Back to resultsRAD001 in Combination With PKC412 in Patients With Relapsed, Refractory or Poor Prognosis AML or MDS
Primary Purpose
Acute Myeloid Leukemia, Myelodysplastic Syndrome
Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
RAD001
PKC412
Sponsored by
About this trial
This is an interventional treatment trial for Acute Myeloid Leukemia focused on measuring AML, MDS
Eligibility Criteria
Inclusion Criteria:
- Cytopathologically or histopathologically confirmed diagnosis of AML, MDS (RAEB-1, -2) or CMML, who are either relapsed or refractory to standard therapy, or are considered inappropriate candidates for standard therapy.
- Inappropriateness for standard therapy requires a) MDS patients: not be a candidate for immediate allogeneic stem cell transplantation, not have a -5q-cytogenetic abnormality (unless previously received lenalidomide), and not be an appropriate candidate for a DNA hypomethylating agent b) AML patients must be 60 years of age or greater and have one of more of the following documented poor risk factors: ECOG Performance Status = 2, 70 years of age or older, unfavorable cytogenetics.
- Life expectancy of at least 12 weeks
- Not likely to require cytoreductive therapy within one month (other than hydroxyurea)
- ECOG Performance Status of 2 or less
- Serum transaminase activity (AST/SGOT & ALT/SGPT) < 2.5 x ULN
- Serum total bilirubin < 1.5 x ULN ( with the exception of individuals with Gilbert's disease)
- INR < 1.3 (or < 3 on anticoagulants)
- Fasting serum cholesterol 300mg/dl or 7.75 mmol/L or less AND fasting triglycerides 2.5 ULN or less
Exclusion Criteria:
- Prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously
- Female patients who are pregnant or breast feeding or adults of child bearing not employing double barrier contraception
- Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study
- Impairment of gastrointestinal function or GI disease that may significantly alter absorption of PKC412 or RAD001
- Uncontrolled active infection
- Any pulmonary infiltrate on teh baseline chest x-ray known to be new in the previous 4 weeks
- Patients with a Grade 2 or higher hypercholesterolemia or hypertriglyceridemia despite lipid-lowering therapy
- Patients with history of another malignancy within the past 5 years, with the exception of adequately treated basal or squamous cell skin carcinoma or cervical carcinoma in situ
- History of non-compliance to medical regimens and patients who are unwilling or unable to comply with this protocol
- Prior treatment with any investigational drug within preceding 4 weeks
- Chronic treatment with systemic steroids or another immunosuppressive agent
- Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
- Any severe or uncontrolled medical conditions or other conditions that could affect their participation
- Known history of HIV seropositivity
- Known hypersensitivity to RAD001 or other rapamycins or to its excipients
- Known hypersensitivity to PKC412 or to its excipients
- Diagnosis of acute promyelocytic leukemia
Sites / Locations
- Massachusetts General Hospital
- Dana-Farber Cancer Institute
- Beth Israel Deaconess Medical Center
Arms of the Study
Arm 1
Arm Type
Other
Arm Label
Only one arm on this study.
Arm Description
Outcomes
Primary Outcome Measures
To identify the maximum tolerated dose of RAD001 that can be given in combination with twice daily PKC412 in patients who are non-chemotherapy candidates with AML or MDS.
Secondary Outcome Measures
To determine the toxicities of combination of RAD001 and PKC412.
Observe anti-leukemic effects of this combination including a coda of patients with mutant FLT3 AML.
Measure pharmacokinetics of each agent when administered in combination.
Observe the pharmacodynamic effects on the phosphorylation of FLT3 and on activation of relevant signaling pathways and correlate such activation with response.
Full Information
NCT ID
NCT00819546
First Posted
January 8, 2009
Last Updated
February 6, 2023
Sponsor
Richard Stone, MD
Collaborators
Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Brigham and Women's Hospital, Novartis
1. Study Identification
Unique Protocol Identification Number
NCT00819546
Brief Title
RAD001 in Combination With PKC412 in Patients With Relapsed, Refractory or Poor Prognosis AML or MDS
Official Title
A Phase I Trial of Escalating Dose of RAD001 in Combination With PKC412 in Patients With Relapsed, Refractory or Poor Prognosis AML or MDS
Study Type
Interventional
2. Study Status
Record Verification Date
February 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
January 2009 (undefined)
Primary Completion Date
December 2023 (Anticipated)
Study Completion Date
December 2023 (Anticipated)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor-Investigator
Name of the Sponsor
Richard Stone, MD
Collaborators
Beth Israel Deaconess Medical Center, Massachusetts General Hospital, Brigham and Women's Hospital, Novartis
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
The purpose of this research study is to determine the safety of the combination of RAD001 and PKC412 as a cancer treatment, and to establish the highest dose of RAD001 that can be given in conjunction with PKC412. These drugs have been used in other research trials for individuals with solid and hematology malignancies. Past research on PKC412 shows that it blocks the abnormal functioning of an enzyme called FLT3. FLT3 is found in your cells in either a normal (wild type) or genetically changed form and plays a role in the survival and growth of AML cells. RAD001 is an inhibitor of a central growth pathway that involves the protein MTOR. The MTOR pathway is overactive in cancer cells, causing the cells to grow abnormally. By inhibiting the abnormal growth activity of the MTOR pathway, RAD001 slows down and possibly stops the growth of cancer cells.
Detailed Description
This is a dose-escalation study in which 3 participants will be given a particular starting dose of RAD001 on a certain schedule. If the dose and schedule are well tolerated, then the next 3 participants enrolled will be assigned a new dosing schedule and/or a higher dose of RAD001. This will continue until a maximum tolerated dose (MTD) is reached for RAD001.
Each cycle of treatment consists of 28 days on an outpatient basis. Participants will receive RAD001 as the assigned schedule and dosage on day 1 and on days 8 through 28 for the first cycle. For all subsequent cycles RAD001 will be taken once daily. Additionally, all participants will take PKC412 twice a day on days 2 through 28 for the first cycle. For all subsequent cycles PKC412 will be taken twice daily.
During the course of the trial the following evaluations and procedures will be completed at various times: review of medical history; review of concomitant medications; physical exam; performance status; vital signs; EKG; chest x-ray; blood tests and bone marrow aspirate/biopsy.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Myeloid Leukemia, Myelodysplastic Syndrome
Keywords
AML, MDS
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
29 (Anticipated)
8. Arms, Groups, and Interventions
Arm Title
Only one arm on this study.
Arm Type
Other
Intervention Type
Drug
Intervention Name(s)
RAD001
Other Intervention Name(s)
everolimus
Intervention Description
Participants will receive RAD001 on day 1 at the dose specified then again on days 8-28 for the first cycle. For all subsequent cycles RAD001 will be taken once daily.
Intervention Type
Drug
Intervention Name(s)
PKC412
Other Intervention Name(s)
midostaurin
Intervention Description
50mg orally twice a day on days 2-28 for the first cycle. For all subsequent cycles 50mg of PKC412 will be taken orally twice daily.
Primary Outcome Measure Information:
Title
To identify the maximum tolerated dose of RAD001 that can be given in combination with twice daily PKC412 in patients who are non-chemotherapy candidates with AML or MDS.
Time Frame
2 years
Secondary Outcome Measure Information:
Title
To determine the toxicities of combination of RAD001 and PKC412.
Time Frame
2 years
Title
Observe anti-leukemic effects of this combination including a coda of patients with mutant FLT3 AML.
Time Frame
2 years
Title
Measure pharmacokinetics of each agent when administered in combination.
Time Frame
2 years
Title
Observe the pharmacodynamic effects on the phosphorylation of FLT3 and on activation of relevant signaling pathways and correlate such activation with response.
Time Frame
2 years
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria:
Cytopathologically or histopathologically confirmed diagnosis of AML, MDS (RAEB-1, -2) or CMML, who are either relapsed or refractory to standard therapy, or are considered inappropriate candidates for standard therapy.
Inappropriateness for standard therapy requires a) MDS patients: not be a candidate for immediate allogeneic stem cell transplantation, not have a -5q-cytogenetic abnormality (unless previously received lenalidomide), and not be an appropriate candidate for a DNA hypomethylating agent b) AML patients must be 60 years of age or greater and have one of more of the following documented poor risk factors: ECOG Performance Status = 2, 70 years of age or older, unfavorable cytogenetics.
Life expectancy of at least 12 weeks
Not likely to require cytoreductive therapy within one month (other than hydroxyurea)
ECOG Performance Status of 2 or less
Serum transaminase activity (AST/SGOT & ALT/SGPT) < 2.5 x ULN
Serum total bilirubin < 1.5 x ULN ( with the exception of individuals with Gilbert's disease)
INR < 1.3 (or < 3 on anticoagulants)
Fasting serum cholesterol 300mg/dl or 7.75 mmol/L or less AND fasting triglycerides 2.5 ULN or less
Exclusion Criteria:
Prior allogeneic, syngeneic, or autologous bone marrow transplant or stem cell transplant less than 2 months previously
Female patients who are pregnant or breast feeding or adults of child bearing not employing double barrier contraception
Concurrent severe and/or uncontrolled medical or psychiatric condition which may interfere with the completion of the study
Impairment of gastrointestinal function or GI disease that may significantly alter absorption of PKC412 or RAD001
Uncontrolled active infection
Any pulmonary infiltrate on teh baseline chest x-ray known to be new in the previous 4 weeks
Patients with a Grade 2 or higher hypercholesterolemia or hypertriglyceridemia despite lipid-lowering therapy
Patients with history of another malignancy within the past 5 years, with the exception of adequately treated basal or squamous cell skin carcinoma or cervical carcinoma in situ
History of non-compliance to medical regimens and patients who are unwilling or unable to comply with this protocol
Prior treatment with any investigational drug within preceding 4 weeks
Chronic treatment with systemic steroids or another immunosuppressive agent
Patients should not receive immunization with attenuated live vaccines within one week of study entry or during study period
Any severe or uncontrolled medical conditions or other conditions that could affect their participation
Known history of HIV seropositivity
Known hypersensitivity to RAD001 or other rapamycins or to its excipients
Known hypersensitivity to PKC412 or to its excipients
Diagnosis of acute promyelocytic leukemia
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard Stone, MD
Organizational Affiliation
Dana-Farber Cancer Institute
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Facility Name
Dana-Farber Cancer Institute
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02115
Country
United States
Facility Name
Beth Israel Deaconess Medical Center
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02215
Country
United States
12. IPD Sharing Statement
Learn more about this trial
RAD001 in Combination With PKC412 in Patients With Relapsed, Refractory or Poor Prognosis AML or MDS
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