Cediranib Maleate and Selumetinib in Treating Patients With Solid Malignancies

Solid Neoplasm Clinical Trial

Official title:

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

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02876068
• Other study ID #: NCI-2012-02906
• Secondary ID: NCI-2012-02906CD
• Status: Active, not recruiting
• Phase: Phase 1
• First received: August 18, 2016
• Last updated: August 18, 2016
• Start date: May 2011

Study information

• Verified date: June 2016
• Source: Mayo Clinic
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

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.

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 12 weeks after 1 year of study treatment.

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

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 19
• Est. primary completion date: June 2016
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Histologic proof of cancer that is now considered clinically unresectable and for whom there is no standard therapy; NOTE: for the maximum tolerated dose (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: non-melanotic 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 aflibercept (vascular endothelial growth factor [VEGF] Trap) are allowed

• Surgery within two weeks prior to registration

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

• Mean QTc interval with Bazetts correction > 480 msec (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

Study Design

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

Related Conditions & MeSH terms

• Solid Neoplasm
• Stage IV Skin Melanoma

Intervention

Drug:
• Cediranib Maleate
Given PO

Other:
• Laboratory Biomarker Analysis
Correlative studies
• Pharmacological Study
Correlative studies

Drug:
• Selumetinib
Given PO

Locations

Country	Name	City	State
United States	Mayo Clinic in Florida	Jacksonville	Florida
United States	Mayo Clinic	Rochester	Minnesota

Sponsors (2)

Lead Sponsor	Collaborator
Mayo Clinic	National Cancer Institute (NCI)

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes of the serum levels of caspase 3 (dose expansion phase)	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.	Baseline up to day 22 of course 1	No
Other	Changes of the serum levels of cytochrome c (dose expansion phase)	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.	Baseline up to day 22 of course 1	No
Other	Changes of the serum levels of M30 (dose expansion phase)	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.	Baseline up to day 22 of course 1	No
Primary	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)	Graded per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).	28 days	Yes
Secondary	Best response, in terms of Response Evaluation Criteria in Solid Tumors	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).	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	No
Secondary	Incidence of adverse events, classified as either possibly, probably, or definitely related to study treatment as per the NCI CTCAE	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.	Up to 3 months	Yes
Secondary	Incidence of hematologic toxicities evaluated via CTC standard toxicity grading	Hematologic toxicity measures of thrombocytopenia, neutropenia, and leukopenia will be assessed using continuous variables as the outcome measures (primarily nadir) as well as categorization.	Up to 3 months	Yes
Secondary	Incidence of non-hematologic toxicities evaluated via the ordinal CTC standard toxicity grading	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.	Up to 3 months	Yes
Secondary	Overall toxicity incidence as per NCI CTCAE	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.	Up to 3 months	Yes