A Phase I Study of AZD6244 in Combination With Capecitabine and Radiotherapy in Locally Advanced Adenocarcinoma of the Rectum
| Status: | Terminated |
|---|---|
| Conditions: | Colorectal Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 99 |
| Updated: | 4/5/2019 |
| Start Date: | May 24, 2010 |
| End Date: | October 22, 2012 |
Background:
- The investigational anti-cancer drug 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.
- The investigational anti-cancer drug 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.
Background:
- Local recurrences of rectal cancer are morbid and difficult to manage effectively.
- Colorectal cancers frequently harbor RAS mutations and EGF/EGFR over-expression.
- AZD6244 is an orally available selective, adenosine triphosphate uncompetitive inhibitor
of MEK1/2 that sensitizes tumor cells to radiation in vitro and in vivo.
Objectives:
Primary
- To define the maximum tolerable dose of AZD6244 Hyd-Sulfate delivered BID, 7 days per
week, in combination with radiation therapy (RT) and Capecitabine in patients with
locally advanced adenocarcinoma of the rectum without distant metastases.
- To define the dose-limiting toxicities and toxicity profile associated with
administration of AZD6244 Hyd-Sulfate delivered BID, 7 days per week in combination with
RT and Capecitabine
Secondary
- To evaluate the pharmacokinetics of AZD6244 delivered alone and in combination with
Capecitabine 825 mg/m(2) PO BID.
- To obtain exploratory information regarding the pathologic response rate obtained after
treatment with the MTD of AZD6244 Hyd-Sulfate in combination with Capecitabine and 50.4
Gy of RT.
- To determine if changes in phosphorylated ERK (pERK) in peripheral blood mononuclear
cells correlates to changes in pERK in rectal tumors in the setting of treatment with
AZD6244.
- To perform an exploratory analysis to determine if the presence of activating mutations
in RAS or BRAF in tumor or changes in plasma transforming growth factor-alpha (TGFalpha)
levels and tumor pERK/total ERK with AZD6244 treatment alone and after AZD6244 in
combination with Capecitabine and RT predicts for down staging or pathologic response.
Eligibility:
- Histologically or cytologically confirmed locally advanced, non-metastatic
adenocarcinoma of the rectum (clinical stage T3AnyN, T4AnyN, or AnyTN+).
- Age greater than or equal to 18 years.
- ECOG performance status less than or equal to 2.
- Normal organ and marrow function.
Design:
- All patients will receive 50.4 Gy of RT to the pelvis and rectal tumor delivered
concurrently with Capecitabine and AZD6244. AZD6244 will be delivered BID daily, 7 days
per week, in a dose escalated fashion. AZD6244 will begin one week prior to Capecitabine
and RT and will conclude on the last day of Capecitabine and RT.
- Capecitabine will be delivered at 825 mg/m(2) PO every 12 hours, 5 days per week,
starting on the first day of RT and continuing until the last day of RT.
- Biopsies of tumor tissue will be obtained prior to treatment, after one week of AZD6244,
and after one week of AZD6244, RT, and Capecitabine for correlative assays.
- Local recurrences of rectal cancer are morbid and difficult to manage effectively.
- Colorectal cancers frequently harbor RAS mutations and EGF/EGFR over-expression.
- AZD6244 is an orally available selective, adenosine triphosphate uncompetitive inhibitor
of MEK1/2 that sensitizes tumor cells to radiation in vitro and in vivo.
Objectives:
Primary
- To define the maximum tolerable dose of AZD6244 Hyd-Sulfate delivered BID, 7 days per
week, in combination with radiation therapy (RT) and Capecitabine in patients with
locally advanced adenocarcinoma of the rectum without distant metastases.
- To define the dose-limiting toxicities and toxicity profile associated with
administration of AZD6244 Hyd-Sulfate delivered BID, 7 days per week in combination with
RT and Capecitabine
Secondary
- To evaluate the pharmacokinetics of AZD6244 delivered alone and in combination with
Capecitabine 825 mg/m(2) PO BID.
- To obtain exploratory information regarding the pathologic response rate obtained after
treatment with the MTD of AZD6244 Hyd-Sulfate in combination with Capecitabine and 50.4
Gy of RT.
- To determine if changes in phosphorylated ERK (pERK) in peripheral blood mononuclear
cells correlates to changes in pERK in rectal tumors in the setting of treatment with
AZD6244.
- To perform an exploratory analysis to determine if the presence of activating mutations
in RAS or BRAF in tumor or changes in plasma transforming growth factor-alpha (TGFalpha)
levels and tumor pERK/total ERK with AZD6244 treatment alone and after AZD6244 in
combination with Capecitabine and RT predicts for down staging or pathologic response.
Eligibility:
- Histologically or cytologically confirmed locally advanced, non-metastatic
adenocarcinoma of the rectum (clinical stage T3AnyN, T4AnyN, or AnyTN+).
- Age greater than or equal to 18 years.
- ECOG performance status less than or equal to 2.
- Normal organ and marrow function.
Design:
- All patients will receive 50.4 Gy of RT to the pelvis and rectal tumor delivered
concurrently with Capecitabine and AZD6244. AZD6244 will be delivered BID daily, 7 days
per week, in a dose escalated fashion. AZD6244 will begin one week prior to Capecitabine
and RT and will conclude on the last day of Capecitabine and RT.
- Capecitabine will be delivered at 825 mg/m(2) PO every 12 hours, 5 days per week,
starting on the first day of RT and continuing until the last day of RT.
- Biopsies of tumor tissue will be obtained prior to treatment, after one week of AZD6244,
and after one week of AZD6244, RT, and Capecitabine for correlative assays.
- INCLUSION CRITERIA:
- 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.
- 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
- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times the institutional upper limit
of normal
- creatinine within normal institutional limits
OR
-- 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.
EXCLUSION CRITERIA:
- 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 MEK inhibitor use.
- Contraindications to radiotherapy to the pelvis such as inflammatory bowel disease or
known genetic sensitivity to ionizing radiation such as ataxia telengiectasia.
- 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 QTc interval greater than 470 msecs or other factors that increase the
risk of 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.
- 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
- Uncontrolled hypertension
- Pregnant or lactating females are excluded
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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