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
Conditions
Brief summary
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
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.
Interventions
DRUGSirolimus
Given PO
DRUGAzacitidine
Given IV
Sponsors
Sidney Kimmel Cancer Center at Thomas Jefferson University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. 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. 2. Patients must be ≥ 18 years old 3. Patients must have an ECOG performance status of \<= 2 (see Attachment 1). 4. Patients must have a life expectancy of at least 4 weeks. 5. Patients must be able to consume oral medication. 6. Patients must have completed any radiotherapy four weeks prior to study entry, 0-2 weeks for local palliative XRT (small port). 7. Patients must have recovered from the toxic effects of any prior chemotherapy to \< Grade 2 (except for alopecia). 8. 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. 9. Patients must be able to sign consent and be willing and able to comply with scheduled visits, treatment plan and laboratory testing. 10. 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
1. 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) 2. Patients must not be receiving growth factors. 3. 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. 4. 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. 5. 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. 6. Patients with known HIV positivity or AIDS-related illness are not eligible. 7. 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. 8. Patients must not have received any investigational agents within 21days of study entry. 9. 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. 10. 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Response | Up to 5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | From the first dose of study drug through 30 days after the last dose of study treatment, an average of 7 months | Adverse events will be assessed and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0. All AEs will be recorded and summarized by frequency and severity. |
| Mean Percentage of pS6-positive Blasts as Measured by Intracellular Flow Cytometry | Up to day 4 before azacitidine administration | The mean percentage of pS6-positive blasts in bone marrow samples was measured using intracellular flow cytometry before and after sirolimus administration. A reduction in pS6-positive blasts indicates inhibition of mTOR signaling. Results are reported as mean values along with the corresponding range. |
| 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 | EORTC QOL a 30-item questionnaire covering functional scales, symptom scales, and a global health status/QOL scale. MHI is a validated patient-reported outcome instrument used to assess psychological well-being across multiple domains. Participants rate items on a 6-point Likert scale. Scores are transformed to a 0-100 scale, with higher scores indicated better mental health. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A: Acute Myeloid Leukemia (AML) 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.
Sirolimus: Given PO
Azacitidine: Given IV | 21 |
| Arm B: High Risk Myleodysplastic Syndrome (MDS) 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.
Sirolimus: Given PO
Azacitidine: Given IV | 28 |
| Arm C: MDS or AML With Prior Azacitadine Therapy 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. | 8 |
| Total | 57 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event/Side Effects/Complications | 0 | 1 | 0 |
| Overall Study | Death | 19 | 18 | 8 |
| Overall Study | Disease Progression | 0 | 1 | 0 |
| Overall Study | Patient off treatment for other complicating disease | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 3 | 0 |
Baseline characteristics
| Characteristic | Arm A: Acute Myeloid Leukemia (AML) | Arm B: High Risk Myleodysplastic Syndrome (MDS) | Arm C: MDS or AML With Prior Azacitadine Therapy | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 24 Participants | 8 Participants | 46 Participants |
| Age, Categorical Between 18 and 65 years | 7 Participants | 4 Participants | 0 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 0 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 19 Participants | 24 Participants | 8 Participants | 51 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 5 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 3 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 18 Participants | 19 Participants | 6 Participants | 43 Participants |
| Region of Enrollment United States | 21 participants | 28 participants | 8 participants | 57 participants |
| Sex: Female, Male Female | 8 Participants | 9 Participants | 1 Participants | 18 Participants |
| Sex: Female, Male Male | 13 Participants | 19 Participants | 7 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 19 / 21 | 18 / 28 | 0 / 8 |
| other Total, other adverse events | 20 / 21 | 11 / 28 | 0 / 8 |
| serious Total, serious adverse events | 8 / 21 | 1 / 28 | 0 / 8 |
Outcome results
Primary
Number of Participants With 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.
Time frame: Up to 5 years
Population: Arm C was included in the study design, and eight participants were enrolled. However, none of them received study treatment, and no safety or efficacy data were collected. As a result, there is no evaluable data available for this outcome measure, and no data will be available in the future.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Arm A: Acute Myeloid Leukemia (AML) | Number of Participants With Response | Stable Disease (SD) | 13 Participants |
| Arm A: Acute Myeloid Leukemia (AML) | Number of Participants With Response | Complete Response (CR) | 1 Participants |
| Arm A: Acute Myeloid Leukemia (AML) | Number of Participants With Response | Progressive Disease (PD) | 4 Participants |
| Arm A: Acute Myeloid Leukemia (AML) | Number of Participants With Response | Partial Response (PR) | 5 Participants |
| Arm B: High risk Myleodysplastic Syndrome (MDS) | Number of Participants With Response | Progressive Disease (PD) | 4 Participants |
| Arm B: High risk Myleodysplastic Syndrome (MDS) | Number of Participants With Response | Partial Response (PR) | 3 Participants |
| Arm B: High risk Myleodysplastic Syndrome (MDS) | Number of Participants With Response | Stable Disease (SD) | 6 Participants |
| Arm B: High risk Myleodysplastic Syndrome (MDS) | Number of Participants With Response | Complete Response (CR) | 4 Participants |
Secondary
Mean Percentage of pS6-positive Blasts as Measured by Intracellular Flow Cytometry
The mean percentage of pS6-positive blasts in bone marrow samples was measured using intracellular flow cytometry before and after sirolimus administration. A reduction in pS6-positive blasts indicates inhibition of mTOR signaling. Results are reported as mean values along with the corresponding range.
Time frame: Up to day 4 before azacitidine administration
Population: Arm C was included in the study design, and eight participants were enrolled. However, none of them received study treatment, and no safety or efficacy data were collected. As a result, there is no evaluable data available for this outcome measure, and no data will be available in the future.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Arm A: Acute Myeloid Leukemia (AML) | Mean Percentage of pS6-positive Blasts as Measured by Intracellular Flow Cytometry | 18.6 percentage change |
| Arm B: High risk Myleodysplastic Syndrome (MDS) | Mean Percentage of pS6-positive Blasts as Measured by Intracellular Flow Cytometry | 37 percentage change |
Secondary
Number of Participants With Adverse Events
Adverse events will be assessed and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v. 4.0. All AEs will be recorded and summarized by frequency and severity.
Time frame: From the first dose of study drug through 30 days after the last dose of study treatment, an average of 7 months
Population: Arm C was included in the study design, and eight participants were enrolled. However, none of them received study treatment, and no safety or efficacy data were collected. As a result, there is no evaluable data available for this outcome measure, and no data will be available in the future.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Arm A: Acute Myeloid Leukemia (AML) | Number of Participants With Adverse Events | 20 Participants |
| Arm B: High risk Myleodysplastic Syndrome (MDS) | Number of Participants With Adverse Events | 11 Participants |
Secondary
Quality of Life (QOL) Assessed by the European Organization for Research and Treatment of Cancer (EORTC) QOL and the Mental Health Inventory (MHI)
EORTC QOL a 30-item questionnaire covering functional scales, symptom scales, and a global health status/QOL scale. MHI is a validated patient-reported outcome instrument used to assess psychological well-being across multiple domains. Participants rate items on a 6-point Likert scale. Scores are transformed to a 0-100 scale, with higher scores indicated better mental health.
Time frame: Up to day 164
Population: QoL questionnaire score analysis was contingent on demonstrating efficacy in the primary endpoint. The study did not met the primary efficacy endpoint, and QoL assessment was not performed as further data collection for secondary endpoints was not pursued.