Cilengitide and Sunitinib Malate in Treating Patients With Advanced Solid Tumors or Glioblastoma Multiforme

PRIMARY OBJECTIVES:

I. Determine the effect of cilengitide on changes in serum VEGFR2, a pharmacodynamic
biomarker of sunitinib malate effects on endothelial function, during the withdrawal phase
of a course of sunitinib malate in patients with advanced solid tumors or glioblastoma
multiforme.

SECONDARY OBJECTIVES:

I. Determine the effect of cilengitide exposure on changes in VEGFR2 over the 14-day
interval from the end of sunitinib malate administration to the end of course 1 in these
patients.

II. Test the safety and efficacy of this regimen in these patients. III. Develop serum
collagen c-telopeptide crosslinks (CTx) as a pharmacodynamic marker for cilengitide.

OUTLINE:

COURSE I: Patients receive oral sunitinib malate on days 1-14 (weeks 1-2). Patients are then
randomized to 1 of 2 treatment arms.

ARM I: Patients receive cilengitide IV over 1 hour twice in weeks 3 and 4.

ARM II: Patients do not receive treatment in weeks 3 and 4.

COURSE II: Patients in both arms then receive oral sunitinib malate on days 1-14 and
cilengitide IV over 1 hour twice in weeks 3 and 4. Treatment repeats every 4 weeks in the
absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for correlative
biomarker studies, including VEGFR2 and collagen C-telopeptide crosslink analysis.

After completion of study therapy, patients are followed up periodically.

Inclusion Criteria:

- Histologically confirmed solid tumor or malignant glioblastoma multiforme meeting ≥ 1
of the following criteria:

- Disease refractory to standard therapy

- No standard therapy exists

- Sunitinib malate monotherapy would be appropriate management

- Measurable disease is not required

- Previously treated brain metastases or primary brain neoplasms allowed provided
patient is not receiving concurrent corticosteroids

- Karnofsky performance status 70-100%

- ANC ≥ 1,500/μL

- WBC ≥ 3,000/μL

- Platelet count ≥ 100,000/μL

- Hemoglobin ≥ 9 g/dL

- Total bilirubin normal (unless due to documented Gilbert syndrome)

- AST and ALT < 2.5 times upper limit of normal (ULN) (< 5 times ULN in the presence of
liver metastases)

- Creatinine normal OR creatinine clearance ≥ 60 mL/min

- Serum calcium ≤ 12.0 mg/dL

- QTc < 500 msec

- Patients with any of the following are allowed provided they have NYHA class I-II
cardiac function and undergo a baseline ECHO/MUGA:

- History of class II heart failure and asymptomatic on treatment

- Prior anthracycline exposure

- Previously treated with central thoracic radiotherapy that included the heart in
the radiotherapy port

- Not pregnant or nursing

- Negative pregnancy test

- Fertile patients must use effective barrier contraception

- No history of allergic reactions attributed to compounds of similar chemical or
biologic composition to sunitinib malate

- No concurrent uncontrolled illness including, but not limited to, any of the
following:

- Ongoing or active infection

- Symptomatic congestive heart failure

- Unstable angina pectoris

- Cardiac arrhythmia

- Psychiatric illness and/or social situation that would limit compliance with
study requirements

- No pre-existing thyroid abnormality for which thyroid function cannot be maintained
in the normal range with medication

- No documented thrombosis (pulmonary embolism or deep vein thrombosis) within the past
6 months

- No known coagulopathy or thrombophilia

- No provengastric or duodenal ulcer or clinically significant gastrointestinal (GI)
blood loss within the past 6 weeks

- No history of CNS hemorrhage

- No life-threatening bleeding diathesis within the past 6 months

- No history of serious ventricular arrhythmia (i.e., ventricular fibrillation or
ventricular tachycardia ≥ 3 beats in a row) or other significant ECG abnormalities

- No poorly controlled hypertension (i.e., systolic BP ≥ 150mm Hg or diastolic BP ≥ 100
mm Hg)

- No condition that would impair the ability to swallow and retain sunitinib malate
tablets, including any of the following:

- GI tract disease resulting in an inability to take oral medications or a
requirement for IV alimentation

- Prior surgical procedures affecting absorption

- Active peptic ulcer disease

- No gastrostomy, jejunostomy, or other forms of enteral tube feeding modalities

- None of the following conditions:

- Serious or non-healing wound or ulcer

- Abdominal fistula, GI perforation, or intra-abdominal abscess within the past 28
days

- Cerebrovascular accident or transient ischemic attackwithin the past 12 months

- Myocardial infarction, cardiac arrhythmia, stable/unstable angina, symptomatic
congestive heart failure, or coronary/peripheral artery bypass graft or stenting
within the past 12 months

- NYHA class III or IV heart failure

- Radiographically or physiologically diagnosed usual interstitial pneumonitis
(UIP) or non-specific interstitial pneumonitis (NSIP)

- No bone fracture within the past 12 months

- No other concurrent anticancer agents or therapies

- More than 4 weeks since prior radiotherapy or systemic antineoplastic therapy (6
weeks for nitrosoureas, mitomycin C, or bevacizumab) and recovered

- More than 2 weeks since prior hormone replacement therapy or hormonal contraceptives

- More than 1 month since prior surgery

- At least 7 days since prior and no concurrent CYP3A4 inhibitors

- At least 12 days since prior and no concurrent CYP3A4 inducers

- Prior luteinizing hormone-releasing hormone agonists for hormone-refractory prostate
cancer allowed

- Prior antiangiogenic agents (e.g., sorafenib, pazopanib, AZD2171, PTK787, or VEGF
Trap) allowed provided there is no disease progression

- No prior cilengitide or sunitinib malate

- No prior bevacizumab

- No other concurrent investigational agents

- No concurrent combination antiretroviral therapy for HIV-positive patients

- No concurrent agents with proarrhythmic potential (e.g., terfenadine, quinidine,
procainamide, disopyramide, sotalol, probucol, bepridil, haloperidol, risperidone,
indapamide, or flecainide)

- No concurrent palliative radiotherapy

- No other concurrent chemotherapy or biologic agents

- No concurrent medications that may cause QTc prolongation

- No concurrent therapeutic doses of coumarin-derivative anticoagulants (e.g.,
warfarin)

- Up to 2 mg of daily warfarin for the prophylaxis of thrombosis allowed

- Low-molecular weight heparin allowed provided PT/INR ≤ 1.5

- No concurrent grapefruit juice