RAD001 in Combination With PKC412 in Patients With Relapsed, Refractory or Poor Prognosis AML or MDS - Full Text View

Sponsor:	Richard Stone, MD
Collaborators:	Beth Israel Deaconess Medical Center Massachusetts General Hospital Brigham and Women's Hospital Novartis
Information provided by (Responsible Party):	Richard Stone, MD, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT00819546

Purpose

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.

Condition	Intervention	Phase
Acute Myeloid Leukemia Myelodysplastic Syndrome	Drug: RAD001 Drug: PKC412	Phase 1

Study Type:	Interventional
Study Design:	Allocation: Non-Randomized Endpoint Classification: Safety Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
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

Resource links provided by NLM:

Genetics Home Reference related topics: familial acute myeloid leukemia with mutated CEBPA

MedlinePlus related topics: Acute Myeloid Leukemia Cancer Leukemia Myelodysplastic Syndromes

Drug Information available for: Sirolimus Everolimus Temsirolimus

U.S. FDA Resources

Further study details as provided by Dana-Farber Cancer Institute:

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. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

To determine the toxicities of combination of RAD001 and PKC412. [ Time Frame: 2 years ] [ Designated as safety issue: Yes ]
Observe anti-leukemic effects of this combination including a coda of patients with mutant FLT3 AML. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
Measure pharmacokinetics of each agent when administered in combination. [ Time Frame: 2 years ] [ Designated as safety issue: No ]
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 ] [ Designated as safety issue: No ]

Estimated Enrollment:	36
Study Start Date:	January 2009
Estimated Study Completion Date:	December 2012
Estimated Primary Completion Date:	June 2012 (Final data collection date for primary outcome measure)

Intervention Details:

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.

Other Name: everolimus

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.

Other Name: midostaurin

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.

Eligibility

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

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00819546

Locations

United States, Massachusetts
Dana-Farber Cancer Institute
Boston, Massachusetts, United States, 02115
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States, 02215
Massachusetts General Hospital
Boston, Massachusetts, United States, 02114

Sponsors and Collaborators

Richard Stone, MD

Beth Israel Deaconess Medical Center

Massachusetts General Hospital

Brigham and Women's Hospital

Novartis

Investigators

Principal Investigator:

Richard Stone, MD

Dana-Farber Cancer Institute

More Information

No publications provided

Responsible Party:	Richard Stone, MD, Professor of Medicine, Dana-Farber Cancer Institute
ClinicalTrials.gov Identifier:	NCT00819546 History of Changes
Other Study ID Numbers:	08-269
Study First Received:	January 8, 2009
Last Updated:	May 10, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Dana-Farber Cancer Institute:

AML
MDS

Additional relevant MeSH terms:

Leukemia
Leukemia, Myeloid, Acute
Leukemia, Myeloid
Myelodysplastic Syndromes
Preleukemia
Neoplasms by Histologic Type
Neoplasms
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Everolimus
Sirolimus
4'-N-benzoylstaurosporine

Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Pharmacologic Actions
Antibiotics, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Antifungal Agents
Anti-Infective Agents
Anti-Bacterial Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on May 23, 2012