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Evaluation of the Safety, Pharmacokinetics and Efficacy of Four Doses of YN968D1 in Subjects With Solid Tumors


Phase 1/Phase 2
18 Years
N/A
Open (Enrolling)
Both
Cancer Patients With Solid Tumors

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Trial Information

Evaluation of the Safety, Pharmacokinetics and Efficacy of Four Doses of YN968D1 in Subjects With Solid Tumors


Part 1 will include a sequential evaluation of 3 subjects per cohort; cohort 1 at a dose of
100 mg YN968D1, followed by a cohorts 2, 3 and 4 at doses of 250 mg, 500 mg and 750 mg
respectively. Initially, each subject will receive one dose of YN968D1 followed by a 7-Day
observation period, during which single dose PK assessments and safety monitoring will be
performed. If the initial dose is well tolerated, the subject will return on Day 8 and
receive 28-Days of continuous YN968D1 oral administration daily. Each subject will
subsequently be assessed for safety and disease progression on Day 35±2 and steady state
pharmacokinetic sampling will be obtained. Patients may continue on therapy for an
additional 28-Day cycles without dose interruption if the therapy is well tolerated.
Efficacy assessments (biomarkers) and disease progression (RECIST imaging) will be assessed
every two 28-Day cycles. The subjects will be assessed for safety for at least 28-Days
after the last dose of YN968D1.

For Part 1 of this study, a Dose Limiting Toxicity (DLT) event is defined as any of the
following events that are assessed by the Investigator as probably or possibly related to
YN968D1 and occur during or after the initial dose on Day 1 through Day 35 of the first
cycle of therapy.

- CTCAE Grade 4 event

- Grade 3 febrile neutropenia (<1,000 neutrophils/mL)

- Grade 3 hematologic toxicity with duration > 7 days

- Grade 3 non-hematologic toxicity (except for nausea, vomiting, diarrhea that continues
despite optimal medical management)

If a DLT is experienced in any cohort, the cohort will be expanded to 6 subjects. If two
(2) DLTs are experienced in any cohort, the study will be paused until the safety events are
evaluated and discussed with the FDA to determine if the trial may continue.

Part 2 of this study will include up to 30 subjects. Each subject will receive a 750 mg
dose or the maximum tolerated dose of YN968D1 from part 1 of the study for continuous 28-Day
cycles of therapy. If a subject experiences an intolerable side effect a dose reduction or a
dose interruption for up to 7-Days is allowed at the discretion of the investigator.
Subjects will be evaluated for RECIST (version 1.1) response at the end of the second cycle
of therapy on Day 56±3 of the Part 2 study. Safety reporting will be continued for 28-Days
from the last dose of study medication.

All subjects in Part 1 and 2 of this trial will be eligible to continue therapy provided
they have a least stable disease or better and are, in the opinion of the investigator,
adequately tolerating treatment with YN968D1.


Inclusion Criteria:



1. 18 years of age or older

2. Subjects may be enrolled with the following malignancies:

- Part 1: Subjects with any solid malignant tumor that are refractory to
conventional therapy or the subject does not tolerate the conventional therapy

- Part 2: Subjects diagnosed with NSCLC, CRC, RCC, Gastric cancer, GIST or triple
negative Breast Cancer that are refractory to conventional therapy or the
subject does not tolerate the conventional therapy

3. Evaluable disease defined by RECIST 1.1 as measured by a suitable imaging technique

4. Life expectancy ≥ 3 months

5. Subject must be suitable for oral administration of study medication

6. Signed written informed consent

7. Adequate bone marrow, renal, and liver function as manifested by the following:

- CBC: ANC ≥ 1500/mm3, platelets ≥ 100,000/mm3, hemoglobin ≥ 9.0 g/dL

- CMP: Creatinine clearance > 50 mL/min or serum creatinine < 1.5 x ULN, serum
bilirubin < 2.5 x ULN, AST and ALT ≤ 5.0 × ULN

- Coagulation profile with PT and INR, each ≤ 1.5 x ULN

- Proteinuria < 200 mg by 24- hour urine collection without evidence of active
sediment or hematuria

8. ECOG performance status ≤ 2

9. Female subjects of child-bearing potential must agree to use contraceptive measures
starting 1 week before the administration of the first dose of YN968D1 until 4 weeks
after discontinuing study drug and male subjects must agree to use contraceptive
measures during the study and ending 4 weeks after last dose of study drug

10. Female patients of child-bearing potential are confirmed to have either a negative
serum ß-hCG test, or have been evaluated by a gynecologist to confirm the patient is
not pregnant, within 7 days prior to administration of initial dose of YN968D1

11. Ability and willingness to comply with the study protocol for the duration of the
study and with follow-up procedures

Exclusion Criteria:

1. Pregnant or lactating women

2. Therapy with clinically significant systemic anticoagulant or antithrombotic agents
within 7 days prior to first scheduled dose of YN968D1 that may prevent clotting and
in the opinion of the investigator would place the subject at risk.

3. Hemoptysis within 3 months prior to first scheduled dose of YN968D1

4. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks in
cases of mitomycin C, nitrosourea, lomustine) prior to first scheduled dose of
YN968D1

5. Surgery or visceral (e.g., hepatic or renal) biopsy within 28 days prior to first
scheduled dose of YN968D1

6. Minor surgical procedure performed within 7 days prior to first scheduled dose of
YN968D1

7. Prior exposure to YN968D1 (prior treatment with an angiogenesis inhibitor is not
exclusionary)

8. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and
CYP2C19.

9. Known history of human immunodeficiency virus infection (HIV)

10. Subjects with active bacterial infections and/or receiving systemic antibiotics

11. Current or past diagnosis of leukemia within the past 5 years

12. Prior radiotherapy at the target lesion

13. Known CNS metastases or clinical evidence of CNS involvement that is not stable for
last 3 months by radiology documentation

14. Medical history of non-healing wound within past 2 weeks

15. History of bleeding diathesis or bleeding within 14 days prior to enrollment

16. Medical history of clinically significant thrombosis (bleeding or clotting disorder)
within the past 3-months that in the opinion of the investigator may place the
patient at risk of side effects on an anti-angiogenesis product

17. History of non-malignant GI bleeding, gastric stress ulcerations, or peptic ulcer
disease within the past 3-months that in the opinion of the investigator may place
the patient at risk of side effects on an anti-angiogenesis product

18. History of idiopathic or hereditary angioedema

19. History of sickle cell or any hemolytic anemia

20. History of uncontrolled hypertension that in the opinion of the investigator is not
well managed by medication and may place the patient at risk when taking a VEGF
inhibitor

21. Complete left bundle branch block (LBBB), bifascicular block (RBBB with either left
anterior hemiblock or left posterior hemiblock)

22. Any clinically significant ST segment and/or T-wave abnormalities

23. Presence of unstable atrial fibrillation (ventricular response rate > 100 bpm).
Patients with stable atrial fibrillation are allowed in the study provided they do
not meet another exclusion criteria

24. Myocardial infarction or unstable angina pectoris within 6 months prior to starting
study medication

25. Congestive heart failure (New York Heart Association class III-IV)

26. History of other significant cardiovascular disease or vesicular disease within the
last 6 months (e.g. such as hypertensive crisis, hypertensive encephalopathy, stroke
or TIA, or significant peripheral vascular disease) that in the opinion of the
investigator may place the patient at risk when taking a VEGF inhibitor

27. History of significant gastrointestinal disorders that in the opinion of the
investigator may place the patient at risk when taking a VEGF inhibitor; such as an
abdominal fistula, GI perforation, or bleeding ulcer within 2 months of treatment

28. QTcF >450 msec on screening ECG

29. Baseline echocardiogram (within 2 months) with left ventricular ejection fraction
(LVEF) <50%

30. History of clinically significant glomerulonephritis, biopsy proven
tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies

31. History of myocardial infarction within the past 6 months

32. Treatment with an investigational agent within the longest time frame of either 5
half-lives or 30 days of initiating study drug

33. Medical or psychiatric illness that, in the opinion of the Investigator, may impact
the safety of the subject or objectives of the study

34. Known recreational substance use or psychiatric illness that, in the opinion of the
Investigator, may affect compliance with scheduled visits

35. Known hypersensitivity to YN968D1 or components of the formulation

Type of Study:

Interventional

Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Safety in the first 28-Days of Therapy

Outcome Description:

The primary endpoint is evaluation of safety during the first 28-day cycle of therapy following the initiation of multiple dosing of YN968D1. The safety variables to be evaluated in this study are adverse events, physical examinations, vital signs (specifically including blood pressure), clinical laboratory evaluations including serum chemistry, hematology (including RBC morphology and reticulocyte count), and urinalysis (with detailed sediment analysis, proteinuria, and 24-hour urine for collection for creatinine clearance and protein), and electrocardiograms (ECGs) in triplicate.

Outcome Time Frame:

28-Days after Discontinuation of YN968D1

Safety Issue:

Yes

Principal Investigator

Sunil Sharma, MD, FACP

Investigator Role:

Principal Investigator

Investigator Affiliation:

Huntsman Cancer Institute

Authority:

United States: Food and Drug Administration

Study ID:

BK-LSK-AM101

NCT ID:

NCT01497704

Start Date:

April 2012

Completion Date:

June 2013

Related Keywords:

  • Cancer Patients With Solid Tumors
  • Cancer
  • Tumor
  • Oncology
  • Antiangiogenesis

Name

Location

Huntsman Cancer InstituteSalt Lake City, Utah  84112