This is a 2-part, Phase 1, open-label study. Phase 1a of this study is designed to determine
the recommended Phase 2 dose (RP2D) in subjects with advanced cancer whose HER2 test results
are in situ hybridization (ISH) positive or immunohistochemistry (IHC) 3+ and Phase 1b is
designed to assess anticancer activity and safety in 2 advanced breast cancer expansion
cohorts: 1) for tumors that test as HER2 ISH positive or IHC3+ and, 2) for tumors that test
as HER2 ISH negative with IHC 2+.
- Age >18 years and ≤75 years.
- Life expectancy >12 weeks.
- BMI 18 to 32 kg/m2.
- Female or male subjects whose advanced HER2 expressing cancer has failed standard of
care treatments, or for whom such therapy is not acceptable to the subject. Subjects
with advanced breast and gastric cancer who test positive for HER2 by ASCO/CAP
criteria (either IHC or FISH) must have received prior treatment with a trastuzumab
containing therapy. Subjects who have been previously treated with pertuzumab, TDM-1,
lapatinib, or other available and accessible HER2-directed therapies or
investigational therapies are eligible.
- Disease measurability:
- Phase 1a: measurable or non-measurable disease per RECIST v 1.1.
- Phase 1b: measurable disease per RECIST v 1.1 (subjects with non-measurable
disease are not eligible for Phase 1b).
- Histopathologic evidence of cancer based upon pathologist's report.
- Tumor tissue local laboratory HER2 testing results (clinical pathology report) based
on FDA or other regulatory agency approved, validated or commercially available IHC or
ISH HER2 assay. Pre-screening for HER2 is allowed only for subjects with breast and
gastric cancer, GE junction or esophageal cancer, where applicable. Subjects with
other types of cancer must have previously tested for HER2 status by HER2 IHC or ISH
- Phase 1a: ISH positive or IHC 3+ advanced cancer (including breast or
gastric/esophageal or other solid tumors).
- Phase 1b:
- Cohort 1: advanced breast cancer, ISH positive or IHC 3+.
- Cohort 2: advanced breast cancer, ISH negative with IHC 2+.
- Eastern Cooperative Oncology Group Performance Status of 0 to 1.
- Acute toxicities from any prior therapy, surgery, or radiotherapy must have resolved
to Grade 0 or 1 as per the NCI-CTCAE v 4.03.
- Adequate renal function assessed by serum creatinine within reference lab normal
limits and creatinine clearance (by Chronic Kidney Disease Epidemiology [CKD-EPI]
Collaboration equation) ≥60 mL/min.
- Adequate cardiac function as assessed by cardiac troponin I within normal range; left
ventricular ejection fraction ≥ 50% or institutional lower limit of normal; cumulative
anthracycline dose <360 mg/m2 doxorubicin or equivalent.
- Willing and able to understand and sign an informed consent inform and to comply with
all aspects of the protocol.
- Female subjects must be surgically sterile, or have a monogamous partner who is
surgically sterile, or at least 2 years postmenopausal, or who commits to use an
acceptable form of birth control (defined as the use of an intrauterine device, a
barrier method with spermicide, condoms, any form of hormonal contraceptives, or
abstinence) for the duration of the study and for 3 months following the last dose of
- Male subjects must be sterile (biologically or surgically) or commit to the use of a
reliable method of birth control (condoms with spermicide) for the duration of the
- History of allergic reactions to any component of the IMP.
- History of interstitial lung disease, pneumonitis or other clinically significant lung
- Any CT imaging findings indicating radiation or drug-induced lung disorders at the
time of screening
- Any known clinically significant prior radiation to the chest area that included lung
- History of ocular events related to keratitis or corneal disorders, or any current
ongoing active ocular infections.
- History of seizure disorder.
- History of unstable central nervous system (CNS) metastases or seizure disorder
related to the malignancy; however, those subjects who were treated for prior CNS
metastases and who are asymptomatic may participate in the study as long as they are
not receiving treatment with steroids.
- History of congestive heart failure, unstable angina pectoris, unstable atrial
fibrillation, or cardiac arrhythmia.
- Grade 2 to 4 peripheral neuropathy (NCI CTCAE v 4.03).
- Non-manageable electrolyte imbalances including hypokalemia, hypocalcemia, or
hypomagnesemia (Grade 2 or greater based on NCI-CTCAE v 4.03).
- Any uncontrollable intercurrent illness, infection, or other conditions that could
limit study compliance or interfere with assessments.
- Exposure to any other investigational or commercial anticancer agents or therapies
administered with the intention to treat malignancy within 28 days before the first
dose of the IMP. Hormonal therapy may be administered up to 7 days prior to the first
dose of the IMP.
- Clinically significant surgical intervention within 21 days of the first dose of the
IMP or with ongoing post-operative complications if more than 21 days.
- Radiotherapy administered less than 21 days prior to the first dose of the IMP, or
localized palliative radiotherapy administered less than 7 days prior to the first
dose of the IMP, or radiotherapy-induced toxicity of Grade 2 or greater based on
NCI-CTCAE v 4.03.
- Pregnancy or breast feeding.
- Refusal to use effective methods of contraception (see inclusion criteria for
- Legal incapacity/limited legal capacity for providing informed consent.
- Known active HCV, HBV, and/or HIV infection.