Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy

Study Overview
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Brief Summary
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This phase II trial studies how well sirolimus and azacitidine works in treating patients with high-risk myelodysplastic syndrome or recurrent acute myeloid leukemia. Sirolimus may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Sirolimus and azacitidine may kill more cancer cells.

Detailed Description
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PRIMARY OBJECTIVE: I. To characterize the rate of response to azacitidine and sirolimus in adults with high-risk myelodysplastic syndrome (MDS), or relapsed or refractory acute myeloid leukemia (AML) or those unable or unwilling to tolerate high dose chemotherapy. SECONDARY OBJECTIVES: I. To determine the pharmacodynamic effect of sirolimus on inhibition of mammalian target of rapamycin (mTOR) signaling in adults with high-risk MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high dose chemotherapy. II. To determine the safety and tolerability of sirolimus and azacitidine in adults with high-risk MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high dose chemotherapy. III. To determine the progression free survival and overall survival in adults with high-risk MDS, or relapsed or refractory AML or those unable or unwilling to tolerate high dose chemotherapy. IV. To determine if the quality of life of patients is improved with the combination of azacitidine and sirolimus when compared to historical controls of azacitidine alone. OUTLINE: Patients receive sirolimus orally (PO) on days 1-10 or 1-12 and azacitidine intravenously (IV) on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months.

Official Title
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A Phase II Study of Azacitidine and Sirolimus for the Treatment of High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia Refractory to or Not Eligible for Intensive Chemotherapy

Conditions
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Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22), Adult Acute Myeloid Leukemia With t(15;17)(q22;q12), Adult Acute Myeloid Leukemia With t(16;16)(p13;q22), Adult Acute Myeloid Leukemia With t(8;21)(q22;q22), de Novo Myelodysplastic Syndromes, Myelodysplastic Syndrome With Isolated Del(5q), Previously Treated Myelodysplastic Syndromes, Recurrent Adult Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Sirolimus
* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a diagnosis of one of the following: MDS (Arm A): High-risk MDS defined as: >5% blasts in bone marrow and/or the following cytogenetic categories: presence of inv(3)/t(3q)/del(3q), -7/del(7q), complex cytogenetics (3 or more abnormalities) AML (Arm B): Relapsed/refractory/unable to tolerate conventional chemotherapy MDS or AML as above BUT with prior therapy with Azacitibine (Arm C): Patients who meet criteria for either Arm A or Arm B but have been treated or are currently treated with Azacitibine *Note: As of July 2018, only high risk MDS patients will be eligible as Arm B is closed. As of October 2017, those patients with MDS who have received prior treatment will now be enrolled in Arm A as Arm C is closed. Patients must be ≥ 18 years old Patients must have an ECOG performance status of <= 2 (see Attachment 1). Patients must have a life expectancy of at least 4 weeks. Patients must be able to consume oral medication. Patients must have completed any radiotherapy four weeks prior to study entry, 0-2 weeks for local palliative XRT (small port). Patients must have recovered from the toxic effects of any prior chemotherapy to < Grade 2 (except for alopecia). Required initial laboratory values: Creatinine≤ 2.0mg/dL; total or direct bilirubin ≤ 1.5mg/dL (if not due to the leukemia itself or known Gilbert's Syndrome);(as documented by treating physician) SGPT(ALT) ≤ 3xULN; glucose <200 mg/dL, negative pregnancy test for women of child-bearing potential. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing. Patients may have had a prior stem cell transplant (autologous or allogeneic), however they may not have active GvHD, nor be on any immunosuppression Exclusion Criteria: Patients must not be receiving any chemotherapy agents (except Hydroxyurea) Intrathecal ARA-C and intrathecal methotrexate are permissible (as they are not systemic and only isolated to the central nervous system). Patients can not have received more than 3 prior lines of therapy for their hematologic malignancy. Patient may have previously had azacitidine or decitabine will be eligible to enroll on Arm A (MDS) Patients must not be receiving growth factors. Patients with a current second malignancy requiring systemic therapy, other than non-melanoma skin cancers, are not eligible. If a patient has had a prior second malignancy that is not currently requiring active treatment, the patient will be considered eligible. Patients with uncontrolled high blood pressure, unstable angina, symptomatic congestive heart failure, myocardial infarction within the past 6 months or serious uncontrolled cardiac arrhythmia are not eligible. Patients may not take any of the following medications while on study, but will be considered eligible if medication is discontinued 72 hrs prior to first dose of Sirolimus: Carbamazepine (e.g. Tegretol) Rifabutin (e.g. Mycobutin) Rifampin (e.g. Rifadin) Rifapentine (e.g. Priftin) St. John's Wort- may decrease effects of sirolimus by decreasing the amount of sirolimus in the body Clarithromycin (e.g. Biaxin) Cyclosporin e.g. (Neoral or Sandimmune) Diltiazem (e.g. Cardizem) Erythromycin (e.g. Akne-Mycin, Ery-Tab) Itraconazole (e.g. Sporanox) Fluconazole (e.g. Diflucan) Ketoconazole (e.g. Nizoral) Telithromycin (e.g. Ketek) Verapamil (e.g. Calan SR, Isoptin, Verelan) Voriconazole (e.g. VFEND) - May increase the effects of sirolimus by increasing the amount of this medicine in the body. Can take 72 hours after last dose of Sirolimus Tacrolimus (e.g. Prograf) - May cause liver transplant rejection or serious side effects in patients on sirolimus. Patients with known HIV positivity or AIDS-related illness are not eligible. Patients with other severe concurrent disease which in the judgment of the investigator would make the patient inappropriate for entry into this study are ineligible. Patients must not have received any investigational agents within 21days of study entry. Patients must not be pregnant or breastfeeding. Pregnancy tests must be obtained for all females of child-bearing potential. Pregnant or lactating patients are ineligible for this study due to the unknown human fetal or teratogenic toxicities of rapamycin. Males or females of reproductive age may not participate unless they have agreed to use an effective contraceptive method. Patients who have uncontrolled infection are not eligible. Patients must have any active infections under control. Fungal disease must be stable for at least 2 weeks before study entry. Patients with bacteremia must have documented negative blood cultures prior to study entry.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High risk Myleodysplastic Syndrome (MDS)<br>Patients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Sirolimus<br>* Given PO<br>* Other names: Rapamune;Drug: Azacitidine<br>* Given IV<br>* Other names: Vidaza;|
| Experimental: Acute Myeloid Leukemia (AML)<br>Patients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Sirolimus<br>* Given PO<br>* Other names: Rapamune;Drug: Azacitidine<br>* Given IV<br>* Other names: Vidaza;|
| Experimental: MDS or AML with prior Azacitadine therapy<br>Patients receive sirolimus PO on days 1-10 or 1-12 and azacitidine IV on days 4-8, 11, and 12 or days 4-10. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity. | Drug: Sirolimus<br>* Given PO<br>* Other names: Rapamune;Drug: Azacitidine<br>* Given IV<br>* Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of response | MDS: Patients meeting an erythroid response, a platelet response, or a neutrophil response will be considered responders. AML: Patients achieving a complete remission (CR), complete response in the absence of a total platelet recovery (CRp), or partial remission (PR) will be considered responders. | Up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity referring to toxic events during the full course of treatment that are attributed as possibly, probably or definitely due to treatment, graded according to the National Institutes of Health (NIH) Common Toxicity Criteria (CTC) v. 4.0 | The combination of these drugs will be deemed safe if the number of adverse events is no more that 10% greater than the additive number of events of azacitidine and sirolimus if administrated separately. This will be based upon data in the original phase 2 trials of azacitidine demonstrating an 8% toxic death rate and therefore be 18% of the total number enrolled (approx. 40 x18% = 7). | Up to 30 days after completion of study treatment | 
| Pharmacokinetic assessment to assess levels of the drug in vivo | Day 4 levels will be drawn prior to initiation of azacitidine to allow for a PK/PD correlation study | Day 4 of course 1 | 
| Inhibition of mTOR signaling by sirolimus measured by intracellular flow cytometry for phosphorylation of the downstream signaling target S6 ribosomal protein as a surrogate for mTOR activity | Distributional characteristics are examined by: histograms, box plots and descriptive statistics (e.g., mean, median, standard deviation, range). Variability will be of particular interest. We will conduct within-patient comparison of baseline versus posts-treatment percentages by Student's paired t test. A nonparametric Wilcoxon signed ranks test will be employed if normality cannot be assumed or achieved by simple transformation. | Up to day 4 before azacitidine administration | 
| Quality of life (QOL) assessed by the European Organization for Research and Treatment of Cancer (EORTC) QOL and the Mental Health Inventory (MHI) |  | Up to day 164 |