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Ph I/II Study of PTK 787 (Vatalanib) and Gleevec (Imatinib) in Patients With Refractory Acute Myelogenous Leukemia (AML), Agnogenic Myeloid Metaplasia (AMM), and Chronic Myelogenous Leukemia- Blastic Phase (CML-BP)


Phase 1/Phase 2
15 Years
N/A
Not Enrolling
Both
Acute Myelogenous Leukemia, Agnogenic Myeloid Metaplasia, Chronic Myelogenous Leukemia

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Trial Information

Ph I/II Study of PTK 787 (Vatalanib) and Gleevec (Imatinib) in Patients With Refractory Acute Myelogenous Leukemia (AML), Agnogenic Myeloid Metaplasia (AMM), and Chronic Myelogenous Leukemia- Blastic Phase (CML-BP)


Rationale: The purpose of this study is to combine PTK-787, a potent orally vascular
endothelial growth factor (VEGF) receptor inhibitor (in disorders where VEGF is known to be
involved in the pathophysiology), with Imatinib mesylate (IM), a protein-tyrosine kinase
inhibitor of abl, Bcr-Abl, platelet derived growth factor (PDGF), and c-Kit (in same
disorders where these kinases are believed to be important). The potential synergy between
oral agents that inhibit these kinases in disorders where each of the two agents have some,
but inadequate, single agent activity is being studied in this protocol. We will also have
an opportunity to assess if there is any correlation between response and individual kinase
mutations e.g., c-Kit in patients with AML. If improved outcomes are observed, further
studies will be indicated to investigate which, if either, agent is predominantly
responsible for such a benefit - these studies will be facilitated by the availability of
more potent e.g., (AMN107 as an abl inhibitor), (Bevacizumab, AG013736 as VEGF inhibitors)
agents which will help to define the relative importance of the various inhibitory
activities.

Objectives: To determine the maximum tolerated doses (MTD) and pharmacokinetics (PK) of PTK
787 and imatinib mesylate, when given in combination to patients with refractory acute
myelogenous leukemia (AML), agnogenic myeloid metaplasia (AMM) and chronic myelogenous
leukemia in blastic phase (CML-BP).

To determine the efficacy (response rate, survival, time to progression, time to treatment
failure, duration of response) of the MTD in these study populations.


Inclusion Criteria:



- Patients with relapsed or refractory AML (including refractory anemia with excess of
blasts [RAEB], refractory anemia with excess of blasts in transition to AML [RAEBT],
or untreated AML when standard chemotherapy is not considered appropriate or is
refused, CML in blastic phase, and agnogenic myeloid metaplasia (AMM)

- Age 15 years or greater (separate pediatric studies will be conducted if results of
adult studies are considered sufficiently positive)

- Laboratory values less than or equal to 2 weeks prior to study entry - Serum
bilirubin 1.5mg/dL, unless considered due to organ leukemic involvement or Gilbert's
syndrome. - SGOT or SGPT less than or equal to 2.5 x upper limit of normal. - Serum
creatinine less than or equal to 2mg/dL,

- Negative for proteinuria based on dip stick reading OR, if documentation of +1 result
for protein on dip stick reading, then total urinary protein less than or equal to
500 mg and measured creatinine clearance (CrCl) greater than or equal to 50 mL/min
from a 24-hour urine collection.

- The effects of PTK 787 and imatinib on the developing human fetus are unknown. For
this reason and because inhibitors of mRNA translation are known to be teratogenic,
women of child-bearing potential and men must agree to use adequate contraception
(barrier method of birth control; abstinence) for the duration of study
participation.

- Due to possible interactions with study drugs, oral contraceptives should not be
used. Should a woman become pregnant or suspect she is pregnant while participating
in this study, she should inform her treating physician immediately. If the partner
of a male patient taking PTK 787 and/or Gleevec conceives, the physician should be
notified

- Ability to understand and the willingness to sign a written informed consent
document.

- Performance Status less than or equal to 2.

Exclusion Criteria:

- Patients who have had cytotoxic chemotherapy, except for hydroxyurea, or radiotherapy
within 7 days prior to entering the study. Patients will have cleared all toxicities
from prior therapies before starting this study combination.

- Patients who have received investigational drugs less than or equal to 2 weeks prior
to study entry

- Prior therapy with anti-VEGF agents.

- Concomitant administration of anticancer drugs is not permitted, except for
hydroxyurea. Leukopheresis is allowed within the first 28 days of treatment if
required to control elevated blast levels or platelet counts. Within the first 28
days of treatment, hydroxyurea may be given at a maximum dose of 5 g daily for up to
a total of 7 days. For leukopheresis, a maximum of 2 procedures per week or 4
procedures during the first 28 days is allowed.

- Patients may not be receiving any other cytotoxic investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to PTK 787 or imatinib.

- Uncontrolled intercurrent illness including, but not limited to, uncontrolled
diabetes, interstitial pneumonia or extensive and symptomatic interstitial fibrosis
of the lung, chronic liver disease or psychiatric illness/social situations that
would limit compliance with study requirements.

- Uncontrolled intercurrent illness including, not limited to, ongoing uncontrolled
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, uncontrolled high blood pressure, history of labile hypertension, history
of poor compliance with an antihypertensive regimen, myocardial infarction less than
or equal to 6 months prior to registration, uncontrolled diabetes, interstitial
pneumonia or extensive and symptomatic interstitial fibrosis of lung, chronic liver
disease or psychiatric illness/social situations that limits compliance with study
requirements.

- Pleural effusion or ascites that causes respiratory compromise (greater than or equal
to Common Toxicity Criteria (CTC) grade 2 dyspnea).

- Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of PTK787 (i.e., ulcerative disease, uncontrolled nausea,
vomiting, diarrhea, malabsorption syndrome, bowel obstruction, or inability to
swallow the tablets).

- Patients with confirmed diagnosis of human immunodeficiency virus (HIV) infection are
excluded - A separate study for patients with HIV will be performed if indicated.

- Pregnant women are excluded from this study because PTK 787 and imatinib may have a
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with PTK 787 or imatinib, breastfeeding patients will not be eligible.

- Patients with known central nervous system (CNS) disease are excluded.

- Patients with a history of another primary malignancy less than or equal to 5 years,
with the exception of inactive basal or squamous cell carcinoma of the skin.

- Patients w/ recent major surgery are excluded (less than 4 wks of starting this
study) or minor surgery less than or equal to 2 weeks prior to randomization.
Insertion of a vascular access device is not considered major or minor surgery in
this regard. Patients must have recovered from all surgery-related toxicities.

- Patients who are taking warfarin sodium (Coumadin) or similar oral anticoagulants
that are metabolized by the cytochrome P450 system. Heparin is allowed.

Type of Study:

Interventional

Study Design:

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

Outcome Measure:

Time to Response

Outcome Description:

Time to response is defined as the period of time from the date of first study drug administration until the first objective documentation of response.

Outcome Time Frame:

28 days

Safety Issue:

Yes

Authority:

United States: Food and Drug Administration

Study ID:

2004-0248

NCT ID:

NCT00088231

Start Date:

July 2004

Completion Date:

October 2006

Related Keywords:

  • Acute Myelogenous Leukemia
  • Agnogenic Myeloid Metaplasia
  • Chronic Myelogenous Leukemia
  • Acute Myelogenous Leukemia (AML)
  • Agnogenic Myeloid Metaplasia (AMM)
  • Chronic Myelogenous Leukemia-Blastic Phase (CML-BP)
  • Primary Myelofibrosis
  • Leukemia
  • Leukemia, Myeloid, Acute
  • Leukemia, Myeloid
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive
  • Metaplasia

Name

Location

M.D. Anderson Cancer CenterHouston, Texas  77030