Study of the Weekly Oral RAD001 in Combination With Oral Topotecan in Patients With Advanced or Recurrent Endometrial Cancers
Primary Purpose
Endometrial Cancer
Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Topotecan
RAD001
Sponsored by
About this trial
This is an interventional treatment trial for Endometrial Cancer
Eligibility Criteria
Inclusion Criteria:
- Patients must have histologically-confirmed advanced or recurrent endometrial cancer
- Patients must be refractory to standard therapy or for which no curative standard therapy exists, to be considered. Metastatic disease, if present, should not be progressing so as to require palliative treatment within 4 weeks of enrollment based on clinical assessment by the investigator.
- Development of new lesions or an increase in preexisting lesions on bone scintigraphy, CT, MRI or by physical examination. Patients in whom the sole criterion for progression is an increase in a biochemical marker, e.g., carcinoembryonic antigen (CEA), or an increase in symptoms, are not eligible.
- Age ≥ 18 years
- WHO performance status ≤ 2
- Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL
- Adequate liver function as shown by:
- serum bilirubin ≤ 1.5 x ULN
- INR < 1.3 (or < 3 on anticoagulants)
- ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)
- Adequate renal function: serum creatinine ≤ 1.5 x mg/dL
- Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
- Signed informed consent
Exclusion Criteria:
- Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)
- Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
- Prior treatment with any investigational drug within the preceding 4 weeks
- Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent, except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg. However, patients receiving corticosteroids must have been on a stable dosage regimen for a minimum of 4 weeks prior to the first treatment with RAD001. Topical or inhaled corticosteroids are allowed.
- Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
- Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
- Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
- Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
- Symptomatic congestive heart failure of New York heart Association Class III or IV
- unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
- severely impaired lung function
- uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN
- active (acute or chronic) or uncontrolled severe infections
- liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
- A known history of HIV seropositivity
- Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
- Patients with an active, bleeding diathesis
- Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001)
- Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).
- Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients
- History of noncompliance to medical regimens
- Patients unwilling to or unable to comply with the protocol
Sites / Locations
- Yale University School of Medicine
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
1
Arm Description
Daily oral RAD001 for 21 days in combination with oral topotecan on days 1-5 of a 21 day cycle
Outcomes
Primary Outcome Measures
To determine the safety, dose-limiting toxicities,and maximum tolerated dose of daily oral RAD001 in combination with oral topotecan given on days 1-5 q 21 days in patients with advanced or recurrent endometrial cancers
Secondary Outcome Measures
To determine if daily administration of RAD001 changes the pharmacokinetic profile of oral topotecan, and if oral topotecan changes the pharmacokinetic profile of oral RAD001.
To determine the anti-tumor effect of the combination using Response Evaluation Criteria in Solid Tumors (RECIST)
Full Information
NCT ID
NCT00703807
First Posted
June 20, 2008
Last Updated
January 13, 2014
Sponsor
Yale University
Collaborators
Novartis
1. Study Identification
Unique Protocol Identification Number
NCT00703807
Brief Title
Study of the Weekly Oral RAD001 in Combination With Oral Topotecan in Patients With Advanced or Recurrent Endometrial Cancers
Official Title
A Phase I Study of the Weekly Oral RAD001 in Combination With Oral Topotecan in Patients With Advanced or Recurrent Endometrial Cancers
Study Type
Interventional
2. Study Status
Record Verification Date
January 2014
Overall Recruitment Status
Completed
Study Start Date
December 2008 (undefined)
Primary Completion Date
May 2010 (Actual)
Study Completion Date
May 2010 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Yale University
Collaborators
Novartis
4. Oversight
Data Monitoring Committee
No
5. Study Description
Brief Summary
Endometrial cancer is the most common malignancy of the female reproductive tract. The majority of patients with endometrial cancer are diagnosed at an early stage and cured with surgery with or without adjuvant radiotherapy. However, a significant number of patients present with metastatic disease outside of the pelvis or develop recurrent disease after primary therapy.
mTOR inhibitors have been shown to be promising agents in reducing tumor growth in vitro and in vivo, in several solid cancers. Inhibitors of mTOR are primarily cytostatic in cancer cells; combination therapy with cytotoxic chemotherapeutics and other biologic agents may prove to be the most advantageous use of these drugs. mTOR inhibition with a rapamycin analogue demonstrated in vitro antiproliferative activity on endometrial AN3 CA and HEC-1-A tumor cells, and this inhibition of proliferation was found to be concentration dependent. Topotecan is an active agent in the treatment of advanced and recurrent endometrial cancers.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Endometrial Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
10 (Actual)
8. Arms, Groups, and Interventions
Arm Title
1
Arm Type
Experimental
Arm Description
Daily oral RAD001 for 21 days in combination with oral topotecan on days 1-5 of a 21 day cycle
Intervention Type
Drug
Intervention Name(s)
Topotecan
Other Intervention Name(s)
Hycamtin
Intervention Description
Dose escalation, 5 dose levels, 1.5 mg/m2 - 2.3 mg/m2, PO day 1-5 every 21 days
Intervention Type
Drug
Intervention Name(s)
RAD001
Other Intervention Name(s)
Everolimus
Intervention Description
Dose level -1, 5 mg qod Dose level 1, 5 mg qod Dose level 2, 5 mg qd Dose level 3, 5 mg qd DOse level 4, 10 mg qd
Primary Outcome Measure Information:
Title
To determine the safety, dose-limiting toxicities,and maximum tolerated dose of daily oral RAD001 in combination with oral topotecan given on days 1-5 q 21 days in patients with advanced or recurrent endometrial cancers
Time Frame
Upon completion of study
Secondary Outcome Measure Information:
Title
To determine if daily administration of RAD001 changes the pharmacokinetic profile of oral topotecan, and if oral topotecan changes the pharmacokinetic profile of oral RAD001.
Time Frame
Upon completion of study
Title
To determine the anti-tumor effect of the combination using Response Evaluation Criteria in Solid Tumors (RECIST)
Time Frame
Upon completion of study
10. Eligibility
Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Patients must have histologically-confirmed advanced or recurrent endometrial cancer
Patients must be refractory to standard therapy or for which no curative standard therapy exists, to be considered. Metastatic disease, if present, should not be progressing so as to require palliative treatment within 4 weeks of enrollment based on clinical assessment by the investigator.
Development of new lesions or an increase in preexisting lesions on bone scintigraphy, CT, MRI or by physical examination. Patients in whom the sole criterion for progression is an increase in a biochemical marker, e.g., carcinoembryonic antigen (CEA), or an increase in symptoms, are not eligible.
Age ≥ 18 years
WHO performance status ≤ 2
Adequate bone marrow function as shown by: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Hb >9 g/dL
Adequate liver function as shown by:
serum bilirubin ≤ 1.5 x ULN
INR < 1.3 (or < 3 on anticoagulants)
ALT and AST ≤ 2.5x ULN (≤ 5x ULN in patients with liver metastases)
Adequate renal function: serum creatinine ≤ 1.5 x mg/dL
Fasting serum cholesterol ≤300 mg/dL OR ≤7.75 mmol/L AND fasting triglycerides ≤ 2.5 x ULN. NOTE: In case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication.
Signed informed consent
Exclusion Criteria:
Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of the start of study drug (including chemotherapy, radiation therapy, antibody based therapy, etc.)
Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study
Prior treatment with any investigational drug within the preceding 4 weeks
Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent, except corticosteroids with a daily dosage equivalent to prednisone ≤ 20 mg. However, patients receiving corticosteroids must have been on a stable dosage regimen for a minimum of 4 weeks prior to the first treatment with RAD001. Topical or inhaled corticosteroids are allowed.
Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
Uncontrolled brain or leptomeningeal metastases, including patients who continue to require glucocorticoids for brain or leptomeningeal metastases
Other malignancies within the past 3 years except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin.
Patients who have any severe and/or uncontrolled medical conditions or other conditions that could affect their participation in the study such as:
Symptomatic congestive heart failure of New York heart Association Class III or IV
unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months of start of study drug, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
severely impaired lung function
uncontrolled diabetes as defined by fasting serum glucose >1.5 x ULN
active (acute or chronic) or uncontrolled severe infections
liver disease such as cirrhosis, chronic active hepatitis or chronic persistent hepatitis
A known history of HIV seropositivity
Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of RAD001 (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome or small bowel resection)
Patients with an active, bleeding diathesis
Female patients who are pregnant or breast feeding, or adults of reproductive potential who are not using effective birth control methods. If barrier contraceptives are being used, these must be continued throughout the trial by both sexes. Hormonal contraceptives are not acceptable as a sole method of contraception. (Women of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to administration of RAD001)
Patients who have received prior treatment with an mTOR inhibitor (sirolimus, temsirolimus, everolimus).
Patients with a known hypersensitivity to RAD001 (everolimus) or other rapamycins (sirolimus, temsirolimus) or to its excipients
History of noncompliance to medical regimens
Patients unwilling to or unable to comply with the protocol
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maysa Abu-Khalaf, M.D.
Organizational Affiliation
Yale University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Yale University School of Medicine
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06520
Country
United States
12. IPD Sharing Statement
Learn more about this trial
Study of the Weekly Oral RAD001 in Combination With Oral Topotecan in Patients With Advanced or Recurrent Endometrial Cancers
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