A Phase I Study of AZD6244 in Combination With Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum

NCT01134601 | Terminated Phase 1 Results FDA Drug

• 2 other identifiers: 10013210-C-0132
• Study Type: interventional
• Target: 1
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- The investigational anti-cancer drug Selumetinib (AZD6244) prevents a protein found in rectal cancer from working properly, which may slow tumor growth and allow radiation and chemotherapy treatments to destroy more cancer cells. Researchers are interested in determining whether AZD6244 can be used to improve treatment outcomes in individuals who have rectal cancer that has spread outside the rectum into the surrounding pelvis. Objectives: \- To determine safe and effective doses of AZD6244, along with radiation and chemotherapy, to treat rectal cancer. Eligibility: \- Individuals at least 18 years of age who have been diagnosed with rectal cancer that has spread outside the inner wall of the rectum or into lymph nodes in the pelvis. Design:

• Eligible participants will be screened with a physical examination, blood and tumor samples, and imaging studies.
• Participants will receive AZD6244 twice a day by mouth for 1 full week (7 days) before starting radiation and chemotherapy and every week thereafter until the end of the radiation and chemotherapy treatment.
• Participants will have radiation therapy daily, 5 days per week, for approximately 6 weeks.
• Participants will receive chemotherapy (capecitabine) twice daily, 5 days per week, for approximately 6 weeks.
• Approximately 4 to 8 weeks after completing the AZD6244, radiation, and chemotherapy treatment, participants may have surgery to remove any tumors and affected lymph nodes. This surgery is not part of the treatment delivered on this protocol.
• Participants will have a follow-up exam 3 weeks after the end of treatment, every 3 months for the first year, and then in the second and third year after the end of treatment. These visits will involve a full medical examination and imaging studies.

Conditions

Non-Metastatic Adenocarcinoma of the Rectum

Keywords

Rectal Cancer; Radiation Therapy; Capecitabine; AZD6244

Outcome Measures

Primary Outcomes (1)

• Maximum Tolerable Dose of Selumetinib (AZD6244) Hyd-Sulfate in Combination With Radiation Therapy (RT) and Capecitabine in Participants With Locally Advanced Adenocarcinoma of the Rectum.

  Maximum tolerable dose is defined as the dose level at which no more than 1 of 6 participants experience dose limiting toxicity (DLT) during treatment and the three weeks after completion. Examples of DLT is recurring and persistent Grade 3 diarrhea despite appropriate medical therapy, absolute neutrophil count \<500 for more than 5 days or neutropenic fever, Grade 3 thrombocytopenia, Grade 4 fatigue, and Grade 4 dermatitis acneiform rash.

  During treatment and within first 3 weeks after treatment

Secondary Outcomes (2)

• Pharmacokinetics of Selumetinib (AZD6244) in Combination With Capecitabine

  Pre-and post treatment

• Changes in Phosphorylated ERK (pERK) in Peripheral Blood Mononuclear Cells and Tumor, and Transforming Growth Factor Alpha (TGFa) Levels

  Pre-and post treatment

Other Outcomes (3)

• Here is the Number of Participants With Non-serious Adverse Events Assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.0).

  Date treatment consent signed to date off study, and up to 30 days following the last dose of study drug, approximately 14 months and 26 days.

• Pathologic Complete Response Rate

  After treatment with the maximum tolerated dose

• Dose-Limiting Toxicity (DLT)

  During treatment and within first 3 weeks after treatment

Study Arms (1)

Selumetinib (AZD6244): 50 mg & Capecitabine: 825 mg/m^2

EXPERIMENTAL

LEVEL 1 - Cycle = 49 days: AZD6244: 50 mg by mouth (PO) everyday (QD) Capecitabine: 825 mg/m\^2 by mouth (PO)

Procedure: Radiation Therapy; Drug: Capecitabine; Drug: AZD6244

Interventions

Radiation Therapy PROCEDURE

Selumetinib (AZD6244): 50 mg & Capecitabine: 825 mg/m^2

Capecitabine DRUG

Also known as: Xeloda

Selumetinib (AZD6244): 50 mg & Capecitabine: 825 mg/m^2

AZD6244 DRUG

Also known as: Selumetinib

Selumetinib (AZD6244): 50 mg & Capecitabine: 825 mg/m^2

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically or cytologically confirmed locally advanced, non-metastatic adenocarcinoma of the rectum (clinical stage T3 anyN, T4 anyN, or AnyT N+).
• Patients with recurrent adenocarcinoma of the rectum with no clinically evident distant disease will be eligible if they are deemed to have pelvic nodal metastases or disease extending through the muscularis of the rectum. These patients should be evaluated by a Radiation Oncologist, Medical Oncologist and Surgeon prior to enrolling on study to confirm anticipated resectability. These patients should not have received prior radiotherapy for management of their rectal cancer.
• Age greater than or equal to 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky greater than or equal to 70%).
• Patients must have normal organ and marrow function as defined below:
• leukocytes greater than or equal to 3,000/mcL
• absolute neutrophil count greater than or equal to 1,500/mcL
• platelets: greater than or equal to 100,000/mcL
• total bilirubin: within normal institutional limits except for patients with Gilbert's who must have a direct bilirubin of less than 1.0 mg/dL
• Aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase (SGOT)/alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) less than or equal to 2.5 times the institutional upper limit of normal
• creatinine within normal institutional limits
• \-- creatinine clearance greater than or equal to 60 mL/min/1.73 m(2) for patients with creatinine levels above institutional normal.
• 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, for the duration of study participation, and for six months after the completion of radiation. Women of child-bearing potential must have a negative pregnancy test prior to entry. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Adequate contraception for male patients should be used for 6 months after irradiation.
• Ability to understand and the willingness to sign a written informed consent document.
• Willingness to sign a release of medical records pertaining to previous and future treatment for rectal cancer.

You may not qualify if:

• Chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or lack of recovery from adverse events due to agents administered more than 4 weeks earlier.
• Patients may not be receiving any other investigational agents.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD6244 or other agents used in study.
• Previous methyl ethyl ketone (MEK) inhibitor use.
• Contraindications to radiotherapy to the pelvis such as inflammatory bowel disease or known genetic sensitivity to ionizing radiation such as ataxia telangiectasia.
• 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.
• Patients with corrected QT interval (QTc) interval greater than 470 msecs or other factors that increase the risk of Q wave, T wave (QT) prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) including heart failure that meets New York Heart Association (NYHA) class III and IV definitions are excluded.
• Required use of a concomitant medication that can prolong the QT interval. A comprehensive list of agents with the potential to cause QTc prolongation can be found at http://www.arizonacert.org/medical-pros/drug-lists/drug-lists.htm.
• Refractory nausea and vomiting, chronic gastrointestinal diseases (e.g. inflammatory bowel disease), or significant bowel resection that would preclude adequate absorption.
• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy.
• Known dihydropyrimidine dehydrogenase deficiency.
• History of prior radiation to the pelvis
• For patients with newly diagnosed rectal cancer, prior therapy for adenocarcinoma of the rectum with the exception of diverting colostomy if required to relieve obstruction (including chemotherapy).
• Patients with recurrent rectal cancer may not have undergone prior radiotherapy for rectal adenocarcinoma or have received therapy for the recurrence with the exception of diverting colostomy if required to relieve obstruction.
• History of myocardial infarction within the past 6 months or history of ventricular arrhythmia

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Davies BR, Logie A, McKay JS, Martin P, Steele S, Jenkins R, Cockerill M, Cartlidge S, Smith PD. AZD6244 (ARRY-142886), a potent inhibitor of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 kinases: mechanism of action in vivo, pharmacokinetic/pharmacodynamic relationship, and potential for combination in preclinical models. Mol Cancer Ther. 2007 Aug;6(8):2209-19. doi: 10.1158/1535-7163.MCT-07-0231.

  PMID: 17699718 BACKGROUND

• O'Neill E, Kolch W. Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br J Cancer. 2004 Jan 26;90(2):283-8. doi: 10.1038/sj.bjc.6601488.

  PMID: 14735164 BACKGROUND

• Wellbrock C, Ogilvie L, Hedley D, Karasarides M, Martin J, Niculescu-Duvaz D, Springer CJ, Marais R. V599EB-RAF is an oncogene in melanocytes. Cancer Res. 2004 Apr 1;64(7):2338-42. doi: 10.1158/0008-5472.can-03-3433.

  PMID: 15059882 BACKGROUND

MeSH Terms

Conditions

Rectal Neoplasms

Interventions

Radiotherapy; Capecitabine; AZD 6244

Condition Hierarchy (Ancestors)

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Therapeutics; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides

Results Point of Contact

• Title: Dr. Deborah E. Citrin
• Organization: National Cancer Institute

citind@mail.nih.gov

301-496-5457

Study Officials

• Deborah E Citrin, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: May 28, 2010
• First Posted: June 2, 2010
• Study Start: May 24, 2010
• Primary Completion: October 22, 2012
• Study Completion: October 22, 2012
• Last Updated: December 1, 2021
• Results First Posted: December 1, 2021

Record last verified: 2021-11

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)