Cediranib Maleate and Selumetinib in Treating Patients With Solid Malignancies

This study is ongoing, but not recruiting participants.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01364051
First received: May 26, 2011
Last updated: September 16, 2014
Last verified: July 2014
  Purpose

This phase I trial studies the side effects and best dose of cediranib maleate and selumetinib in treating patients with solid malignancies. Cediranib maleate and selumetinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Cediranib maleate may also stop the growth of tumor cells by blocking blood flow to the tumor.


Condition Intervention Phase
Stage IV Melanoma
Unspecified Adult Solid Tumor, Protocol Specific
Drug: cediranib maleate
Drug: selumetinib
Other: laboratory biomarker analysis
Other: pharmacological study
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I Study of the Combination of the VEGFR Inhibitor, AZD2171, and MEK Inhibitor, AZD6244, in the Treatment of Solid Malignancies

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • 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) [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).


Secondary Outcome Measures:
  • Incidence of adverse events, classified as either possibly, probably, or definitely related to study treatment as per the NCI CTCAE [ Time Frame: Up to 3 months ] [ Designated as safety issue: Yes ]
    The number and severity of all adverse events (overall, by dose-level, and by tumor group) will be tabulated and summarized in this patient population. The grade 3+ adverse events will also be described and summarized in a similar fashion.

  • Incidence of hematologic toxicities evaluated via CTC standard toxicity grading [ Time Frame: Up to 3 months ] [ Designated as safety issue: Yes ]
    Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization

  • Incidence of non-hematologic toxicities evaluated via the ordinal CTC standard toxicity grading [ Time Frame: Up to 3 months ] [ Designated as safety issue: Yes ]
    Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.

  • Overall toxicity incidence as per NCI CTCAE [ Time Frame: Up to 3 months ] [ Designated as safety issue: Yes ]
    Overall toxicity incidence as well as toxicity profiles by dose level, patient and tumor site will be explored and summarized. Frequency distributions, graphical techniques and other descriptive measures will form the basis of these analyses.

  • Best response, in terms of Response Evaluation Criteria in Solid Tumors (RECIST) [ Time Frame: From the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started), assessed up to 3 months ] [ Designated as safety issue: No ]
    Responses will be summarized by simple descriptive summary statistics delineating complete and partial responses as well as stable and progressive disease in this patient population (overall and by tumor group).


Other Outcome Measures:
  • Changes of the serum levels of M30 (dose expansion phase) [ Time Frame: Baseline up to day 22 of course 1 ] [ Designated as safety issue: No ]
    Descriptive statistics, scatter plots and longitudinal data plot will form the basis of presentation of these data. Multiple comparison corrections (e.g. Bonferroni) will be performed during data analyses.

  • Changes of the serum levels of caspase 3 (dose expansion phase) [ Time Frame: Baseline up to day 22 of course 1 ] [ Designated as safety issue: No ]
    Descriptive statistics, scatter plots and longitudinal data plot will form the basis of presentation of these data. Multiple comparison corrections (e.g. Bonferroni) will be performed during data analyses.

  • Changes of the serum levels of cytochrome c (dose expansion phase) [ Time Frame: Baseline up to day 22 of course 1 ] [ Designated as safety issue: No ]
    Descriptive statistics, scatter plots and longitudinal data plot will form the basis of presentation of these data. Multiple comparison corrections (e.g. Bonferroni) will be performed during data analyses.


Estimated Enrollment: 87
Study Start Date: May 2011
Estimated Primary Completion Date: June 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (cediranib maleate, selumetinib)
Patients receive cediranib maleate PO QD and selumetinib PO QD or BID on days 1-28 (days 8-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Courses may be extended to 56 days after 1 year of study treatment at the discretion of the treating physician.
Drug: cediranib maleate
Given PO
Other Names:
  • AZD2171
  • Recentin
Drug: selumetinib
Given PO
Other Names:
  • ARRY-142886
  • AZD6244
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

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

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 (QD) and selumetinib PO QD or twice daily (BID) on days 1-28 (days 8-28 of course 1). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Courses may be extended to 56 days after 1 year of study treatment at the discretion of the treating physician.

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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • Absolute neutrophil count (ANC) >= 1500/uL
  • Platelets (PLT) >= 100,000/uL
  • Total bilirubin =< 1.5 x upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) =< 2.5 x ULN or =< 5 x ULN in presence of liver metastases
  • Creatinine =< 1.5 x ULN
  • Hemoglobin (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
  • Eastern Cooperative Oncology Group (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 (blood pressure [BP] >= 150/95 despite optimal therapy)
    • Heart failure New York Heart Association (NYHA) class II or above or Left ventricular ejection fraction < 50%
    • Atrial fibrillation with heart rate >100 bpm
    • Unstable ischemic heart disease (myocardial infarction [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 corrected QT interval (QTc)
  • Known brain or central nervous system (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 computed tomography (CT) or magnetic resonance imaging (MRI) imaging obtained 3 months apart
  • Any of the following:

    • Pregnant women
    • Nursing women
    • Men or women of childbearing potential who are unwilling to employ adequate contraception
  • Other concurrent chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered investigational (utilized for a non-Food and Drug Administration [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 human immunodeficiency virus [HIV] positive and have a cluster of differentiation [CD]4 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 hour (hr) period or urine protein/creatinine ratio < 1.5
  • History of exposure to AZD2171 (cediranib), AZD6244 hydrogen sulfate, or mitogen-activated protein kinase kinase (MEK), retrovirus-associated deoxyribonucleic acid (DNA) sequence (Ras) or v-RAF-1 murine leukemia viral oncogene homolog (Raf) inhibitors (sorafenib); Note: prior therapy with bevacizumab, sunitinib, pazopanib or aflivercept (vascular endothelial growth factor [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 (Common Toxicity Criteria [CTC] grade 1) in screening electrocardiogram (ECG) or history of familial long QT syndrome
  • Patients who are unable to swallow tablets and capsules
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01364051

Locations
United States, Florida
Mayo Clinic in Florida
Jacksonville, Florida, United States, 32224-9980
United States, Minnesota
Mayo Clinic
Rochester, Minnesota, United States, 55905
Sponsors and Collaborators
Investigators
Principal Investigator: Paul Haluska Mayo Clinic
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01364051     History of Changes
Other Study ID Numbers: NCI-2012-02906, NCI-2012-02906, CDR0000700596, MC1012, 8810, P30CA015083, U01CA069912
Study First Received: May 26, 2011
Last Updated: September 16, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Cediranib
Maleic acid
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on October 02, 2014