Selumetinib and Cetuximab in Treating Patients With Refractory Solid Tumors

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01217450
First received: October 7, 2010
Last updated: May 28, 2014
Last verified: December 2013
  Purpose

This phase I trial is studying the side effects and the best dose of MEK Inhibitor AZD6244 when given together with cetuximab in patients with advanced or refractory solid tumors that cannot be removed by surgery. MEK inhibitor AZD6244 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as cetuximab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving MEK Inhibitor AZD6244 together with cetuximab may kill more tumor cells.


Condition Intervention Phase
Recurrent Colon Cancer
Recurrent Rectal Cancer
Stage IVA Colon Cancer
Stage IVA Rectal Cancer
Stage IVB Colon Cancer
Stage IVB Rectal Cancer
Unspecified Adult Solid Tumor, Protocol Specific
Drug: selumetinib
Biological: cetuximab
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: A Phase 1 Study of AZD6244 in Combination With Cetuximab in Refractory Solid Tumors

Resource links provided by NLM:


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

Primary Outcome Measures:
  • MTD of selumetinib combined with cetuximab [ Time Frame: 28 days ] [ Designated as safety issue: Yes ]
    Graded using the NCI Common Toxicity Criteria.

  • Tumor response, as evaluated by the RECIST [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: No ]
    Analyzed by descriptive statistics, and summarized in tabular format. 95% confidence intervals will be computed using the method proposed by Chang.


Secondary Outcome Measures:
  • Toxicities graded using the NCI Common Toxicity Criteria [ Time Frame: Up to 4 weeks after completion of study treatment ] [ Designated as safety issue: Yes ]
    Summarized in terms of types and severities. Analyzed descriptively in tabular format. Ninety percent confidence intervals for the proportions of patients with complications (grade 3 or higher toxicities) will be constructed using the Wilson's score method.


Enrollment: 33
Study Start Date: October 2012
Study Completion Date: May 2014
Primary Completion Date: December 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (selumetinib, cetuximab)
Patients receive oral MEK inhibitor AZD6244 once or twice daily on days 1-28 and cetuximab IV over 60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Drug: selumetinib
Given orally
Other Names:
  • ARRY-142886
  • AZD6244
Biological: cetuximab
Given IV
Other Names:
  • C225
  • C225 monoclonal antibody
  • IMC-C225
  • MOAB C225
  • monoclonal antibody C225
Other: laboratory biomarker analysis
Correlative studies
Other: pharmacological study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the dose limiting toxicities and the maximum tolerated dose of AZD6244 in combination with cetuximab in advanced, refractory solid tumors.

II. To assess for evidence of anti-tumor activity with this combination, per tumor measurements using RECIST criteria.

SECONDARY OBJECTIVES:

I. To evaluate the pharmacokinetics of AZD6244 and cetuximab when administered concomitantly.

II. To evaluate the safety and tolerability of the combination of AZD6244 and cetuximab in patients with K-RAS mutated metastatic colorectal cancer.

TERTIARY OBJECTIVES:

I. To assess the inhibition of the RAF/MEK/ERK pathway in peripheral blood mononuclear cells secondary to treatment with AZD6244.

II. To evaluate the pharmacokinetics of AZD6244 in combination with cetuximab and the relation to treatment side effects.

OUTLINE: This is a dose-escalation study of MEK inhibitor AZD6244.

Patients receive oral MEK inhibitor AZD6244 once or twice daily on days 1-28 and cetuximab IV over 60 minutes on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Blood samples are collected at baseline and periodically during study for pharmacokinetic and biomarker analyses.

After completion of study treatment, patients are followed up for 1 month or every 3 months for 1 year.

  Eligibility

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

Inclusion Criteria:

  • In the dose escalation cohorts: Patients must have histologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective; histology can be based on either the primary tumor or metastases
  • In the MTD expansion cohort: Patients must have biopsy proven K-RAS mutant, metastatic colorectal cancer that has progressed on at least 2 prior standard therapies; K-RAS mutation status must be verified by a CLIA-certified laboratory (NOTE: colorectal patients enrolled during the dose escalation portion do not need to be K-RAS mutant in order to be eligible)
  • Patients must be at least 4 weeks since prior chemotherapy, 6 weeks if the last regimen included nitrosureas or mitomycin C; prior radiation is allowed as long as the radiation was completed 4 weeks prior to study treatment and no more than 35% of marrow irradiated
  • ECOG performance status =< 2 (Karnofsky >= 60%)
  • Life expectancy of greater than 3 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • AST(SGOT)/ALT(SGPT) =< 2.5 X institutional upper limit of normal (AST and ALT =< 5.0 X institutional upper limit of normal will be permitted if liver metastases are present)
  • Creatinine =< 1.5 X institution upper limit of normal OR creatinine clearance >= 45 mL/min/1.73 m^2, as calculated by Cockroft-Gault formula, for patients with creatinine levels above institutional normal
  • Patients may have received prior cetuximab
  • The effects of AZD6244 on the developing human fetus are unknown; for this reason and because small molecule kinase inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential and men must agree to use adequate contraception prior to study entry and for 16 weeks following the last dose of study treatment. Acceptable methods of birth control include implants, injectables, combined oral contraceptives, (which must all be combined with barrier methods of contraception), some IUDs, sexual abstinence, and vasectomized partner; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately
  • Ability to understand and the willingness to sign a written informed consent document
  • Patients with brain metastases that have been treated and stable for 2 months will be eligible for this study
  • Subjects undergoing anti-coagulation therapy with LMWH and warfarin are eligible; subjects receiving both warfarin and AZD6244 should have more frequent PT/INR monitoring

Exclusion Criteria:

  • Patients who have had chemotherapy, radiotherapy or hormonal therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered (=< grade 1) from adverse events due to agents administered more than 4 weeks earlier
  • Concurrent treatment with an investigational agent other than the investigational agent(s) used in this study OR treatment within 4 weeks of study entry with any investigational agent(s) or device(s)
  • Failure to recover fully (as judged by the investigator) from prior surgical procedures
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 or other agents used in study
  • Patients taking high doses (more than recommended daily dose) of vitamin E will be excluded; patients can discontinue use of high dose vitamin E prior to study entry to be considered eligible
  • 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 and retain AZD6244 capsules
  • Patients with malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel are excluded; subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, prior cardiomyopathy, LVEF < 50%, unstable angina pectoris, cardiac arrhythmia (i.e. atrial fibrillation), or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because AZD6244 is a small molecule 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 AZD6244, breastfeeding should be discontinued if the mother is treated with AZD6244; these potential risks may also apply to other agents used in this study
  • HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD6244; 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
  • Patients who are serologically positive for Hepatitis B or C, or have a history of liver disease, other forms of hepatitis or cirrhosis are ineligible
  • Use of strong CYP1A2 or 3A4 inducers and/or inhibitors (for example, but not limited to, ketoconazole, rifampicin, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin (TAO), voriconazole, grapefruit or grapefruit juice, rifabutin, rifapentine, phenytoin, carbamazepine, phenobarbital and St. John's Wort) is not permitted while on study or within 7 days prior to study enrollment
  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: NCT01217450

Locations
United States, Maryland
National Cancer Institute Medicine Branch
Bethesda, Maryland, United States, 20892
United States, Wisconsin
University of Wisconsin Hospital and Clinics
Madison, Wisconsin, United States, 53792
Wisconsin Clinical Cancer Center
Milwaukee, Wisconsin, United States, 53226
Sponsors and Collaborators
Investigators
Principal Investigator: William Schelman University of Wisconsin Medical School
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01217450     History of Changes
Other Study ID Numbers: NCI-2012-02915, NCI-2012-02915, CDR0000686619, CO10901, 8627, P30CA014520, U01CA062491
Study First Received: October 7, 2010
Last Updated: May 28, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Colonic Neoplasms
Neoplasms
Rectal Neoplasms
Colonic Diseases
Colorectal Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms by Site
Rectal Diseases
Antibodies
Antibodies, Monoclonal
Cetuximab
Antineoplastic Agents
Immunologic Factors
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on October 23, 2014