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Phase II Study of MLN518 in Patients With Metastatic Clear Cell Renal Cell Carcinoma

Phase 2
18 Years
Not Enrolling
Clear Cell Renal Cell Carcinoma, Recurrent Renal Cell Cancer, Stage IV Renal Cell Cancer

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Trial Information

Phase II Study of MLN518 in Patients With Metastatic Clear Cell Renal Cell Carcinoma


I. To determine the overall efficacy of MLN518 in patients with metastatic clear cell renal


I. To evaluate the effect of MLN518 on progression-free survival and overall survival in
patients with metastatic clear cell renal carcinoma.

II. To evaluate the toxicity of MLN518 in patients with metastatic clear cell renal

III. To evaluate the effects of MLN518 on serum VEGF-A, VEGF-R2, PIGF, and PDGF levels of
patients with metastatic renal cell carcinoma receiving MLN518.

IV. To determine the VHL gene status, methylation, and pVHL in archived material from the
primary nephrectomy specimen of patients receiving MLN518.

V. To evaluate tumor blood flow and vessel permeability based on functional imaging with
dynamic contrast enhanced magnetic resonance imaging (dceMRI) in metastatic renal cell
carcinoma patients treated with MLN518.

OUTLINE: This is an open-label, nonrandomized study.

Patients receive oral tandutinib twice daily on days 1-28. Treatment repeats every 28 days
in the absence of disease progression or unacceptable toxicity.

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

Inclusion Criteria:

- Histologically confirmed RCC of clear cell histology; subjects must have a component
of conventional clear cell RCC with or without sarcomatoid features

- Patients must have evidence of metastatic disease and must have had a cytoreductive
nephrectomy at least 28 days prior to first day of treatment

- Archival tissue from nephrectomy must be available for correlative studies

- Patients must have measurable disease, defined by RECIST criteria

- Patients must have received at least one prior FDA approved therapy for metastatic
renal cell carcinoma with either Sutent, or Nexavar, and may have received up to
three prior systemic therapies for metastatic disease; prior cytokine therapy is also

- Prior systemic therapy with other antiangiogenic agents such as Thalidomide,
Bevacizumab, or AG013736 is permitted

- Patients must have a life expectancy of >= 3 months

- Patients must have an ECOG performance status of 0-1 (Karnofsky >= 70%)

- Patients must be at least 4 weeks from radiation therapy and recovered from all
related toxicity

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Hemoglobin >= 8.5 g/dl

- Total Bilirubin =< 1.5 X institutional upper limit of normal

- AST (SGOT)/ALT (SGPT) =< 3.5 X institutional upper limit of normal

- Alkaline phosphatase =< 2.5 ULN (=< 10 x ULN in presence of bone metastasis)

- Serum calcium of =< 12 mg/dl

- Creatinine =< 1.5 X institutional upper limit of normal

- INR =< 1.5, except for subjects receiving warfarin therapy; for subjects who are
receiving warfarin for prophylaxis or treatment of thrombosis, INR values should be
carefully monitored while patients are on study

- Electrocardiogram (12-lead) with cQTC < 500 msec using the Bazett's formula

- Absence of significant effusions and/or ascites

- No major surgery requiring general anesthesia within the past 28 days

- Patients may not have had brain metastasis

- Eligibility of patients receiving any medications or substances known to affect or
with the potential to affect the activity or pharmacokinetics of MLN518 will be
determined following review of their case by the Principal Investigator; because
MLN518 is a substrate of the P-glycoprotein (P-gp) drug efflux pump, co-
administration of agents that inhibit or induce this mechanism may alter exposure to

- The effects of MLN518 on the developing human fetus at the recommended therapeutic
dose are unknown; for this reason and because receptor tyrosine kinase inhibitors are
known to be teratogenic, women of child-bearing potential and men must agree to use
adequate contraception (hormonal or barrier method of birth control; abstinence)
prior to study entry and for the duration of study participation; should a woman
become pregnant or suspect she is pregnant while participating in this study, she
should inform her treating physician immediately; sexually active patients must
continue to use contraception for three months after completion of study therapy

- All patients must be informed of the investigational nature of this study and must
provide written informed consent in accordance with institutional and federal
guidelines; a copy of the informed consent document signed by the patient must be
given to the patient

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier

- Patients may not be receiving any other investigational agents

- Patients may not be co-medicated with an agent that causes QTc prolongation

- Patients with a mean QTc > 500 msec using the Bazett's formula taken from the
screening electrocardiogram or history of familial long QT syndrome are ineligible

- Left ventricular ejection fraction (LVEF) < 40%

- Myocardial infarction within 6 months of enrollment or New York Heart Association
(NYHA) Class III or IV heart failure, uncontrolled angina, severe uncontrolled
ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or
active conduction system abnormalities

- Ongoing vomiting, or nausea >= grade 2 (NCI CTCAE v3.0)

- Patients with any condition (e.g., gastrointestinal tract disease resulting in an
inability to take oral medication or a requirement for IV alimentation, prior
surgical procedures affecting absorption, or active peptic ulcer disease) that
impairs their ability to swallow pills or absorb oral medications are excluded

- Known or suspected primary muscular or neuromuscular disease (e.g., muscular
dystrophy, myasthenia gravis)

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MLN518 such as Tarceva™, Iressa® and Cardura® XL

- Patients with any CNS metastases or uncontrolled seizure disorder

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infections or psychiatric illness/social situations that would limit compliance with
study requirements

- Any malignancy other than a renal cell carcinoma, with the following exceptions:

- Basal or squamous cell carcinomas of the skin

- Carcinoma in-situ of the uterine cervix

- Any malignancy treated with curative intent and in complete remission for > 3

- Patients with organ allografts

- Patients with non-clear cell carcinoma i.e., papillary, collecting duct, or

- Pregnant women are excluded from this study because MLN518 is a receptor tyrosine
kinase inhibitor with the 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 MLN518, breastfeeding should be
discontinued if the mother is treated with MLN518

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with MLN518; in addition, these
patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy; appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated

- Inability to comply with study and/or follow-up procedures

Type of Study:


Study Design:

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

Outcome Measure:

Overall efficacy, taking into account both objective response and meaningful reductions in tumor burden that do not meet the RECIST criteria for PR or CR (e.g., 5-30% reduction in RECIST defined tumor burden)

Outcome Time Frame:

Up to 4 weeks after completion of study treatment

Safety Issue:


Principal Investigator

Jorge Garcia

Investigator Role:

Principal Investigator

Investigator Affiliation:

Case Comprehensive Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

November 2006

Completion Date:

Related Keywords:

  • Clear Cell Renal Cell Carcinoma
  • Recurrent Renal Cell Cancer
  • Stage IV Renal Cell Cancer
  • Carcinoma
  • Carcinoma, Renal Cell



Case Western Reserve UniversityCleveland, Ohio  44106