This is an open label nonrandomized Phase I/ IIA trial designed to assess the safety,
tolerability, and efficacy of apatinib in combination with pembrolizumab. Phase I will assess
the safety of combining increasing oral daily doses of apatinib with a fixed dose of IV
pembrolizumab every three weeks and will determine the RP2D (Recommended Phase 2 Dose). Phase
II will assess the efficacy of the RP2D of apatinib in combination with pembrolizumab and
provide additional safety and tolerability data in three disease-specific cohorts
- Male or female subject aged ≥ 18 years.
- One of the following advanced solid malignancies which qualifies for standard of care
pembrolizumab treatment per FDA approval:
- Locally advanced or metastatic urothelial carcinoma that has progressed during or
following platinum-based chemotherapy or within 12 months of neoadjuvant/adjuvant
platinum-based therapy, ONLY in the second- or later-line setting.
- Unresectable or metastatic MSI-H or dMMR solid tumors that have progressed during
or following prior treatment and have no satisfactory alternative treatment
options (including MSI-H or dMMR colorectal cancer that has progressed following
treatment with a fluoropyrimidine, oxaliplatin, and irinotecan).
- Recurrent locally advanced or metastatic, gastric or gastroesophageal junction
(GEJ) adenocarcinoma expressing PD-L1 (as determined by an FDA-approved test)
that have progressed on or after two or more systemic therapies, including
fluoropyrimidine- and platinum-containing chemotherapy and, if appropriate,
- Patients must have available and be willing to provide formalin fixed paraffin
embedded tissue sample from archival tissue (patients who can't provide archival
tissue will be offered an optional biopsy; lack of tissue will not be exclusionary).
- Have measurable disease based on RECIST 1.1.
- Female subject of childbearing potential should have a negative urine or serum
pregnancy test within 72 hours prior to receiving the first dose of study drug. If the
urine test is positive, a serum pregnancy test will be required.
- Female subjects of childbearing potential should be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study through 120 days after the last dose of study medication. Subjects of
childbearing potential are those who have not been surgically sterilized or have not
been free from menses for at least 1 year.
- Male subjects should agree to use an adequate method of contraception starting with
the first dose of study therapy through 120 days after the last dose of study drug.
- ECOG Performance Status ≤ 1.
- Adequate organ function as defined in the protocol
- Recovery to baseline or Grade ≤ 1 CTCAE v4 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
- Patients must be able to provide informed consent and be willing to sign an approved
consent form that conforms to federal and institutional guidelines
- Previous treatment with and disease progression on a combination of a VEGF inhibitor
and an immune checkpoint inhibitor. Patients who have been treated with and have
progressed on a single agent VEGF inhibitor OR an immune checkpoint inhibitor will not
- Current use of immunosuppressive medication, EXCEPT for the following:
- Topical, ocular, intra-articular, intranasal, and inhaled corticosteroids.
- Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone
- Steroids as premedication for hypersensitivity reactions.
- Active autoimmune disease that might deteriorate when receiving an immune-stimulatory
agent per treating physician's clinical judgment. Subjects with type 1 diabetes,
vitiligo, psoriasis, hypothyroidism, or hyperthyroidism not requiring
immunosuppressive medications are eligible.
- Prior organ transplant including allogenic hematopoietic stem cell transplant.
- Active infection requiring intravenous antibiotics (must be completed prior to
- Known brain metastases or cranial epidural disease unless adequately treated with
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
before first dose of study treatment. Eligible subjects must be neurologically
asymptomatic and without corticosteroid treatment at the time of first dose of study
- Uncontrolled, significant intercurrent or recent illness including, but not limited
to, the following conditions:
- Cardiovascular disorders:
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
- Congestive heart failure New York Heart Association Class 3 or 4, unstable
angina pectoris, serious cardiac arrhythmias.
- Stroke (including transient ischemic attack [TIA]), myocardial infarction
(MI), or other ischemic event, or thromboembolic event (eg, deep venous
thrombosis, pulmonary embolism) within 6 months before first dose.
- Any history of congenital long QT syndrome.
- Presence of a non-healing wound.
- Other clinically significant disorders that would preclude safe study
participation including colitis, inflammatory bowel disease, pneumonitis,
pulmonary fibrosis, psychiatric conditions with active suicidal ideation within
the past year; or laboratory abnormalities that may increase the risk associated
with study participation or study treatment administration and, in the judgment
of the investigator, would make the patient inappropriate for entry into this
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to apatinib or pembrolizumab.
- History of severe hypersensitivity reaction to any monoclonal antibody.
- Known history of testing positive for HIV or known acquired immunodeficiency syndrome.
- Known history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at
screening (positive HBV surface antigen or detectable HCV RNA if anti-HCV antibody
screening test positive).
- Live vaccine within 4 weeks of the first dose of pembrolizumab and while on trial is
- Packed red blood cell transfusions or erythropoietin therapy within 14 days prior to
the study enrollment unless erythropoietin therapy has been used to maintain a stable
condition for at least 1 month prior to the enrollment.
- Major surgery within 4 weeks of first dose of study medications. Minor procedures
(e.g. port placement, endoscopy with intervention) within 2 weeks of first dose of
study medications are allowed.
- Known prior severe hypersensitivity to investigational product or any component in its
formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v4 Grade ≥ 3).
- Subjects taking prohibited medications as described in the protocol with the exception
of systemic corticosteroids as defined in the protocol. A washout period of at least 5
elimination half-lives (or as clinically indicated) should occur for prohibited
medications prior to the start of treatment.