not
considered significant (Arm 1 only). For patients in Arm 2, the investigator is
referred to Exclusion Criterion 21 and should consult with the Medical Monitor in the
case of a history of these or similar events.
6. Chronic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs; e.g., indomethacin,
ibuprofen, naproxen or similar agents) or other antiplatelet agents (e.g.,
clopidogrel, ticlopidine, dipyridamole, anagrelide); aspirin up to 325 mg per day is
permitted
7. Significant bleeding disorders, vasculitis or a significant bleeding episode from the
GI tract within 3 months prior to study entry
8. Arterial thromboembolic event within 6 months prior to study entry
9. History of acute coronary syndromes, including myocardial infarction, coronary artery
bypass graft, unstable angina, coronary angioplasty or stenting within past 24 weeks
10. History of or current Class II, III or IV heart failure as defined by the New York
Heart Association (NYHA) functional classification system or symptomatic or poorly
controlled cardiac arrhythmia
11. History of ejection fraction drop below the lower limit of normal with trastuzumab or
other HER2-directed therapy
12. Uncontrolled or poorly-controlled hypertension (arterial hypertension =150 mm Hg or
diastolic =90 mmHg) for > four weeks despite standard medical management; the patient
may be re-screening after treatment for hypertension
13. Any arterial thromboembolic event, including but not limited to myocardial infarction,
transient ischemic attack, cerebrovascular accident or unstable angina, within six
months prior to first dose of study treatment
14. Bowel obstruction, history or presence of inflammatory enteropathy or extensive
intestinal resection (hemicolectomy or extensive small intestine resection with
chronic diarrhea), Crohn's disease, ulcerative colitis or chronic diarrhea
15. Gastrointestinal perforation or fistula within 6 months prior to study entry or have
risk factors for perforation (these events may be acceptable for patients enrolled in
Arm 2 after discussion with the Medical Monitor)
16. Grade 3 or Grade 4 GI bleeding within 3 months prior to first study treatment (these
events may be acceptable for patients enrolled in Arm 2 after discussion with the
Medical Monitor)
17. Arm 2 only: Inability to swallow pills or presence of any significant gastrointestinal
disease which would preclude the adequate absorption of an oral medication.
18. Cirrhosis at a level of Child-Pugh B or worse OR cirrhosis of any degree and a history
of hepatic encephalopathy or hepatorenal syndrome or clinically meaningful ascites
resulting from cirrhosis. Clinically meaningful cirrhosis is defined as ascites from
cirrhosis requiring diuretics or paracentesis.
19. Serious or non-healing wound, ulcer or bone fracture within 28 days prior to first
study treatment (these events may be acceptable for patients enrolled in Arm 2 after
discussion with the Medical Monitor)
20. Any medical, psychiatric, cognitive or other condition that compromises the patient's
ability to understand information, to give informed consent or to comply with the
study protocol
21. Any severe concurrent disease or condition (including active infection, cardiac
arrhythmia, interstitial lung disease) that in the judgment of the Investigator would
make study participation inappropriate for the patient
22. Arm 2 only: Prior anthracycline exposure (epirubicin > 720 mg/m2)
23. Arm 2 only: Having used a strong cytochrome P450 CYP2C8 inhibitor within three
elimination half-lives of the inhibitor or have used a strong CYP3A4 or
moderate/strong CYP2C8 inducer within five days prior to first dose of study
treatment. Patients on the strong CYP2C8 inhibitor gemfibrozil at screening must
discontinue its use at least 24 hours before the first dose of study drug and if
needed, substitute an alternate lipid-lowering agent.
24. Active human immunodeficiency virus (HIV) disease, hepatitis B, or hepatitis C
25. Any severe infection within 28 days prior to study start or requirement for oral or
intravenous antibiotics within 14 days prior to study start
26. Administration of live attenuated vaccines within 28 days prior to start of treatment
or anticipated need for vaccination with live attenuated vaccine during the study.
Vaccination for SARS-CoV-2 is permitted:
- Patients in screening, who have not started study treatment, and who are
receiving a two-dose vaccine should schedule their vaccination(s) to receive the
second dose at least two weeks prior to initiation of treatment (Cycle 1, Day 1).
- If the patient is receiving a single-dose vaccine, the single dose should be at
least two weeks prior to initiation of treatment (Cycle 1, Day 1).
- Vaccination during Cycle 1 between the first and the second cycle of cinrebafusp
alfa is discouraged.
- Beginning with Cycle 2 a minimum of 7 days must elapse from last study treatment
to administration of vaccine and patients must have seven days elapse from
vaccination to next treatment on study.
- Efforts should be made to avoid treatment delays, but where necessary a delay of
up to seven days in next treatment of the study drug will be permitted.
27. History of infusion or other reactions to any components/excipients of cinrebafusp
alfa (Arm 1 and Arm 2), or ramucirumab or paclitaxel (Arm 1); Arm 2 only: history of
allergic reactions to tucatinib or compounds chemically or biologically similar to
tucatinib, or known allergy to any of the excipients in tucatinib
28. History of severe hypersensitivity reactions to monoclonal antibodies or Grade =3
immune-mediated adverse reaction to immune checkpoint inhibitor agents
29. Systemic steroid therapy (>10 mg daily prednisone or equivalent) or any other form of
immunosuppressive therapy within 7 days prior to the first dose of study treatment;
topical, inhaled, nasal and ophthalmic steroids are not prohibited
30. History of autoimmune disease that has required systemic treatment with
disease-modifying agents, corticosteroids, or immunosuppressive drugs unless in the
opinion of the investigator the patient is in a complete and durable remission;
physiologic replacement therapies, such as thyroxine, insulin, or physiologic
corticosteroid replacement therapy for adrenal or pituitary insufficiency, is allowed
31. Prior organ transplantation including allogeneic or autologous stem cell
transplantation
32. Arm 2 only: Prior receipt of HER2-directed and/or EGFR-directed tyrosine kinase
inhibitor (TKI) agents
33. Concurrent or previous other malignancy within 3 years of study entry with the
exception of cured basal or squamous cell skin cancer, superficial bladder cancer,
prostate intra-epithelial neoplasm, carcinoma in situ of the cervix, or other
non-invasive or indolent malignancy
34. Receipt of an investigational agent, chemotherapy or other cancer-directed therapy
within 4 weeks (6 weeks for nitrosoureas and mitomycin C) of initiation of study
treatment
35. Receipt of radiation therapy within 4 weeks of scheduled Day 1 dosing, unless the
radiation comprised a limited field to non-visceral structures; palliative
radiotherapy is permitted
36. Receipt of trastuzumab or adotrastuzumab emtansine or any other commercial or
experimental drug that engages the same epitope as trastuzumab within 4 weeks of
scheduled C1D1 dosing
37. Concurrent enrollment in another therapeutic clinical study
38. Major surgery within 28 days of scheduled C1D1 dosing or minor surgery or subcutaneous
venous access device placement within 7 days prior to initiation of study treatment or
elective or planned major surgery to be performed during the course of the clinical
trial (these events may be acceptable for patients enrolled in Arm 2 after discussion
with the Medical Monitor)
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