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Relapsed Lymphoblastic LeukemiaEarly Phase 1SIR-MO-1101NCT01658007

Pilot Study Of Sirolimus Plus Multiagent Chemotherapy For Relapsed/Refractory Acute Lymphoblastic Leukemia/Lymphoma

A Early Phase 1 study testing Sirolimus in people with Relapsed Lymphoblastic Leukemia and Recurrent Adult Lymphoblastic Lymphoma, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

The investigators want to learn about treating relapsed/refractory lymphoblastic leukemia and lymphoma with a drug called sirolimus. The investigators are using sirolimus along with other cancer drugs that are often given to patients with relapsed leukemia and lymphoma. Read more about this study

Who is it for?
Ages Up to 30 years
What is being tested?
Sirolimus
Could I receive a placebo?
No, everyone receives an active treatment
How many people
3 participants
Where
1 siteUnited States
Study dates
Aug 2012to Jan 2017
Phase
Early Phase 1
Are there results?
None posted in the registry

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 Up to 30 years
  • All sexes
  • No healthy volunteers
  • Child, Adult

Who may be able to join

  • Age: Patients must be < 30 years of age at the time of enrollment
  • Diagnosis
  • Acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL)
  • Histology: B-precursor or T-cell
  • Disease status: first or greater relapse OR primary disease refractory to two prior induction attempts
  • Patients with active relapse (> 5% bone marrow blasts if ALL, detectable disease by imaging with CT and/or PET scan if LL) without prior re-induction attempt are eligible for induction (block 1) therapy followed by consolidation (block 2) therapy
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  • Patients with documented history of relapse who have received alternative induction therapy are eligible for consolidation (block 2) therapy
  • Patients with CNS involvement are eligible for the induction block with intensified intrathecal therapy. Those enrolling post-induction for the consolidation block must have cleared the CNS of blasts at the time of enrollment on this study. (See Appendix I for method of evaluating traumatic lumbar punctures.)
  • Performance status
  • -Karnofsky >/= 50 for patients > 10 years of age OR Lansky >/= 50 for children </= 10 years of age (see Appendix II).
  • Oral medication -Patient must be able to consume oral medication in the form of solution or have nasogastric tube placed for administration of medication.
  • Prior Therapy
  • Patients who relapse while receiving standard ALL maintenance chemotherapy will not be required to have a waiting period before entry onto this study.
  • Patients who relapse on therapy other than standard ALL maintenance therapy must have recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study, unless deemed stable and irreversible by the investigator.
  • Recovery is defined as a toxicity grade < 2 as defined by the Common Toxicity Criteria Version (CTCAE) 4.0, unless otherwise specified in the Inclusion and Exclusion criteria.
  • Cytotoxic chemotherapy: At least 7 days must have elapsed from prior cytotoxic chemotherapy regimen before initiation of treatment with sirolimus on this trial, including administration of treatment dosing of corticosteroids (physiologic replacement for adrenal insufficiency is allowed)
  • Hydroxyurea: patients with peripheral blasts may receive hydroxyurea until the first dose of cytotoxic chemotherapy for cytoreduction.
  • Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth factor (e.g. Neulasta) or 7 days for short-acting growth factor.
  • Biologic (anti-neoplastic) agent: At least 7 days after the last dose of a biologic agent or donor lymphocyte infusion (DLI). For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair.
  • Immunotherapy: At least 6 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines.
  • Monoclonal antibodies: At least 3 half-lives since prior therapy with a monoclonal antibody.
  • XRT: >/= 2 wks for local palliative XRT (small port); >/= 24 weeks must have elapsed if prior TBI, craniospinal XRT or if >/= 50% radiation of pelvis; >/= 6 weeks must have elapsed if other substantial bone marrow radiation.
  • Stem Cell Transplant or Rescue without TBI: No evidence of active graft vs. host disease and ≥ 12 weeks must have elapsed since transplant or stem cell infusion.
  • Organ Function Requirements
  • Adequate Renal Function Defined as:
  • Creatinine clearance or radioisotope GFR >/= 70ml/min/1.73 m2 or
  • A serum creatinine based on age/gender as follows:
  • The threshold creatinine values in this Table were derived from the Schwartz formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing child length and stature data published by the CDC.
  • Adequate Liver Function Defined as:
  • Total bilirubin >/= 1.5 x upper limit of normal (ULN) for age
  • SGPT (ALT)</= 5x ULN.
  • Fasting serum cholesterol </=300 mg/dL AND fasting triglycerides </=300mg/dL. NOTE: If one or both of these thresholds are exceeded, the patient can only be enrolled after initiation of appropriate lipid lowering medication and improvement in laboratory parameters to meet eligibility.
  • Fasting serum glucose </= 160 mg/dL. May be achieved with insulin
  • Adequate Cardiac Function Defined as:
  • NOTE: this applies for patients enrolling for induction block 1 only. Patients who do not meet these criteria may be eligible for block 2 therapy after alternative induction block
  • Shortening fraction of >/= 27% by echocardiogram
  • Cumulative prior anthracycline exposure must not exceed 400 mg/m2 (each 10 mg/m2 of idarubicin/mitoxantrone should be calculated as the isotoxic equivalent of 30 mg/m2 of daunorubicin or doxorubicin)
  • Hematologic parameters
  • NOTE: this applies for patients enrolling for consolidation block 2 only. Patients enrolling for induction have no blood count requirements
  • Patients enrolling for consolidation block 2 after receiving alternative re-induction not on study must have ANC >/= 750/uL, platelets >/= 75,000/uL and bone marrow with </= 5% blasts (M1).

Who cannot join

  • Pregnancy or Breast-Feeding
  • -Pregnancy tests must be obtained in females of childbearing potential. Pregnant or lactating patients are ineligible for this study. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method.
  • Patients With Uncontrolled Infection
  • Patients must have any active infection under control. Fungal disease must be stable for at least 2 weeks before enrollment. Patients with bacteremia must have documented negative blood cultures for > 48 hours prior to initiation of treatment.
  • Patients who have a known allergy to sirolimus, FK506 (cross-reactive), or other mTOR inhibitors
  • Patients who have a history of asparaginase-associated pancreatitis ARE eligible but will have asparaginase omitted from therapy. Patients who have a history of E-coli asparaginase allergy will receive Erwinia asparaginase.
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  • Patients with active lung disease as defined by presence of pulmonary infiltrates on screening chest x-ray or baseline room air oxygen saturation of < 93%
  • Patients with a known history of hepatitis B, C, or HIV
  • Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study
  • Concomitant Medications
  • Hematopoietic growth factor(s): Must not have received within 7 days of entry onto this study for a short-acting growth factor, or within 14 days for a long-acting growth factor
  • Azoles: Due to interference with sirolimus metabolism, voriconazole, itraconazole, fluconazole, and ketoconazole should be avoided and alternative antifungal therapy initiated. If one of these agents must be given, sirolimus dosing will be decreased by 80% and trough levels monitored every other day for the first week and then weekly per protocol.
  • Calcineurin inhibitors: Must be off of tacrolimus and/or cyclosporine for at least 2 weeks prior to entry on this study
  • Additional medications that interact with CYP3A4: See Appendix III of the protocol for medications to be avoided while receiving sirolimus. Patients should be off these medications at least 2 weeks prior to entry on this study. If the medication is deemed essential and cannot be discontinued, sirolimus dosing will be adjusted following discussion with the study pharmacologist, Dr. Vinks, depending on the degree of expected interaction. Levels should be monitored every other day during the first week, then weekly per protocol.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Cincinnati Children's Hospital Medical Center

    Cincinnati, Ohio, 45229

Other trials in United States

About this study

The investigators want to learn about treating relapsed/refractory lymphoblastic leukemia and lymphoma with a drug called sirolimus. The investigators are using sirolimus along with other cancer drugs that are often given to patients with relapsed leukemia and lymphoma.

The main purpose of this study is to determine if sirolimus can be given safely in combination with standard drugs used to treat relapsed lymphoblastic leukemia/lymphoma.

Read the detailed description

You will receive the drug sirolimus in addition to standard chemotherapy drugs.

Just like your original cancer treatment, relapsed leukemia/lymphoma treatment is divided into different parts. You will get sirolimus during the first two parts:

  1. Re-induction: We give chemotherapy drugs to try to put your cancer back into remission, meaning that no cancer cells are found in the bone marrow samples (if you have leukemia) or on imaging studies (if you have lymphoma). From start to finish, this part of therapy lasts 35 days. On this study, you will take the drug sirolimus daily in addition to the normal re-induction chemotherapy drugs. You will swallow liquid sirolimus and you must take it with food. You will take sirolimus three times on the first day and two times each day after that during re-induction. Altogether, this is the schedule for re-induction:
  • Sirolimus by mouth starting 7 days before standard re-induction starts, and continuing every day through day 28
  • Mitoxantrone by vein on days 1 and 2
  • Vincristine by vein on days 3, 10, 17 and 24
  • Dexamethasone by vein or by mouth on days 1-5 and 15-19
  • PEG-asparaginase* on days 3 and 17
  • IT Methotrexate given in spinal fluid on day 1 (all patients) day 8,29 (if no cancer found in spinal fluid)
  • IT Triples given in spinal fluid on days 8,15,22,29 (if cancer found in spinal fluid) (If you have an allergic reaction to PEG-asparaginase, you may be given 6 doses of Erwinia L-asparaginase instead)
  1. Consolidation: We give drugs to continue to kill cancer cells in your body and prevent them from coming back. From start to finish, this part of therapy will last 63 days (it could be longer if we have to interrupt your treatment because you have low blood counts, and you need to wait for them to come up). On this study, you will take the drug sirolimus daily in addition to the normal consolidation chemotherapy drugs. You will take sirolimus three times on the first day and two times each day after that during consolidation. Altogether, this is the schedule for consolidation:
  • Sirolimus by mouth starting 7 days before consolidation starts, and continuing every day through day 56.
  • Cyclophosphamide by vein on days 1 and 29
  • Cytarabine by vein or under skin on days 1-4, 8-11, 29-32, 36-39
  • 6-mercaptopurine by mouth on days 1-14, 29-42
  • PEG-asparaginase* by vein on days 15 and 43
  • Vincristine by vein on days 15 and 43
  • It Methotrexate in spinal fluid on Days 1 and 29
  1. After you complete re-induction and consolidation, your doctor will determine the next steps of your treatment. This will depend on how you are doing and it will be up to you and your doctor. It will not be part of this study.

This research only includes the re-induction and consolidation portions of treatment (1 and 2, above). If you have already done re-induction, you can enter the study for consolidation only.

In addition to all the regular tests and procedures done to check on your cancer during this study, we will also take additional blood samples to monitor the levels of sirolimus in your blood (in order to adjust your dose) and we will also take blood samples to find certain markers in your blood that might indicate that the sirolimus is doing what it is supposed to do.

Being tested
Sirolimus
Medical subject headings
Precursor Cell Lymphoblastic Leukemia-Lymphoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • SirolimusDrug

    Also called Rapamycin, Rapamune

    Adding sirolimus to established induction and consolidation chemotherapy for relapsed/refractory acute lymphoblastic leukemia

Study groups in NCT01658007
Study groupRoleWhat they receive
SirolimusExperimentalAdding sirolimus to established induction and consolidation chemotherapy for relapsed/refractory acute lymphoblastic leuk
Receives: Drug: Sirolimus

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Determine rate of dose limiting toxicities

    The safety of the regimen will be assessed by the occurrence of unexpected or severe adverse events attributable to sirolimus

    Measured: 35 days

  2. Number of participants with adverse events to determine maximum tolerated level of sirolimus in combination with chemotherapy

    MAST (maximum acceptable sirolimus trough) will be the serum trough range at which fewer than one third of patients experience dose limiting toxicities during the observation period (28 days)

    Measured: 28 Days

Secondary outcomes (4)

  1. Measure the number of residual leukemia cells in the bone marrow.

    Disease response will be assessed according to standard criteria

    Measured: At day 35 of induction and day 56 of consolidation

  2. Measure protein phosphorylation

    Peripheral blood samples (5mL) will be obtained at day -6 (baseline), 1, 3,8, 29 of induction and day -6 (baseline), 1, 8, 29, 36 of consolidation for measurement of pAKT, p-S6, p70S6 kinase activity, and single-cell phosphoflow studies in peripheral blood mononuclear cells

    Measured: Samples collected at Baseline, Days 1, 3, 8 and 29 of induction and Baseline, and Days 1, 8, 29, and 36.

  3. Tumor measurement by PET and/or CT scan

    Disease response will be assessed according to standard criteria

    Measured: After day 35 of induction and/or Day 56 of Consolidation

  4. Measure changes in sirolimus plasma concentration (ng/ml).

    Use serial measurements of sirolmus trough levels and PK modeling to adjust individual patient sirolimus dose.

    Measured: 56 Days

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Aug 2012 (estimated)
  2. Study startAug 2012
  3. Primary completionJan 2017
  4. Study completionJan 2017

Why it stopped: Slow Accrual

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
3 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01658007
Sponsor's protocol ID
SIR-MO-1101
Other IDs
2012-0361
Acronym
SIR-MO-1101
Status last verified
Sep 2017
First submitted
19 Mar 2012
Last updated
14 Sep 2020
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Sirolimus in people with Relapsed Lymphoblastic Leukemia and Recurrent Adult Lymphoblastic Lymphoma, run by Children's Hospital Medical Center, Cincinnati at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 40 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 14 Sep 2020. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Slow Accrual). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Determine rate of dose limiting toxicities (time frame: 35 days). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01658007.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Sep 2020.

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