This study is to characterize the safety, tolerability, pharmacokinetics (PK),
immunogenicity, pharmacodynamics (PD) and anti-tumor activity of AK112, a PD-1/VEGF
bispecific antibody, as a single agent in adult subjects with advanced solid tumor
malignancies. The study consists of a dose escalation phase (Phase 1a) to determine the
maximum tolerated dose (MTD), or recommended Phase 2 dose (RP2D) for AK112 as a single agent,
and a dose expansion phase (Phase 1b) in subjects with specific tumor types which will
characterize treatment of AK112 as a single agent at the MTD or RP2D.
- Written and signed informed consent and any locally required authorization obtained
from the subject/legal representative.
- In dose-escalation cohorts (Phase 1a), histologically or cytologically documented
advanced or metastatic solid tumor that is refractory/relapsed to standard therapies,
or for which no effective standard therapy is available, or the subject refuses
- In the dose-expansion cohorts (Phase 1b), histologically or cytologically confirmed
selected advanced solid tumors.
- Subject must have at least one measurable lesion according to RECIST Version1.1.
- Eastern Cooperative Oncology Group (ECOG) Performance Score of 0 or 1.
- Available archived tumor tissue sample to allow for correlative biomarker studies. In
the setting where archival material is unavailable or unsuitable for use, the subject
must consent and undergo fresh tumor biopsy.
- Adequate organ function.
- Subjects with central nervous system (CNS) metastases must have been treated, be
- Females of childbearing potential and non-sterilized males who are sexually active
must use an effective method.
- Adequate life expectancy
- History of severe hypersensitivity reactions to other mAbs.
- For subjects enrolled in the dose escalation phase of the study (Phase 1a) who have
received prior anti-PD-1, anti-PD-L1, anti-CTLA-4 or any other immunotherapy or
immune-oncology (IO) agent:
1. Subjects have received anti-PD-1, anti-PD-L1, anti-CTLA-4 or any other
immunotherapy or IO agent within 28 days of commencing treatment with
2. Subjects have experienced a toxicity that led to permanent discontinuation of
prior immunotherapy. Subjects have experienced a ≥ Grade 3 irAE or a neurologic
or ocular AE of any grade while receiving prior immunotherapy.
3. All AEs while receiving prior immunotherapy have not completely resolved or
resolved to Grade 1 prior to screening for this study.
4. Subjects have required the use of additional immunosuppression other than
corticosteroids for the management of an AE, or have experienced recurrence of an
AE if re-challenged with corticosteroids while receiving prior immunotherapy.
- For dose-expansion phase (Phase 1b), prior exposure to any anti-PD-1, anti-PD-L1,
anti-CTL4 antibody or any other antibody or drug targeting T-cell costimulation or
checkpoint pathways such as ICOS, or agonists such as CD40, CD137, GITR, OX40 etc.
- Receipt of any immunotherapy, any conventional or investigational systemic anticancer
therapy within 4 weeks prior to the first dose of AK112 except for treatment with
small-molecule tyrosine kinase-targeted agents within 2 weeks prior to the first dose
- Any concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer
treatment. Concurrent use of hormones for non-cancer related conditions is acceptable.
- History or concurrent gastrointestinal perforation, surgery and wound healing
complications, hemorrhage events.
- Subjects with clinically significant cardiovascular disease
- Subjects with a condition requiring systemic treatment with either corticosteroid (>
10 mg daily prednisone equivalents) or other immunosuppressive medications within 14
days of study drug administration.
- Current or recent (within 10 days of the first dose of investigational product) use of
aspirin (> 325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and
- Current use of full-dose oral or parenteral anticoagulants or thrombolytic agents for
therapeutic purposes that has not been stable for > 2 weeks prior to the first dose of
- Active or prior documented autoimmune disease within the past 2 years. NOTE: Subjects
with vitiligo, alopecia, Grave's disease, type I diabetes mellitus, hypothyroidism
(e.g., following Hashimoto syndrome) only requiring hormone replacement on a stable
dose, psoriasis or eczema not requiring systemic treatment (within the past 2 years),
or conditions not expected to recur in the absence of an external trigger are not
- Active or prior documented inflammatory bowel disease (eg, Crohn's disease, ulcerative
- History of primary immunodeficiency.
- History of organ transplant or hematopoietic stem cell that requires use of
- Known allergy or reaction to any component of the AK112 formulation.
- History of interstitial lung disease or non-infectious pneumonitis except for those
induced by radiation therapies.
- Unresolved toxicities from prior anticancer therapy, defined as having not resolved to
NCI CTCAE v5.0 Grade 0 or 1, or to levels dictated in the inclusion/exclusion
- Major surgical procedure within 30 days prior to the first dose of AK112 or still
recovering from prior surgery.
- Known history of tuberculosis.
- Known history of HIV.
- Known active hepatitis B or C infections. Note: Subjects with HCC and positive HBsAg
result are eligible if the subjects were treated with antiviral therapy and HBV viral
load less than 500 IU/mL prior to first dose of AK112. Subjects positive for HCV
antibody are eligible only if quantitative HCV RNA results less than the lower limits
of detection of the assay.
- An active infection requiring systemic therapy 25. with the exception of anti-viral
therapy for hepatitis as specified by the protocol.
- Receipt of live attenuated vaccination within 30 days prior to the first dose of
- Any condition that, in the opinion of the investigator, would interfere with
evaluation of the investigational product or interpretation of subject safety or study