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Open-Label, Sequential, Ascending, Multi-Dose, Phase 1 Study of KW-2450 as Monotherapy in Subjects With Previously Treated Advanced Solid Tumor

Phase 1
18 Years
Not Enrolling
Solid Tumor

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Trial Information

Open-Label, Sequential, Ascending, Multi-Dose, Phase 1 Study of KW-2450 as Monotherapy in Subjects With Previously Treated Advanced Solid Tumor

This open-label, sequential, ascending, multi-dose, Phase 1 study will enroll up to 72
subjects with previously treated advanced solid tumor. Subjects at each dose level will
receive KW-2450 orally, once daily for 28 days followed by a 1-week observation period.
After completing the 1 week observation period, all subjects will receive KW-2450 on a
continuous daily schedule. All doses of KW-2450 will be administered to subjects under
overnight fasting conditions.

Dose escalation may proceed once >= 3 subjects have completed the Day 29 blood sample to
evaluate glucose. The safety of each dose level will be established prior to enrollment of
subjects in the next dose level. Dose escalation will proceed sequentially with accelerated
titration. Once the criteria for completing the accelerated titration are reached, dose
escalation will follow a modified Fibonacci schedule. Up to 6 subjects will be enrolled at
each dose level. Enrollment will proceed until the maximum tolerated dose (MTD) has been
established or the highest dose level (800 mg/day) has been reached.

Inclusion Criteria:

1. Voluntary signed and dated Institutional Review Board (IRB) approved informed consent
form and Health Insurance Portability and Accountability Act (HIPAA) authorization in
accordance with regulatory and institutional guidelines. This must be obtained before
performing protocol-related procedures that are not part of standard subject care

2. Histopathologically- or cytologically-documented, advanced primary or recurrent solid
tumor that has not responded to an adequate course of available therapy, that has
progressed or recurred despite an adequate course of available therapy, that is not
curable by available therapy or for which no accepted standard therapy exists

3. Ability to comply with visits/procedures required by the protocol. Subjects enrolled
in this trial must be treated at a participating center

4. A life expectancy of >3 months

5. Eastern Cooperative Oncology Group (ECOG) performance status score of <= 2 at study

6. Adequate hematologic function, as defined by:

an absolute neutrophil count (ANC) >= 1500/mm3 a hemoglobin level >=8.5 gm/dL a
platelet count >=100,000/mm3

7. Adequate hepatic function, as defined by:

a total bilirubin level <= 1.5 x the upper limit of normal (ULN); aspartate
aminotransferase (AST) and alanine transaminase (ALT) levels <= 2.5 x the ULN or
<= 5 x the ULN if known liver metastases

8. Adequate renal function, as defined by:

a serum creatinine (Scr) <= 1.5 mg/dL for male subjects; Scr <= 1.40 mg/dL for female
subjects Calculated creatine clearance > 60 mL/min based on Cockcroft-Gault formula

9. Subjects must be recovered from the effects of any prior anti-neoplastic therapy. The
ongoing adverse events due to these therapies must be <=Grade 1 prior to entering the
study. At least 5 half-lives should have elapsed for any investigational agents prior
to the administration of study medication

10. Subjects with central nervous system (CNS) metastases are eligible for enrollment if
they have received prior radiotherapy and/or surgery to site(s) of CNS metastatic
disease, have been off glucocorticoids for at least 4 weeks, are not taking
anticonvulsants, and have no overt evidence of neurological deficit

11. Men and women, >= 18 years of age at the time of enrollment

12. Women of childbearing potential (WOCBP) must agree to use effective contraception,
defined as oral contraceptives, double barrier method (condom plus spermicide or
diaphragm) or abstain from sexual intercourse during the study and for 90 days
following the last dose of KW-2450.

WOCBP include females who have experienced menarche and who have not undergone
successful sterilization (hysterectomy, bilateral tubal ligation, or bilateral
oophorectomy) or are not postmenopausal (defined as amenorrhea >= 12 consecutive

13. Male subjects must be willing to use an appropriate method of contraception (e.g.,
condoms) or abstain from sexual intercourse and inform any sexual partners that they
must also use a reliable method of contraception (e.g., birth control pills) during
the study and for 90 days following the last dose of KW-2450

14. WOCBP must have a negative pregnancy test within 7 days of receiving study

Exclusion Criteria:

1. Women who are pregnant or lactating

2. Known diabetes defined as:

- random serum glucose concentration of > 200 mg/dL

- fasting plasma glucose (FPG) of > 126 mg/dL

- 2-hour post load serum glucose concentration of > 200 mg/dL following an oral
glucose tolerance test

- the need for an oral hypoglycemic agent or insulin in order to keep the serum
glucose below the above levels; or

- any diabetic complication (cataract, retinopathy, nephropathy, etc.).

3. Subjects showing clinical evidence or with a history of cataract(s) or retinopathy

4. Abnormal free T4 values. Abnormal thyroid stimulating hormone (TSH) values at
enrollment will be further evaluated by free T4. Subjects with abnormal free T4
values and a history or evidence of thyroid disease will be excluded.

5. Subjects who are unable or unwilling to take metformin

6. Uncontrolled intercurrent illness including, but not limited to:

- Ongoing or active infection requiring parenteral antibiotics;

- A serious or nonhealing active wound, ulcer, or bone fracture;

- Uncontrolled hypertension (systolic blood pressure >160 mm Hg, diastolic blood
pressure >100 mm Hg, found on two consecutive measurements separated by a 1week
period despite treatment with two antihypertensive agents)

7. Unstable cardiovascular disease (i.e., including uncontrolled ischemic heart disease,
congestive heart failure, arrhythmia or hypertension; New York Heart Association >=
class III; or myocardial infarction or acute coronary syndrome within 6 months)

8. Positive for human immunodeficiency virus, hepatitis B or C

9. Subjects with inflammatory diseases of the gastrointestinal tract or malabsorption

10. Major surgery within 4 weeks prior to the administration of study medication

11. Evidence of organ dysfunction or any clinically significant deviation in physical
examination, vital signs, or clinical laboratory determination;

12. Prolonged QT intervals or any clinically significant abnormalities on ECG

13. A history of prior treatment with other agents specifically targeting IGFRs

14. Subjects who require pharmacological doses of glucocorticoids beyond replacement
doses. The use of topical, intra-ocular or inhalation glucocorticoids is permitted

15. Strong inhibitors/inducers of CYP3A4/5, herbal medications (within 1 week of
administration of study medication), or drugs for prevention of graft versus host
disease or transplant rejection (within 2 months prior to the administration of study

16. Hematopoetic growth factors and erythropoiesis-stimulating agents within 3 weeks
prior to the administration of study medication

Type of Study:


Study Design:

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

Outcome Measure:

To establish the safety, tolerability, and recommended Phase 2 dose of KW 2450 administered orally in subjects with advanced solid tumor who have not responded to standard therapy or for whom no standard therapy is available

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Michael Kurman, MD

Investigator Role:

Study Director

Investigator Affiliation:

Kyowa Hakko Kirin Pharma, Inc.


United States: Food and Drug Administration

Study ID:




Start Date:

June 2009

Completion Date:

August 2010

Related Keywords:

  • Solid Tumor
  • subjects with advanced Solid tumor who have not responded to standard therapy or for whom no standard therapy is available
  • Neoplasms



University of Maryland Greenbaum Cancer Center Baltimore, Maryland  21201
Karmanos Cancer Institute Detroit, Michigan  48201
Memorial Sloan Kettering New York, New York  10021