Clinical Trials /

Aflac LL1602 ENCERT

NCT03328104

Description:

T- cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LLy) has an increase in proteins in a specific pathway called the mTOR pathway within the cancer cells. In cancer cells it can encourage untimely cell growth, cell production, and cell survival. Everolimus is an inhibitor of the mTOR pathway and can decrease the growth and survival of cancer cells. It also prevents communication within cells and stops proteins from being made that may contribute to leukemia. The main purpose of the study is to find the maximum tolerated dose of everolimus when used together with standard chemotherapy.

Related Conditions:
  • Peripheral T-Cell Lymphoma
  • T-Cell Acute Lymphoblastic Leukemia
  • T-Cell Lymphoblastic Leukemia/Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Aflac LL1602 ENCERT
  • Official Title: Aflac LL1602 ENCERT: A Phase 1 Trial Using Everolimus in Combination With Nelarabine, Cyclophosphamide and Etoposide in Relapsed T Cell Lymphoblastic Leukemia/Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: IRB00095500
  • NCT ID: NCT03328104

Conditions

  • Lymphoblastic Leukemia
  • Lymphoblastic Lymphoma

Interventions

DrugSynonymsArms
EverolimusEverolimus in combination with standard chemotherapy
NelarabineEverolimus in combination with standard chemotherapy
CyclophosphamideEverolimus in combination with standard chemotherapy
EtoposideEverolimus in combination with standard chemotherapy

Purpose

T- cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LLy) has an increase in proteins in a specific pathway called the mTOR pathway within the cancer cells. In cancer cells it can encourage untimely cell growth, cell production, and cell survival. Everolimus is an inhibitor of the mTOR pathway and can decrease the growth and survival of cancer cells. It also prevents communication within cells and stops proteins from being made that may contribute to leukemia. The main purpose of the study is to find the maximum tolerated dose of everolimus when used together with standard chemotherapy.

Detailed Description

      T- cell acute lymphoblastic leukemia (T-ALL) or T-cell lymphoblastic lymphoma (T-LLy) has an
      increase in proteins in a specific pathway called the mTOR pathway within the cancer cells.
      In cancer cells it can encourage untimely cell growth, cell production, and cell survival.
      Everolimus is an inhibitor of the mTOR pathway and can decrease the growth and survival of
      cancer cells. It also prevents communication within cells and stops proteins from being made
      that may contribute to leukemia.

      Two to six participants will receive the starting dose of everolimus. If the side effects are
      not too severe, the next group of participants will take the study drug at a higher dose
      level. Up to two dose levels of the study drug will be tested. The main purpose of the study
      is to find the maximum tolerated dose of everolimus when used together with standard
      chemotherapy. Everolimus has been found to be safe and effective in adults and children for
      treatment of T- and B-cell leukemias and lymphomas.
    

Trial Arms

NameTypeDescriptionInterventions
Everolimus in combination with standard chemotherapyExperimentalA treatment course lasts 28 days, during which participants take everolimus by mouth every day and also get standard chemotherapy via IV on certain days.
  • Everolimus
  • Nelarabine
  • Cyclophosphamide
  • Etoposide

Eligibility Criteria

        Inclusion Criteria:

        1.1 Age: Subjects must be > than 1 year and < 30 years of age at the time of study
        enrollment.

        1.2 Diagnosis Leukemia

        Patients must have relapsed (first or greater relapse) or refractory T-cell acute
        lymphoblastic leukemia (T-ALL) with:

          1. Relapsed T-ALL with an M2 (blasts ≥ 5 to ≤ 25%) or M3 (>25% blasts) marrow with or
             without an extramedullary site of relapse; including CNS 2 OR

          2. Refractory disease after induction failure of newly diagnosed patients OR no more than
             two more cycles of therapy OR

          3. Refractory disease with no more than one prior salvage attempt following the current
             relapse

        Lymphoma

        Patients must have relapsed (first or greater relapse) or refractory lymphoma with:

          1. Lymphoblastic lymphoma or peripheral T-cell lymphoma.

          2. Histologic verification of disease at original diagnosis or subsequent relapse.

          3. Evaluable or measurable disease documented by clinical or radiographic criteria or
             bone marrow disease present at study entry.

          4. Patient may have CNS 2 status if other sites of leukemia or lymphoma involvement are
             present.

             1.3 Performance Score Patients must have a Karnofsky ≥ 50% for subjects > 16 years of
             age and Lansky score ≥ 50 for subjects ≤ 16 years of age (See Appendix I).

             Note: Subjects who are unable to walk because of paralysis, but who are up in a
             wheelchair, will be considered ambulatory for the purpose of assessing the performance
             score.

             1.4 Prior Therapy A. Patients who relapse while receiving standard ALL maintenance
             chemotherapy will not be required to have a waiting period before entry onto this
             study.

             B. Patients who relapse on therapy other than standard ALL maintenance therapy must
             have fully recovered from the acute toxic effects of all prior chemotherapy,
             immunotherapy, or radiotherapy prior to entering this study.

               -  Cytotoxic Chemotherapy: At least 7 days must have elapsed since the completion of
                  cytotoxic therapy (other than standard ALL maintenance therapy as per 4.1.4.B)
                  with the exception of hydroxyurea, which is permitted up to 24 hours prior to the
                  start of protocol therapy.

               -  Nitrosureas: At least 42 days must have elapsed since administration of
                  nitrosureas.

               -  Hematopoietic growth factors: At least 14 days after the last dose of long acting
                  hematopoietic growth factor (e.g. Neulasta) or 7 days for short acting growth
                  factor (e.g. Neupogen)

               -  Radiation: At least 84 days must have elapsed since administration of
                  craniospinal, hemipelvic or other radiation therapy to more than 25% of the bone
                  marrow containing spaces. At least 42 days must have elapsed if other substantial
                  marrow radiation has been given.

               -  Nelarabine Prior therapy: Patients who have previously been treated with
                  nelarabine are eligible, however if they have previously received a regimen of
                  nelarabine, cyclophosphamide and etoposide, they are not eligible.

               -  Biologic (anti-neoplastic agent): At least 7 days after the last dose of a
                  biologic agent. 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 42 days after the completion of any type of immunotherapy
                  (e.g., tumor vaccines or chimeric antigen receptor T cell (CART) therapy

               -  Monoclonal Antibodies: Monoclonal antibodies: At least 3 half-lives of the
                  antibody must have elapsed after the last dose of a monoclonal antibody (See
                  Appendix II for details)

               -  Stem Cell Infusion: No evidence of active graft vs. host disease and at least 84
                  days must have elapsed after transplant or stem cell infusion.

               -  Study specific limitations on prior therapy: Patient may not have previously
                  received therapy with an mTOR inhibitor.

               -  Prior Intrathecal Therapy: Patients may be enrolled on study regardless of the
                  timing of prior Intrathecal therapy; however, they MAY NOT BEGIN TREATMENT ON
                  THIS PROTOCOL UNTIL A MINIMUM OF 7 DAYS HAS ELAPSED SINCE PRIOR INTRATHECAL
                  THERAPY.

             1.5 Adequate organ function

             A. Adequate Bone Marrow Function Defined as:

             • Patients should not be known to be refractory to red blood cell or platelet
             transfusions.

             • Blood counts are not required to be normal prior to enrollment on trial.

             B. Adequate Hepatic Function defined as:

             • Total bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x institutional upper limit
             of normal for age

               -  SGPT (ALT) and SGOT (AST) must be ≤ 3 x institutional upper limit of normal
                  (Grade 1 or less per CTCAE 4).

               -  GGT must be ≤ 2.5 x institutional upper limit of normal (Grade 1 or less per
                  CTCAE 4).

               -  Serum albumin ≥ 2 g/dL.

               -  The hepatic requirements may be waived for patients with Grade 1 or 2 elevations
                  of hepatic transaminases clearly due to leukemic infiltration after consultation
                  with a study Co-Chair.

             C. Adequate Renal Function defined as:

             • Serum creatinine ≤ 1.5x upper limit of normal (ULN) for age. If the serum creatinine
             is above these values, the calculated creatinine clearance or radioisotope GFR must be
             ≥ 70 mL/min/1.73m2.

             D. Adequate Cardiac Function defined as:

               -  Shortening fraction of ≥ 27% by echocardiogram, OR

               -  Ejection fraction of ≥ 50% by gated radionuclide study/echocardiogram

             E. Adequate Pulmonary Function defined as:

               -  Pulse oximetry > 94% on room air

               -  No evidence of dyspnea at rest and no exercise intolerance.

               -  Baseline chest x-ray with no evidence of active infectious disease or
                  pneumonitis.

             F. Reproductive Function

             • Female patients of childbearing potential must have a negative urine or serum
             pregnancy test confirmed prior to enrollment.

               -  Female patients with infants must agree not to breastfeed their infants while on
                  the study.

               -  Male and female patients of child-bearing potential must agree to use an
                  effective method of contraception approved by the investigator during the study.

             G. Normal blood glucose levels as defined as:

               -  Fasting or random blood glucose within the upper limits of normal for age.

               -  If random blood glucose is above upper limits for age, a fasting blood glucose
                  can be obtained and must be within normal limits for age

             H. Normal triglyceride and cholesterol as defined as:

             • Fasting or non-fasting serum triglyceride level ≤ 300 mg/dL and serum cholesterol
             level ≤ 300 mg/dL.

             1.6 Informed Consent Patients and/or their parents or legal guardians must be capable
             of understanding the investigational nature, potential risks and benefits of the
             study. All patients and/or their parents or legal guardians must sign a written
             informed consent. Age appropriate assent will be obtained per institutional
             guidelines. To allow non-native speaking patients to participate in this study,
             bilingual health services will be provided in the appropriate language, when feasible,
             according to individual institutional practices and guidelines

             1.7 Protocol Approval All institutional, local, state, FDA, and OHRP requirements for
             human studies must be met.

             Exclusion Criteria:

             2.1 Diagnosis

             • Patients with CNS3 disease as defined in section 4.3.1

             • Patients with isolated extra-medullary relapse involving only sanctuary sites (eg.
             Testicular relapse) but patients with extramedullary disease involving nodal or other
             non-sanctuary sites are eligible

             • Patients with isolated testicular relapse

             • Patients with Ph+ T-ALL/T-LLy

               -  Patients with Down Syndrome

               -  Patients with pre-existing Grade 2 (or higher) peripheral motor or sensory
                  neurotoxicity per CTCAE 4.03

               -  Patients with a history of prior veno-occlusive disease (VOD)/sinusoidal
                  obstruction syndrome (SOS) or findings consistent with a diagnosis of VOD/SOS,
                  defined as: conjugated serum bilirubin >1.4 mg/dL AND unexplained weight gain
                  greater than 10% of baseline weight or ascites AND hepatomegaly or right upper
                  quadrant pain without another explanation, OR reversal of portal vein flow on
                  ultrasound, OR pathological confirmation of VOD on liver biopsy.

             2.2 Infection Criteria

             • Positive blood culture within 48 hours of study enrollment;

             • Fever above 38.2 within 48 hours of study enrollment with clinical signs of
             infection. Fever that is determined to be due to tumor burden is allowed if patients
             have documented negative blood cultures for at least 48 hours prior to enrollment and
             no concurrent signs or symptoms of active infection or hemodynamic instability.

             • Active fungal, viral, bacterial, or protozoal infection requiring IV treatment.
             Chronic prophylaxis therapy to prevent infections is allowed

             2.3 Skin condition Patients with pre-existing Grade 1 or higher ulcerations, fistulas,
             mucosal lesions, or skin barrier breakdown

             2.4 Concomitant Medications

               -  Corticosteroids: Patients receiving corticosteroids who have not been on a stable
                  or decreasing dose of corticosteroid for at least 7 days prior to enrollment are
                  not eligible. Corticosteroids must be held for 24 hours prior to initiation of
                  study therapy.

               -  Investigational Drugs: Patients who are currently receiving another
                  investigational drug are not eligible. The definition of "investigational" for
                  use in this protocol means any drug that is not licensed by the FDA

               -  Anti-cancer agents: Patients who are currently receiving or may receive while on
                  therapy, other anti-cancer agents, radiation therapy or immunotherapy are not
                  eligible [except leukemia patients who relapsed on Maintenance therapy or
                  patients receiving hydroxyurea, which may be continued until 24 hours prior to
                  start of protocol therapy]. Intrathecal therapy may be given up to one week prior
                  to initiation of study treatment.

               -  Anti-GVHD or agents to prevent organ rejection post-transplant: Patients who are
                  receiving cyclosporine, tacrolimus or other agents to prevent either
                  graft-versus-host disease post bone marrow transplant or organ rejection
                  post-transplant are not eligible for this trial. At least 3 half-lives must have
                  elapsed after the last dose of GVHD meds.

               -  Angiotensin-converting enzyme (ACE) inhibitors: Patients who are currently
                  receiving ACE inhibitors are not eligible due to the development of angioneurotic
                  edema-type reactions in some subjects who received concurrent treatment with
                  everolimus + ACE inhibitors. At least 3 half-lives must have elapsed after the
                  last dose of ACE inhibitors.

               -  Anti-convulsants: Patients who are currently receiving CYP3A4/PgP enzyme inducing
                  anticonvulsants (eg. phenytoin, phenobarbitol, or carbamazepine) are not
                  eligible. Stabilizing on a non-hepatic inducing metabolizing anti-convulsant (ie:
                  gabapentin or levetiracetam) prior to study entry is acceptable. At least 3
                  half-lives must have elapsed after the last dose of enzyme inducing
                  anti-convulsants.

               -  Inhibitors of everolimus metabolism: Patients receiving treatment with azoles
                  such as fluconazole or voriconazole which are potent inhibitors of everolimus
                  metabolism. At least 3 half-lives must have elapsed after the last dose of
                  azoles.

             2.5 Patients with significant concurrent disease, illness, psychiatric disorder or
             social issue that would compromise patient safety or compliance with protocol
             treatment or required observations, interfere with consent, study participation,
             follow up, or interpretation of study results.
      
Maximum Eligible Age:29 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Determine the maximum tolerated dose (MTD).
Time Frame:Day 1-29
Safety Issue:
Description:Maximum Tolerated Dose (MTD) will be defined as the highest dose level tested at which 0/6 or 1/6 patients experience Dose Limiting Toxicity (DLT) with at least 2/3 or 2/6 patients encountering DLT at the next higher dose.

Secondary Outcome Measures

Measure:Determine area under the concentration versus time curve (AUC)
Time Frame:Day 1, 8 and 15 of course 1
Safety Issue:
Description:Blood will be collected on day 1, 8 and 15 of course 1 to determine the levels of everolimus in the body. On each of the three days, levels will be determined 30 min prior to administration of everolimus (hr 0), and 2, 6 and 24 hours after administration of everolimus. Everolimus concentrations will be measured by liquid chromatography/mass spectrometric analysis following a high throughput liquid/liquid extraction. Professional software and standard noncompartmental methods will be used to calculate area under the concentration versus time curve (AUC).
Measure:Determine maximum observed concentration (Cmax)
Time Frame:Day 1, 8 and 15 of course 1
Safety Issue:
Description:Blood will be collected on day 1, 8 and 15 of course 1 to determine the levels of everolimus in the body. On each of the three days, levels will be determined 30 min prior to administration of everolimus (hr 0), and 2, 6 and 24 hours after administration of everolimus. Everolimus concentrations will be measured by liquid chromatography/mass spectrometric analysis following a high throughput liquid/liquid extraction. Professional software and standard noncompartmental methods will be used to calculate maximum observed concentration (Cmax).
Measure:Determine elimination half-life (t1/2)
Time Frame:Day 1, 8 and 15 of course 1
Safety Issue:
Description:Blood will be collected on day 1, 8 and 15 of course 1 to determine the levels of everolimus in the body. On each of the three days, levels will be determined 30 min prior to administration of everolimus (hr 0), and 2, 6 and 24 hours after administration of everolimus. Everolimus concentrations will be measured by liquid chromatography/mass spectrometric analysis following a high throughput liquid/liquid extraction. Professional software and standard noncompartmental methods will be used to calculate elimination half-life (t1/2).
Measure:Changes in phosphoprotein (pAkt and p4EBP1) expression at time points pre- and post everolimus therapy in peripheral blood mono-nuclear cells (PBMCs) and bone marrow.
Time Frame:Day 1, 8 and 15 and day 29/ at count recovery at the end of course 1 (whichever is earlier)
Safety Issue:
Description:Levels of phosphorylated p-Akt and p-4EBP1 will be determined in PBMC's using nano-immunoassay. Mean levels of p-Akt and p-4EBP1 will be calculated at each time point and compared with response at the end of course 1 using repeated measures ANOVA.
Measure:Changes in Mer expression at time points pre- and post everolimus therapy in peripheral blood mono-nuclear cells (PBMCs) and bone marrow.
Time Frame:Day 1, 8 and 15 and day 29/ at count recovery at the end of course 1 (whichever is earlier)
Safety Issue:
Description:Mer expression (total and phosphorylated Mer) will be determined using traditional western blotting and/or phospho-flow cytometry in bone marrow and peripheral blood. Mean levels of Mer expression will be calculated at each time point and compared with response at the end of course 1 using repeated measures ANOVA.
Measure:Determine the response rate
Time Frame:Day 1-29; qualifying marrow and peripheral counts will be performed within 1 week of each other.
Safety Issue:
Description:The response rate is defined by the ability to achieve complete remission (CR) after 1 and 2 courses of this therapy in children with bone marrow relapse of T-ALL or relapsed T-LLy.
Measure:Mean time from start of study treatment to transplant in patients with bone marrow relapse of T-ALL or relapsed T-LLy.
Time Frame:Day 1-29
Safety Issue:
Description:Time from start of study treatment to transplant in patients with bone marrow relapse of T-ALL or relapsed T-LLy will be recorded, and mean time will be calculated.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Emory University

Trial Keywords

  • T- cell acute lymphoblastic leukemia
  • T-ALL
  • T-cell lymphoblastic lymphoma
  • T-LLy
  • Everolimus
  • Maximum tolerated dose

Last Updated

December 11, 2019