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Phase I Study of the Combination of the VEGFR Inhibitor, AZD2171, and MEK Inhibitor, AZD6244, in the Treatment of Solid Malignancies

Phase 1
18 Years
Open (Enrolling)
Stage IV Melanoma, Unspecified Adult Solid Tumor, Protocol Specific

Thank you

Trial Information

Phase I Study of the Combination of the VEGFR Inhibitor, AZD2171, and MEK Inhibitor, AZD6244, in the Treatment of Solid Malignancies


I. To determine the maximally tolerated dose of AZD2171 (cediranib) in combination with
AZD6244 hydrogen sulfate.

II. To describe the toxicity profile associated with AZD2171 (cediranib) in combination with
AZD6244 hydrogen sulfate.

III. To describe the tumor responses and identify any activity of this AZD2171 (cediranib)
in combination with AZD6244 hydrogen sulfate.

IV. To explore, through correlative studies, the effect of AZD2171 (cediranib) with or
without AZD6244 hydrogen sulfate on serum markers of apoptosis.

V. To assess the pharmacokinetic interaction of AZD2171 (cediranib) in combination with
AZD6244 hydrogen sulfate.

VI. To study the association of clinical (toxicity and/or tumor response or activity) with
the pharmacologic (pharmacokinetic/pharmacodynamic) parameters, and/or biologic (correlative
laboratory study) results.

OUTLINE: This is a dose-escalation study followed by a dose-expansion cohort study.

Patients receive cediranib maleate orally (PO) once daily and selumetinib PO once or twice
daily on days 1-28 (days 8-28 of course 1). Courses repeat every 28 days in the absence of
disease progression or unacceptable toxicity.

Some patients undergo blood sample collection at baseline and periodically during study for
correlative studies.

After completion of study therapy, patients are followed up at 3 months.

Inclusion Criteria:

- Histologic proof of cancer that is now considered clinically unresectable and for
whom there is no standard therapy; NOTE: For the MTD expansion cohort only:
Metastatic melanoma histology is required

- Measurable and non-measurable disease are eligible

- Ability to provide informed consent

- ANC >= 1500/uL

- PLT >= 100,000/uL

- Total bilirubin =< 1.5 x upper limit of normal (ULN)

- AST =< 2.5 x ULN or =< 5 x ULN in presence of liver metastases

- Creatinine =< 1.5 x ULN

- HgB >= 9.0 gm/dL

- Alkaline phosphatase =< 2.5 x ULN

- Creatinine clearance > 50 ml/min, by either Cockcroft-Gault formula or 24-hour urine
collection analysis

- ECOG Performance Status (PS) 0, 1

- Willing to return to Mayo for follow up

- Life expectancy >= 12 weeks

- Women of childbearing potential only: Negative serum pregnancy test done =< 7 days
prior to registration, for women of childbearing potential only

- Expansion Phase only: Willing to provide blood samples and archived tumor tissue for
correlative research purposes

Exclusion Criteria:

- Known standard therapy for the patient's disease that is potentially curative or
definitely capable of extending life expectancy

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Any of the following prior therapies:

- Chemotherapy =< 28 days prior to registration

- Mitomycin C/nitrosoureas =< 42 days prior to registration

- Immunotherapy =< 28 days prior to registration

- Biologic therapy =< 28 days prior to registration

- Radiation therapy =< 28 days prior to registration

- Radiation to > 25% of bone marrow

- Failure to fully recover from acute, reversible effects of prior chemotherapy
regardless of interval since last treatment

- Cardiac conditions as follows:

- Uncontrolled hypertension (BP >= 150/95 despite optimal therapy)

- Heart failure NYHA Class II or above or Left ventricular ejection fraction < 50%

- Atrial fibrillation with heart rate >100 bpm

- Unstable ischemic heart disease (MI within 6 months prior to starting treatment,
or angina requiring use of nitrates more than once weekly)

- Patients who require concomitant agents that prolong QTc

- Known brain or CNS metastases without definitive therapy; patients who have received
definitive therapy for CNS lesions may be considered if there is no evidence of
progression on CT or MRI imaging obtained 3 months apart

- Any of the following because this study involves an investigational agent whose
genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are

- Pregnant women

- Nursing women

- Men or women of childbearing potential who are unwilling to employ adequate

- Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy
considered investigational (utilized for a non-FDA-approved indication and in the
context of a research investigation)

- Co-morbid systemic illnesses or other severe concurrent disease which, in the
judgment of the investigator, would make the patient inappropriate for entry into
this study or interfere significantly with the proper assessment of safety and
toxicity of the prescribed regimens

- Immunocompromised patients (other than that related to the use of corticosteroids)
with the exception of patients known to be HIV positive and have a CD4 count > 400
and do not require antiretroviral therapy

- Receiving any other investigational agent which would be considered as a treatment
for the primary neoplasm

- Other active malignancy =< 3 years prior to registration; EXCEPTIONS: Nonmelanotic
skin cancer or carcinoma-in-situ of the cervix; NOTE: If there is a history or prior
malignancy, they must not be receiving other specific treatment (i.e. hormonal
therapy) for their cancer

- Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week
apart unless urinary protein < 1.5g in a 24 hr period or urine protein/creatinine
ratio < 1.5

- History of exposure to AZD2171 (cediranib), AZD6244 hydrogen sulfate, or MEK, Ras or
Raf inhibitors (sorafenib); Note: prior therapy with bevacizumab, sunitinib,
pazopanib or aflivercept (VEGF Trap) are allowed

- Surgery within two weeks prior to registration

- Significant hemorrhage (> 30mL bleeding/episode in previous 3 months) or hemoptysis
(> 5mL fresh blood in previous 4 weeks)

- Mean QTc interval with Bazetts correction > 480msec (CTC Grade 1) in screening ECG or
history of familial long QT syndrome

- Patients who are unable to swallow tablets and capsules

Type of Study:


Study Design:

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

Outcome Measure:

MTD, defined as the dose level below the lowest dose that induces dose limiting toxicity in at least one-third of patients (at least 2 of a maximum of 6 new patients)

Outcome Time Frame:

28 days

Safety Issue:


Principal Investigator

Paul Haluska

Investigator Role:

Principal Investigator

Investigator Affiliation:

Mayo Clinic


United States: Food and Drug Administration

Study ID:




Start Date:

December 2012

Completion Date:

Related Keywords:

  • Stage IV Melanoma
  • Unspecified Adult Solid Tumor, Protocol Specific
  • Melanoma



Mayo ClinicRochester, Minnesota  55905
Mayo Clinic in FloridaJacksonville, Florida  32224