Advanced Malignancy

Primary: To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of intravenous LipoVNB given every 4 weeks (Q4W) in patients with advanced malignancies. Secondary:  To characterize the pharmacokinetics (PK) and dose-exposure relationship of single and multiple doses of LipoVNB  To evaluate the safety and tolerability of LipoVNB given Q4W  To evaluate the antitumor activity of intravenous LipoVNB using objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), and duration of response (DoR)  To evaluate progression-free survival (PFS)

LipoVNB Vinorelbine Tartrate

Vinorelbine Tartrate

Injection

10mg

Pharmacokinetics:
Plasma PK parameters, including maximum plasma concentration (Cmax), time of
maximum plasma concentration (tmax), area under the plasma concentration time curve
(AUC[0-last]), AUC(0-inf)
, apparent terminal half-life (t1/2), and mean residence time
(MRT[0-inf]), of total form of LipoVNB and its known major metabolite
4-O-deacetylvinorelbine at all dose levels on Cycle 1 and Cycle 3.
Efficacy:
Overall objective response (OR), for evaluation of ORR, CBR, DCR, DoR, and PFS.
For patients with solid tumors, tumor size for evaluation of response will be measured
per RECIST 1.1. For skin lesions of MF and SS, mSWAT criteria will be used, and for
other lymphomas, Cheson criteria will be used.
Tumor assessments will be performed every 8±1 weeks since start of treatment by the
local Investigator/radiologist.
Safety:
Incidence of serious adverse events (SAEs), incidence and severity of AEs coded to
preferred term and system organ class using the Medical Dictionary for Regulatory
Activities (MedDRA Version 19.0 or higher) and graded according to the National
Cancer Institute’s (NCI) CTCAE Version 4.03 or higher, will be reported on a
continuous basis during the trial duration

Main Criteria for Inclusion:
Before the start of any screening procedure, all patients must have signed an informed
consent form and be willing to follow the procedures as described in the protocol.
(1) Male or female, ≥18 years of age (≥20 years of age in Taiwan)
(2) Patients with histologically/cytologically confirmed solid tumor, or lymphoma.
For the expansion cohort, only patients with peripheral/cutaneous T-cell
lymphoma, Hodgkin’s lymphoma, and other non-Hodgkin’s lymphoma would be
considered eligible
(3) Malignancies for which there is no standard therapy, or previously treated locally
advanced, refractory/relapsed or metastatic disease for which local curative
surgery, curable radiotherapy, or satisfactory systemic anticancer therapy is no
longer available
(4) Assessable disease status defined by Cheson (for lymphoma) or modified severity
weighted assessment tool (mSWAT) (for mycosis fungoides [MF] and Sézary
syndrome [SS]) criteria, or having measurable tumors defined by Response
Evaluation Criteria in Solid Tumors guidelines (RECIST 1.1) (for solid tumor)
(5) Eastern Collaborative Oncology Group (ECOG) Performance Status of ≤2
(6) Anticipated life expectancy of more than 3 months per Investigator’s judgement
(7) Women of childbearing potential must have a negative urine pregnancy test at the
screening visit
(8) Male patients with female partners of childbearing potential, and female patients
of childbearing potential must agree to use effective birth control. Effective birth
control and cessation of lactation must be complied at least 2 weeks prior to first
study drug administration, during the trial participation, and for 3 months after the
last dose of study drug
(9) Willing and able to comply with the study procedure and sign a written informed
consent

Main Criteria for Exclusion
(1) Patient with untreated or inadequate controlled brain metastases. Brain
metastases or lymphoma with CNS involvement previously treated by
radiotherapy or other modality and stable for at least 3 months prior to screening
without requirement of corticosteroids or anticonvulsants are permitted
(2) Prior systemic standard or investigational anticancer therapy, including target
therapy, chemotherapy, immunotherapy within 28 days prior to the first dose of
study drug. The above mentioned conditions which the Investigator considers
there is no more drug effect, such as ≥5 half-lives are permitted
(3) More than 5 lines of previous cytotoxic therapies. For patients of CTCL who
failed romidepsin, more than 4 lines of previous therapies
(4) Extensive prior radiotherapy on more than 30% of bone marrow reserves or prior
bone marrow/stem cell transplantation within 2 years before screening. Limited
field radiation for ≤2 weeks prior to screening period is permitted
(5) Any toxicity due to prior therapy that has not been resolved to less than Grade 2
severity by Common Terminology Criteria for Adverse Events (CTCAE,
Version 4.03 or higher) criteria
(6) Medical history of uncontrolled but clinically significant abnormal cardiac
conduction abnormalities at electrocardiogram (ECG), any history or evidence of
long QT syndrome or QTcF interval >450 msec for males and ≥470 msec for
females (according to Fridericia’s correction) at screening
(7) Poor vital organ function defined as:
a. Absolute neutrophil count (ANC) <1,500/mm3
, pre-transfusion platelets
<100,000/mm3
, or pre-transfusion hemoglobin <9.0 mg/dL (the patient is
required to have at least 2 weeks free from blood transfusion, G-CSF and
erythropoietin use prior to the hematology test)
b. International Normalized Ratio (INR) for coagulation above upper normal
range
c. Total bilirubin >2 mg/dL
d. Aspartate amino transferase (AST) or Alanine amino transferase (ALT) >3
times upper limit of normal (ULN) in patient without liver metastasis or
liver cirrhosis, >5 times ULN in patient with liver metastasis or liver
cirrhosis
e. Child-Pugh B or C stage liver disease
f. Creatinine clearance (by Cockcroft-Gault formula) <40 mL/min
(8) Use of potent inhibitors or inducers of cytochrome P450 enzymes CYP3A4
within 14 days prior to first study drug administration.