Advanced Solid Tumors

Primary Objectives : To evaluate the safety and tolerability and determine the recommended phase 2 dose (RP2D) of AMG 404 in patients with advanced solid tumors Secondary Objectives : 1. To evaluate the pharmacokinetics (PK) of AMG 404 2. To assess the immunogenicity of AMG 404 3. To evaluate the preliminary antitumor activity of AMG 404

AMG 404

AMG 404
ticagrelor

solution for IV infusion

90 mg
70 mg

1. Dose limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events, and changes in vital signs, and clinical laboratory tests
2. PK parameters of AMG 404 including, but not limited to, maximum observed serum concentration (Cmax), time to achieve Cmax (tmax), and area under the serum concentration-time curve (AUC)
3. Subject incidence of anti-AMG 404 antibodies
4.  Objective tumor response, duration of overall response, progression-free survival, disease control rate (DCR), and
duration of stable disease measured by CT/MRI and assessed per modified RECIST 1.1
5. AMG 404 exposure /QTc interval relationship
6. AMG 404 exposure-safety and exposure-efficacy relationships
7. Quantification of biomarker expression at protein, RNA, and DNA levels, as appropriate
8. Potential biomarkers by biochemical and/or genetic analysis of blood and/or tumor samples

Subjects are eligible to participate in the study only if all of the following criteria apply:
101 Subject has provided informed consent prior to initiation of any study specific activities/procedures.
102 Age ≥ 18 years old at the time of signing informed consent
103 Life expectancy of > 3 months, in the opinion of the investigator
104 Subject must have histologically or cytologically confirmed metastatic or locally
advanced solid tumors not amenable to curative treatment with surgery or
radiation. Additionally, for:
• Cohort 7: subject must have a tumor as specified in the Study Schema
(Section 2.1)
• Cohort 8: subject must be MSI-H or MMR-deficient
• Cohort 9: subject must have NSCLC, PD-L1 positive, TPS ≥ 50%; not have
EGFR or ALK genomic tumor aberrations and may not have received prior
systemic treatment for the advanced disease (prior neoadjuvant or adjuvant
treatment is allowed).
105 At least 1 measurable lesion as defined by modified RECIST 1.1 which has not
undergone biopsy within 3 months of the screening scan. This lesion cannot be
biopsied at any time during the study. Note: If there is only one lesion available
for biopsy and radiographic assessment, it may be permitted to be biopsied after
discussion with sponsor.
106 Subjects with treated brain metastases are eligible provided they meet the
following criteria:
• Definitive therapy was completed at least 2 weeks prior to enrollment.
• No evidence of radiographic CNS progression or CNS disease following
definitive therapy and by the time of study screening. Patients manifesting
progression in lesions previously treated with stereotactic radiosurgery may still
be eligible if pseudoprogression can be demonstrated by appropriate means and
after discussion with the medical monitor.
• Any CNS disease is asymptomatic, any neurologic symptoms due to CNS
disease have returned to baseline or are deemed irreversible, the patient is off
steroids for at least 7 days (physiologic doses of steroids are permitted), and the
patient is off or on stable doses of anti-epileptic drugs for malignant CNS
disease.
107 Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2.
108 Hematologic function, as follows without growth factor support within 2 weeks
prior to study day 1:
• Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
• Platelet count ≥ 75 x 109/L
• Hemoglobin ≥ 9 g/dL (90 g/L)
109 Adequate renal laboratory assessments, as follows:
Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal
Disease) calculation ≥ 60 ml/min/1.73 m2 for Cohorts 1, 2, 4, and 5.
Estimated glomerular filtration rate based on MDRD (Modification of Diet in Renal
Disease) calculation ≥ 45 ml/min/1.73 m2 for Cohorts 3, 6, 7, 8 and 9.
110 Hepatic function, as follows:
• Total bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN for subjects with liver metastasis
• AST ≤ 3 x ULN or ≤ 5 x ULN for subjects with liver metastasis
• ALT ≤ 3 x ULN or ≤ 5 x ULN for subjects with liver metastasis
• Alkaline phosphatase ≤ 2.5 x ULN or ≤ 5 x ULN for subjects with liver
metastasis.
111 Cohort 5 only: Subject is a resident in China of Chinese ancestry.
112 Subjects enrolled to Cohorts 7-9, must submit tumor. Fresh tumor biopsies may
be performed if subject has a readily accessible tumor lesion and who consent to
the biopsies. If fresh biopsies cannot be obtained, archival tumor samples
<1 year from screening date. Prior to enrollment it is required to determine that
there is enough tumor tissue available to be sent to the central laboratory.

Subjects are excluded from the study if any of the following criteria apply:
Disease Related
201 Primary brain tumor, untreated or symptomatic brain metastases and leptomeningeal disease.
Other Medical Conditions
202 History of other malignancy within the past 2 years, with the following
exception[s]:
• Malignancy treated with curative intent and with no known active disease present for ≥ 2 years before enrollment and felt to be at low risk for recurrence by the treating physician.
• Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
• Adequately treated cervical carcinoma in situ without evidence of disease.
• Adequately treated breast ductal carcinoma in situ without evidence of disease.
• Prostatic intraepithelial neoplasia without evidence of prostate cancer.
• Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ.
203 History of solid organ transplantation.
204 Major surgery within 28 days of study day 1.
Prior/Concomitant Therapy
205 Prior treatment with anti-programmed death 1 (PD-1), anti-PD-L1, CTLA-4 or other checkpoint inhibitor drugs.
206 Anti-tumor therapy (radiotherapy, chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 21 days prior to study day 1.
Note: Palliative radiotherapy is permitted.
207 Live vaccine therapy within 4 weeks prior to study drug administration
208 Current treatment or within 14 days of day 1 with immunosuppressive corticosteroid defined as > 10 mg prednisone daily or equivalent. Corticosteroids with no or minimal systemic effect (such as topical or inhalation) are permitted.
Prior/Concurrent Clinical Study Experience
209 Currently receiving treatment in another investigational device or drug study, or
less than 21 days prior to study day 1 since ending treatment on another
investigational device or drug study(ies).
Diagnostic Assessments
210 Evidence of interstitial lung disease or active, non-infectious pneumonitis.
211 History of any immune-related colitis. Infectious colitis is allowed if evidence of
adequate treatment and clinical recovery exists and at least 3 months interval
observed since diagnosis of colitis.
212 History of allergic reactions or acute hypersensitivity reaction to antibody therapies.
213 Positive/Non-negative test for Human Immunodeficiency Virus (HIV).
214 Has known active Hepatitis B (eg, hepatitis B antigen [HBsAg] reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected).
215 Subject currently has an active infection requiring systemic therapy
216 Active or history of any autoimmune disease or immunodeficiencies. Subjects
with Type I diabetes, vitiligo, psoriasis, hypo- or hyper- thyroid disease not
requiring immunosuppressive treatment are permitted.
217 Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association > class II), unstable angina, or cardiac
arrhythmia requiring medication
218 Unresolved toxicities from prior anti-tumor therapy, defined as not having
resolved to Common Terminology Criteria for Adverse Events (CTCAE) version
5.0 grade 1, or are stable and well controlled with minimal, local, or non-invasive
intervention AND there is agreement to allow by both the investigator and the
Amgen Medical Monitor.
Other Exclusions
219 Males and females of reproductive potential who are unwilling to practice highly
effective methods of birth control while on study through 4 months after receiving
the last dose of study drug. See Section 12.6 for additional details regarding
contraception requirements).
220 Females with a positive pregnancy test.
221 Females who are lactating/breast feeding or planning to breastfeed while on study through 120 days after receiving the last dose of study drug.
222 Females planning to become pregnant while on study through 120 days after
receiving the last dose of the study drug.
223 Males unwilling to abstain from donating sperm during treatment and for an additional 120 days after the last dose of study drug.
224 Subject has known sensitivity to any of the products or components to be administered during dosing.
225 Subject likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the
subject and investigator’s knowledge.
226 History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.