Open-label, Phase I-II, first-in-human (FIH) study for A166 monotherapy in HER2-expressing or
amplified patients who progressed on or did not respond to available standard therapies.
Patients must have documented HER2 expression or amplification. The patient must have
exhausted available standard therapies. Patients will receive study drug as a single IV
infusion. Cycles will continue until disease progression or unacceptable toxicity.
This is an open-label, Phase I-II, first-in-human (FIH) study for A166 as monotherapy in
HER2-expressing patients who progressed on or did not respond to available standard
therapies. Patients enrolled in this Phase III study must have documented HER2 positivity
defined as positive on in situ hybridization (ISH) or next-generation sequencing (NGS) or
HER2 expression, defined as at least 1+ by validated immunohistochemistry (IHC) test. The
patient must be, in the judgment of the investigator, an appropriate candidate for
experimental therapy after available standard therapies have ceased to provide clinical
benefit for their disease. Patients will receive study drug as a single IV infusion at the
prescribed dose level in each treatment cycle. Cycles will continue until disease progression
or unacceptable toxicity. The study is divided into 2 parts (Phase I and Phase II).
Inclusion Criteria:
Phase I
Patients must meet the following criteria for inclusion into the study:
1. Patients must be able to provide documented voluntary informed consent.
2. Male or female patient ≥ 18 years.
3. Histologically documented, incurable, locally advanced or metastatic cancer.
4. Evaluable or measurable HER2 positive (by ISH or NGS) disease or HER2 expressing
disease. HER2 expressing is defined in this protocol as HER2 expression of ≥ 1+
determined by validated IHC.
5. Patients should have no available therapy likely to convey clinical benefit.
6. Granulocyte count ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 9 g/dL.
7. Serum bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN),
with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and
patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).
8. Creatinine clearance ≥ 50 mL/min calculated by Cockroft-Gault, Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD)
formulas. Note that 24 hour urine collection is not required but is allowed.
9. ECOG Performance Status ≤ 1.
10. Women of childbearing potential and men must agree to use an approved method of birth
control (e.g., hormonal, barrier) while receiving study drug, and for at least 7
months after the last dose of study drug. Women are excluded from birth control if
they had had tubal ligation or a hysterectomy.
11. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute
toxicities from previous therapy, excluding alopecia and vitiligo.
Phase II
Patients must meet the following criteria for inclusion into the study:
1. Patients must be able to provide documented voluntary informed consent.
2. Male or female patient ≥ 18 years.
3. Histologically documented, incurable, locally advanced or metastatic cancer.
4. Evaluable or measurable HER2 positive (by ISH or NGS) disease or HER2 expressing
disease. HER2 expressing is defined in this protocol as HER2 expression of ≥ 1+
determined by validated IHC.
5. Regarding previous therapy:
5.1. Cohort 1: HER2 positive (IHC 2+ with FISH confirmation and Immunohistochemistry
(IHC 3+) breast cancer: patients should have progressed after at least 2 previous HER2
directed regimens in metastatic disease with approved therapies.
5.2. Cohort 2: HER2 positive (IHC 2+ with FISH confirmation and IHC 3+) gastric
cancer: patients should have progressed after at least 1 previous HER2 directed
regimens in metastatic disease with approved therapies.
5.3. Cohort 3: HER2 low expressing (IHC 1+ and IHC 2+ without FISH confirmation)
breast cancer: patients should have no available therapy likely to convey clinical
benefit.
5.4. Cohort 4: all cancers other than breast cancer with low HER2 expression (IHC 1+
and IHC 2+ without FISH confirmation) and HER2 positive (IHC 2+ with FISH confirmation
and Immunohistochemistry (IHC) 3+) cancers other than breast and gastric cancer:
patients should have no available therapy likely to convey clinical benefit.
6. Granulocyte count ≥ 1,500/μL, platelet count ≥ 100,000/μL, and hemoglobin ≥ 9 g/dL.
7. Serum bilirubin ≤ 1.5 mg/dL, aspartate aminotransferase (AST), alanine
aminotransferase (ALT), and alkaline phosphatase ≤ 2.5 × upper limit of normal (ULN),
with the exception of patients with hepatic metastases (ALT and AST ≤ 5 × ULN) and
patients with hepatic and/or bone metastases (alkaline phosphatase ≤ 5 × ULN).
8. Creatinine clearance ≥ 50 mL/min calculated by Cockroft-Gault, Chronic Kidney Disease
Epidemiology Collaboration (CKD-EPI), or Modification of Diet in Renal Disease (MDRD)
formulas. Note that 24 hour urine collection is not required but is allowed.
9. ECOG Performance Status ≤ 1.
10. Women of childbearing potential and men must agree to use an approved method of birth
control (e.g., hormonal, barrier) while receiving study drug, and for at least 7
months after the last dose of study drug. Women are excluded from birth control if
they had had tubal ligation or a hysterectomy.
11. Patients must have recovered (i.e., improvement to Grade 1 or better) from all acute
toxicities from previous therapy, excluding alopecia and vitiligo.
Exclusion Criteria:
Phase I:
1. Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure
(New York Heart Association) III or IV, unstable angina pectoris even if medically
controlled, history of myocardial infarction during the last 6 months, serious
arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal
supraventricular tachycardia).
2. History of Grade ≥ 3 hypersensitivity reaction to trastuzumab.
3. History of any toxicity to trastuzumab that resulted in trastuzumab being permanently
discontinued.
4. Symptomatic brain metastases or any radiation or surgery for brain metastases within 3
months of first infusion of study drug.
5. Require supplemental oxygen for daily activities.
6. Documented Grade ≥ 2 peripheral neuropathy.
7. Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy
treatment within 4 weeks of first infusion of study drug.
8. Any experimental therapy within 4 weeks of first infusion of study drug.
9. Any major surgical procedure within 4 weeks of first infusion of study drug.
10. Diagnosed active liver disease, including viral or other hepatitis, current or history
of alcoholism, or cirrhosis. Patients who have positive hepatitis B virus test results
due to having been previously vaccinated against hepatitis B, as evidenced by negative
hepatitis B surface antigen (HBsAg), negative anti hepatitis B core protein, and
positive antibody to the HBsAg (anti-HBs) are not excluded.
11. Have known prior positive test results for human immunodeficiency virus.
12. Uncontrolled hypertension or diabetes.
13. Pregnancy or lactation.
14. Resting corrected QT interval (QTc) > 470 ms at baseline.
15. Left ventricular ejection fraction (LVEF) < 45% determined by echocardiogram (ECHO) or
multigated acquisition (MUGA) scan.
16. Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent.
Phase II:
1. Any patient who was treated in the Phase I part of this study.
2. Severe or uncontrolled cardiac disease requiring treatment, congestive heart failure
(New York Heart Association) III or IV, unstable angina pectoris even if medically
controlled, history of myocardial infarction during the last 6 months, serious
arrhythmias requiring medication (with exception of atrial fibrillation or paroxysmal
supraventricular tachycardia).
3. History of Grade ≥ 3 hypersensitivity reaction to trastuzumab.
4. History of any toxicity to trastuzumab that resulted in trastuzumab being permanently
discontinued.
5. Symptomatic brain metastases or any radiation or surgery for brain metastases within 3
months of first infusion of study drug.
6. Require supplemental oxygen for daily activities.
7. Documented Grade ≥ 2 peripheral neuropathy.
8. Any chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or biologic therapy
treatment within 4 weeks of first infusion of study drug.
9. Any experimental therapy within 4 weeks of first infusion of study drug.
10. Any major surgical procedure within 4 weeks of first infusion of study drug.
11. Diagnosed active liver disease, including viral or other hepatitis, current or history
of alcoholism, or cirrhosis. Patients who have positive hepatitis B virus test results
due to having been previously vaccinated against hepatitis B, as evidenced by negative
hepatitis B surface antigen (HBsAg), negative anti hepatitis B core protein, and
positive antibody to the HBsAg (anti-HBs) are not excluded.
12. Have known prior positive test results for human immunodeficiency virus.
13. Uncontrolled hypertension or diabetes.
14. Pregnancy or lactation.
15. Resting QTc > 470 ms at baseline.
16. LVEF < 45% determined by ECHO or MUGA scan.
17. Prior cumulative doxorubicin dose of > 360 mg/m2 or equivalent.
