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A Phase I, Single-institution Open Label, Dose-escalation Trial With an Expansion Trial Cohort Evaluating the Safety and Tolerability of AZD6244 and IMCA12 in Subjects With Advanced Solid Malignancies

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

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Trial Information

A Phase I, Single-institution Open Label, Dose-escalation Trial With an Expansion Trial Cohort Evaluating the Safety and Tolerability of AZD6244 and IMCA12 in Subjects With Advanced Solid Malignancies


I. Determine the safety and toxicity of the combination of AZD6244 and IMC-A12 in advanced
solid tumors that have progressed on standard therapy.

II. Finding the maximum tolerated dose (MTD)/recommended phase II dose of the combination.


I. Explore preliminary evidence of efficacy of the combination of AZD6244 and IMC-A12 in
advanced solid tumors using RECIST criteria for tumor response.

II. Define pharmacodynamic (PD) profile of the combination of IMC-A12 and AZD6244.

III. Correlate pharmacokinetics (PK) of the combination of IMC-A12 and AZD6244 to
pharmacodynamic (PD) endpoints.

IV. Assess the PK/PD (phospho-S6) link with AZD6244 when administered in combination with

OUTLINE: This is a dose-escalation study of selumetinib and cixutumumab.

Patients receive selumetinib orally (PO) twice daily (BID) on days 1-28 and cixutumumab
intravenously (IV) on days 1 and 15. Courses repeat every 28 days in the absence of disease
progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 4 weeks.

Inclusion Criteria:

- Patients must have a histologically-confirmed metastatic or locally advanced solid
tumor that has failed to respond to standard therapy, progressed despite standard
therapy, or for which standard therapy does not exist

- There is no limit on the number of prior treatment regimens

- Patients must be off prior chemotherapy, radiation therapy, hormonal therapy, or
biological therapy for at least 4 weeks; patients who were receiving mitomycin C,
nitrosoureas, or carboplatin must be 6 weeks from the last administration of
chemotherapy; patients with prostate cancer may continue to receive LHRH agonist
(unless orchiectomy has been performed)

- ECOG performance status 0-1

- Life expectancy of greater than 3 months

- Leukocytes >= 3,000/mcL

- Absolute neutrophil count >= 1,200/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 9 mg/dL

- Albumin >= 2.5 g/dL

- Total bilirubin =< 1.5 X institutional upper limits of normal in the absence of
Gilbert's syndrome

- AST(SGOT) and ALT(SGPT) =< 2.5 X institutional upper limit of normal

- Serum glucose =< 120 mg/dL

- Creatinine =< 1.5 mg/dL OR creatinine clearance >= 45 mL/min for patients with
creatinine levels above institutional normal.

- Patients must have recovered from toxicity related to prior therapy to at least grade
1 (defined by CTEP Active Version of the CTCAE); chronic stable grade 2 peripheral
neuropathy secondary to neurotoxicity from prior therapies may be considered on a
case by case basis by the Principal Investigator

- As the effect of AZD6244 and IMC-A12 in combination on the developing human fetus is
not known, women of child-bearing potential and men must agree to use adequate
contraception (abstinence; hormonal or barrier method of birth control) for the study
and at least 3 months after completion

- Female patient of childbearing potential has a negative serum pregnancy test within 7
days of study enrollment

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

- Measurable disease

- Patient must be able to swallow pills

- Patients must have LVEF > 45% before starting therapy as measured by echocardiogram

- Patients should have a baseline ophthalmologic examination before starting therapy

Exclusion Criteria:

- Patient current evidence of active and uncontrolled infection, documented Child's
class B-C cirrhosis, or active pancreatitis

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

- Left ventricular ejection fraction of =< 45% or NYHA Class II-IV CHF

- Prior or current cardiomyopathy

- Atrial fibrillation with heart rate > 100 bpm

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

- Patients receiving any medications that are inhibitors or inducers of specific CYP450
enzyme(s) are ineligible

- History of growth hormone deficiency or excess, or patient is concurrently using
growth hormone (GH), or growth hormone inhibitors

- Patient has a known hypersensitivity to the components of study drugs, its analogs,
or drugs of similar chemical or biologic composition

- Patient has prior exposure to IGF-1R or RAF/MEK inhibitors

- The patient has poorly controlled diabetes mellitus, defined as a Hba1c > 7%

- Patients with active CNS metastases and/or carcinomatous meningitis are excluded;
however, patients with CNS metastases who have completed a course of therapy would be
eligible for the study provided they are clinically stable for 3 months prior to
entry as defined as:

- No evidence of new or enlarging CNS metastasis

- No new signs or symptoms consistent with CNS metastasis

- Off steroids or on a stable dose of steroids for at least four weeks

- Patient with a primary central nervous system tumor

- Patient has known psychiatric or substance abuse disorders that is uncontrolled and
would interfere with cooperation with the requirements of the trial

- Patient is pregnant or breastfeeding.

- Patient is Human Immunodeficiency virus (HIV)-positive and on highly active
antiretroviral therapy (HAART), as drug interactions between those agents and these
experimental agents are wholly unknown; if this combination goes forward, this
regimen will need to be tested in this group of patients in the future; patients with
HIV who are well compensated and do not require HAART therapy are eligible for the

- Patient has active hepatitis B or C on treatment

- Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
of day 1 of therapy

- Use of any other concurrent investigational agents or anticancer agents including
hormonal therapy, except in the case of prostate cancer patients who are being
treated with LHRH agonist at the time of trial entry

- Patients should avoid excessive sun exposure and use adequate sunscreen protection if
sun exposure is anticipated

- History of any serious intraocular or retinal pathology as determined by the
reference ophthalmologist, with the exception of controlled glaucoma or cataracts; in
particular, patients with a history of retinal vein occlusion (RVC) or central serous
retinopathy (CSR), or predisposing factors to RVO or CSR as assessed by ophthalmic
exam (e.g. evidence of new optic disc cupping, new visual field defects, intraocular
pressure > 21 mmHg, uncontrolled glaucoma or ocular hypertension, uncontrolled
systemic disease such as hypertension, diabetes mellitus, or history of
hyperviscosity or hypercoagulability syndromes) must be excluded

Type of Study:


Study Design:

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

Outcome Measure:

Maximum tolerated dose of selumetinib in combination with cixutumumab defined as the dose produced DLT in =< 1 out of 6 patients

Outcome Description:

The proportion of patients with serious or life threatening toxicities will be estimated along with 95% confidence intervals. Tabulated by dose combination, by toxicity type, and by the severity.

Outcome Time Frame:

Up to 4 weeks

Safety Issue:


Principal Investigator

Nilofer Azad

Investigator Role:

Principal Investigator

Investigator Affiliation:

Johns Hopkins University


United States: Food and Drug Administration

Study ID:




Start Date:

November 2009

Completion Date:

Related Keywords:

  • Unspecified Adult Solid Tumor, Protocol Specific



Johns Hopkins University Baltimore, Maryland  21205