Adult Acute Myeloid Leukemia With 11q23 (MLL) AbnormalitiesPhase 2NCT01869114
Sirolimus and Azacitidine in Treating Patients With High Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia That is Recurrent or Not Eligible for Intensive Chemotherapy
A Phase 2 study testing Sirolimus and Azacitidine in people with Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities and Adult Acute Myeloid Leukemia With Del(5q), run by Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University at 5 sites in United States.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Adult Acute Myeloid Leukemia With 11q23 (MLL) Abnormalities, Adult Acute Myeloid Leukemia With Del(5q), Adult Acute Myeloid Leukemia With Inv(16)(p13;q22)
- What is being tested?
- Sirolimus and Azacitidine
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 57 participants
- Where
- 5 sitesUnited States
- Study dates
- 8 Jul 2013to 3 Jan 2024
- Phase
- Phase 2
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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).
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- 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
Who cannot join
- 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.
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- 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.
Trial locations and contacts
5 sites in 1 country.
5 sites in 1 country
United States5 sites
Abington Hospital - Jefferson Health
Abington, Pennsylvania, 19001
Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University
Philadelphia, Pennsylvania, 19107
Jefferson Health, Aria Hospital
Philadelphia, Pennsylvania, 19124
Jefferson Health, Methodist Hospital
Philadelphia, Pennsylvania, 19148
Jefferson Health NJ Division (Kennedy Hospital)
Sewell, New Jersey, 08012
About this study
Official title: 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
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.
Read the detailed description
PRIMARY OBJECTIVE:
- 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:
- 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.
- Conditions
- 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)
- Being tested
- Sirolimus, Azacitidine
- Medical subject headings
- Congenital Abnormalities, Chromosome 5q Deletion Syndrome, Leukemia, Myeloid, Acute
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
SirolimusDrug
Also called rapamycin, Rapamune
Given PO
AzacitidineDrug
Also called 5-azacytidine, Vidaza
Given IV
| Study group | Role | What they receive |
|---|---|---|
| High risk Myleodysplastic Syndrome (MDS) | Experimental | 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. Receives: Drug: Sirolimus; Drug: Azacitidine |
| Acute Myeloid Leukemia (AML) | Experimental | 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. Receives: Drug: Sirolimus; Drug: Azacitidine |
| MDS or AML with prior Azacitadine therapy | Experimental | 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. Receives: Drug: Sirolimus; Drug: Azacitidine |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: Up to 5 years
Secondary outcomes (3)
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.
Measured: From the first dose of study drug through 30 days after the last dose of study treatment, an average of 7 months
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.
Measured: 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)
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.
Measured: Up to day 164
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted5 Jun 2013 (estimated)
- Study start8 Jul 2013
- Primary completion3 Jan 2024
- Study completion3 Jan 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (40)Papers the sponsor has linked to this study.
- Other trials for Adult Acute Myeloid Leukemia With 11q23 (MLL) AbnormalitiesStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 57 participants (actual)
Sponsor and investigators
- Lead sponsor
- Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Margaret Kasner, MD, Principal investigator, Sidney Kimmel Comprehensive Cancer Center at Thomas Jefferson University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01869114
- Sponsor's protocol ID
- 12D.587
- Other IDs
- 2012-50, JT 3016
- Status last verified
- Nov 2025
- First submitted
- 28 May 2013
- Last updated
- 10 Dec 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J, Lister TA, Bloomfield CD. The World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues. Report of the Clinical Advisory Committee meeting, Airlie House, Virginia, November, 1997. Ann Oncol. 1999 Dec;10(12):1419-32. doi: 10.1023/a:1008375931236.
PubMed 10643532Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G, Sanz M, Vallespi T, Hamblin T, Oscier D, Ohyashiki K, Toyama K, Aul C, Mufti G, Bennett J. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood. 1997 Mar 15;89(6):2079-88.
PubMed 9058730Garcia-Manero G, Fenaux P. Hypomethylating agents and other novel strategies in myelodysplastic syndromes. J Clin Oncol. 2011 Feb 10;29(5):516-23. doi: 10.1200/JCO.2010.31.0854. Epub 2011 Jan 10.
PubMed 21220589Rollison DE, Howlader N, Smith MT, Strom SS, Merritt WD, Ries LA, Edwards BK, List AF. Epidemiology of myelodysplastic syndromes and chronic myeloproliferative disorders in the United States, 2001-2004, using data from the NAACCR and SEER programs. Blood. 2008 Jul 1;112(1):45-52. doi: 10.1182/blood-2008-01-134858. Epub 2008 Apr 28.
PubMed 18443215Silverman LR, Demakos EP, Peterson BL, Kornblith AB, Holland JC, Odchimar-Reissig R, Stone RM, Nelson D, Powell BL, DeCastro CM, Ellerton J, Larson RA, Schiffer CA, Holland JF. Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B. J Clin Oncol. 2002 May 15;20(10):2429-40. doi: 10.1200/JCO.2002.04.117.
PubMed 12011120Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, Schoch R, Gattermann N, Sanz G, List A, Gore SD, Seymour JF, Bennett JM, Byrd J, Backstrom J, Zimmerman L, McKenzie D, Beach C, Silverman LR; International Vidaza High-Risk MDS Survival Study Group. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009 Mar;10(3):223-32. doi: 10.1016/S1470-2045(09)70003-8. Epub 2009 Feb 21.
PubMed 19230772Jabbour E, Garcia-Manero G, Batty N, Shan J, O'Brien S, Cortes J, Ravandi F, Issa JP, Kantarjian H. Outcome of patients with myelodysplastic syndrome after failure of decitabine therapy. Cancer. 2010 Aug 15;116(16):3830-4. doi: 10.1002/cncr.25247.
PubMed 20564137Fenaux P, Gattermann N, Seymour JF, Hellstrom-Lindberg E, Mufti GJ, Duehrsen U, Gore SD, Ramos F, Beyne-Rauzy O, List A, McKenzie D, Backstrom J, Beach CL. Prolonged survival with improved tolerability in higher-risk myelodysplastic syndromes: azacitidine compared with low dose ara-C. Br J Haematol. 2010 Apr;149(2):244-9. doi: 10.1111/j.1365-2141.2010.08082.x. Epub 2010 Feb 5.
PubMed 20136825Cashen AF, Schiller GJ, O'Donnell MR, DiPersio JF. Multicenter, phase II study of decitabine for the first-line treatment of older patients with acute myeloid leukemia. J Clin Oncol. 2010 Feb 1;28(4):556-61. doi: 10.1200/JCO.2009.23.9178. Epub 2009 Dec 21.
PubMed 20026803Sudan N, Rossetti JM, Shadduck RK, Latsko J, Lech JA, Kaplan RB, Kennedy M, Gryn JF, Faroun Y, Lister J. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer. 2006 Oct 15;107(8):1839-43. doi: 10.1002/cncr.22204.
PubMed 16967444Maurillo L, Venditti A, Spagnoli A, Gaidano G, Ferrero D, Oliva E, Lunghi M, D'Arco AM, Levis A, Pastore D, Di Renzo N, Santagostino A, Pavone V, Buccisano F, Musto P. Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer. 2012 Feb 15;118(4):1014-22. doi: 10.1002/cncr.26354. Epub 2011 Jul 14.
PubMed 21761399Sun D, Toan X, Zhang Y, Chen Y, Lu R, Wang X, Fang J. Mammalian target of rapamycin pathway inhibition enhances the effects of 5-aza-dC on suppressing cell proliferation in human gastric cancer cell lines. Sci China C Life Sci. 2008 Jul;51(7):640-7. doi: 10.1007/s11427-008-0080-2. Epub 2008 Jul 13.
PubMed 18622747Zhang YJ, Zhao SL, Tian XQ, Sun DF, Xiong H, Dai Q, Li XQ, Fang JY. Combined inhibition of Dnmt and mTOR signaling inhibits formation and growth of colorectal cancer. Int J Colorectal Dis. 2009 Jun;24(6):629-39. doi: 10.1007/s00384-009-0664-8. Epub 2009 Feb 20.
PubMed 19229543Wei AH, Tan PT, Catalano J, et al. Azacitidine in Combination with the mTOR Inhibitor Everolimus in Relapsed and Refractory AML. ASH Annual Meeting Abstracts. 2011;118:2599.
Morris RE. Rapamycin: FK506's fraternal twin or distant cousin? Immunol Today. 1991 May;12(5):137-40. doi: 10.1016/S0167-5699(05)80040-4.
PubMed 1715165