This is an open label, dose escalation study to evaluate the safety and tolerability of
KN035 in advanced and metastatic solid tumor.
The dose escalation will follow the traditional 3+3 design. Cohorts of 3-6 subjects will be
enrolled sequentially at escalating doses of 1, 2.5, 5 and 10 mg/kg weekly. Dosing schedule
for cohorts 2 and above may change after interim PK analysis after Cohort 1 Cycle 1 to
bi-weekly or other regimen based on elimination profile of KN035 to avoid excessive drug
accumulation. Dose escalation will continue until identification of MTD, up to a maximum
dose of 10 mg/kg. MTD is defined as the highest dose studied at which no more than 1 of 6
subjects has experienced a dose-limiting toxicity (DLT) in Cycle 1.
- Subjects must have a histological or cytological diagnosis of any type of carcinoma,
progressive metastatic disease, or progressive locally advanced disease not amenable
to local therapy. Subjects must have failed established standard medical anti-cancer
therapies for a given tumor type or have been intolerant to such therapy, or in the
opinion of the Investigator have been considered ineligible for a particular form of
standard therapy on medical grounds.
- Subject is male or female and ≥ 18 years of age on day of signing informed consent.
- Subject must have a performance status of 0 or 1 on the Eastern Cooperative Oncology
Group (ECOG) Performance Scale.
- Subject must have adequate hematologic and organ function. Note: If subject is
receiving anticoagulants, then value must be within therapeutic range for the
condition the subject is being treated for.
- Subject has voluntarily agreed to participate by giving written informed consent. If
subject has agreed to a newly obtained biopsy of tumor (that can be biopsied based on
Investigator's assessment). Tissue obtained for the biopsy must not be previously
irradiated. No systemic antineoplastic therapy may be received by the subject between
the time of the biopsy and the first administration of KN035.
- Female subject of childbearing potential has a negative urine or serum pregnancy
test. If the urine test is positive or cannot be confirmed as negative, a serum
pregnancy test will be required. The serum pregnancy test must be negative for the
subject to be eligible.
- Female subjects enrolled in the study, who are not free from menses for > 2 years,
post hysterectomy/oophorectomy, or surgically sterilized, must be willing to use
either 2 adequate barrier methods or a barrier method plus a hormonal method of
contraception to prevent pregnancy or to abstain from heterosexual activity
throughout the study, starting with Visit 1 through 120 days after the last dose of
study therapy. Approved contraceptive methods include for example; intra uterine
device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or
female condom with spermicide. Spermicides alone are not an acceptable method of
Male subjects must agree to use an adequate method of contraception starting with the
first dose of study drug through 120 days after the last dose of study therapy.
- Subject who not recovered from the effects of any prior chemotherapy, radioactive, or
biological cancer therapy prior to the first dose of study therapy (for prior cancer
therapy drugs, a washout of 5 half-lives is required), or who has not recovered to
CTCAE Grade 1 or better from the adverse events due to cancer therapeutics
administered more than 4 weeks earlier. Subject who has had erlotinib, gefitinib,
afatinib, or crizotinib within 1 week prior to the first dose of study therapy, or
who has not recovered to CTCAE Grade 1 or better from the adverse events due to any
of these drugs administered more than 1 week earlier.
- Subject is expected to require any other form of antineoplastic therapy while on
study (including maintenance therapy with another agent for NSCLC).
- Subject had prior treatment targeting PD-L1 axis or CTLA 4. Subjects with prior
treatment targeting PD-1 are allowed to enroll if the subject has a washout time of
at least 4 weeks. Examples of such agents include (but are not limited to):
BMS-936559 (MDX 1105); MPDL3280A (RG7446); and MEDI4736.
- Subject has a medical condition that requires chronic systemic steroid therapy or
requires any other form of immunosuppressive medication. However, subjects using
physiologic replacement doses of hydrocortisone, or its equivalent, will be
considered eligible for this study: up to 20 mg hydrocortisone (or 5 mg of
prednisone) in the morning and 10 mg hydrocortisone (or 2.5 mg of prednisone) in the
- Subject has risk factors for bowel obstruction or bowel perforation (examples include
but not limited to a history of acute diverticulitis, intra-abdominal abscess, or
- Subject has a known history of a hematologic malignancy, malignant primary brain
tumor or malignant sarcoma, or of another malignant primary solid tumor, unless the
subject has undergone potentially curative therapy with no evidence of that disease
for 5 years.
Note: The time requirement does not apply to subjects who underwent successful definitive
resection of basal cell carcinoma of the skin, superficial bladder cancer, squamous cell
carcinoma of the skin, in situ cervical cancer, or other in situ cancers.
- Subject has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate
provided they are clinically stable for at least 4 weeks prior to study entry, have
no evidence of new or enlarging brain metastases and are off steroids for at least 7
days from first dose of KN035.
- Subject previously had a severe hypersensitivity reaction to treatment with another
- Subject has a history of pneumonitis or interstitial lung disease.
- Subject has an active autoimmune disease or a documented history of autoimmune
disease or syndrome that requires systemic steroids or immunosuppressive agents.
Subjects with vitiligo or resolved childhood asthma/atopy would be exception to this
rule. Subjects that require intermittent use of bronchodilators or local steroid
injections would not be excluded from the study. Subjects with hypothyroidism that is
stable on hormone replacement will not be excluded from the study.
- Subject has an active infection requiring therapy.
- Subject is positive for Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies),
active hepatitis B (HBsAg reactive) or hepatitis C (HCV RNA (qualitative) is
detected); subjects with negative hepatitis C antibody testing may not need RNA
- Subject has a history or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
subject's participation for the full duration of the study, or is not in the best
interest of the subject to participate, in the opinion of the treating Investigator.
- Subject has known psychiatric or substance abuse disorders that would interfere with
cooperation with the requirements of the trial.
- Subject has a marked baseline prolongation of QT/QTc interval (e.g., repeated
demonstration of a QTc interval >450 milliseconds (ms)), or a history of additional
risk factors for torsade de pointes (TdP, e.g., heart failure, hypokalemia, family
history of Long QT Syndrome), or is using concomitant medications that prolong the
- Subject is, at the time of signing informed consent, a regular user (including
"recreational use") of any illicit drugs or had a recent history (within the last
year) of substance abuse (including alcohol).
- Subjects with symptomatic ascites or pleural effusion. A subject who is clinically
stable following treatment for these conditions (including therapeutic thoraco- or
paracentesis) is eligible.
- Subject is pregnant or breastfeeding, or expecting to conceive or father children
within the projected duration of the study.