A Trial of Temsirolimus With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma

This study has suspended participant recruitment.
Sponsor:
Collaborator:
Pfizer
Information provided by (Responsible Party):
Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier:
NCT01614197
First received: May 18, 2012
Last updated: January 31, 2014
Last verified: January 2014
  Purpose

This is a phase I study of temsirolimus (Torisel) combined with dexamethasone, cyclophosphamide and etoposide in patients with relapsed acute lymphoblastic leukemia (ALL), lymphoblastic lymphoma (LL) or peripheral T-cell lymphoma (PTL).


Condition Intervention Phase
Lymphoblastic Leukemia, Acute, Childhood
Lymphoblastic Lymphoma
Peripheral T-cell Lymphoma
Drug: Temsirolimus
Drug: Dexamethasone
Drug: Etoposide
Drug: Etoposide phosphate
Drug: Cyclophosphamide
Drug: Methotrexate
Drug: Hydrocortisone
Drug: Cytarabine
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Trial of Temsirolimus (CCI-779, Pfizer, Inc.) in Combination With Etoposide and Cyclophosphamide in Children With Relapsed Acute Lymphoblastic Leukemia and Non-Hodgkins Lymphoma

Resource links provided by NLM:


Further study details as provided by Therapeutic Advances in Childhood Leukemia Consortium:

Primary Outcome Measures:
  • The dose of temsirolimus that can be safely given with dexamethasone, etoposide and cyclophosphamide. [ Time Frame: 5 weeks ] [ Designated as safety issue: Yes ]
    The incidence of dose limiting toxicity (DLT) will be measured. The maximum tolerated dose will be the highest study dose at which 1 or fewer of six patients experience DLT during cycle 1 of therapy.


Secondary Outcome Measures:
  • The response rate after treatment. [ Time Frame: 10 weeks ] [ Designated as safety issue: No ]
    The rate of remission will be assessed after 1 and 2 courses of therapy.

  • Responsiveness of patient lymphoblasts to mTOR inhibition using in-vitro and in-vivo pharmacodynamic (PD) assessments. [ Time Frame: 3 years ] [ Designated as safety issue: No ]
  • Minimal residual disease (MRD) levels present at end of cycle 1 therapy in patients with bone marrow involvement. [ Time Frame: 3 years ] [ Designated as safety issue: No ]

Estimated Enrollment: 30
Study Start Date: May 2012
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Intervention Details:
    Drug: Temsirolimus
    Dose will be assigned at study entry. Give IV over 30 minutes on days 3 and 9.
    Other Names:
    • Torisel
    • CCI-779
    Drug: Dexamethasone
    10 mg/m2/day divided twice daily (5 mg/m2/dose) given by mouth or IV days 1-5.
    Other Names:
    • Decadron
    • Dexasone
    • Diodex
    • Hexadrol
    • Maxidex
    • dexamethasone sodium phosphate
    • dexamethasone acetate
    Drug: Etoposide
    100 mg/m2 IV over 1-2 hours daily x 5 on Days 6-10.
    Other Names:
    • Toposar
    • VePesid
    • VP-16
    Drug: Etoposide phosphate
    For patients allergic to etoposide. 100 mg/m2 IV daily x 5 days on days 6-10.
    Other Name: Etopophos
    Drug: Cyclophosphamide
    440 mg/m2 IV daily x 5 on Days 6-10 given over 30-60 minutes.
    Other Names:
    • Cytoxan
    • Neosar
    Drug: Methotrexate

    PATIENTS WITH CNS1 OR 2 DISEASE Give intrathecally to patients with CNS1 and CNS 2 disease at the dose defined by age below on day 1 of course 1 if not given within 1 week of day 1 of course 1. COURSES 2, 4, 6, 8: Give intrathecally to patients who were CNS1 or CNS 2 at study entry day 1 of each course.

    PATIENTS WITH CNS 3 DISEASE COURSE 1: Give intrathecally to patients with CNS 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.

    COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.

    • 8 mg for patients age 1-1.99
    • 10 mg for patients age 2-2.99
    • 12 mg for patients 3-8.99 years of age
    • 15 mg for patients >9 years of age
    Other Names:
    • MTX
    • Amethopterin
    • Trexall
    Drug: Hydrocortisone

    Given with Methotrexate and Cytarabine for patients with CNS 3 disease.

    COURSE 1: Give intrathecally to patients with CNS 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.

    COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.

    • 8 mg for patients age 1-1.99
    • 10 mg for patients age 2-2.99
    • 12 mg for patients 3-8.99 years of age
    • 15 mg for patients >9 years of age
    Other Names:
    • Hydrocortisone sodium succinate
    • Solu-cortef
    Drug: Cytarabine

    Given with Methotrexate and Hydrocortisone for patients with CNS 3 disease.

    COURSE 1: Give intrathecally to patients with CNS 3 disease at the doses defined by age below on day 6 and then weekly until the patient is CNS 1.

    COURSES 2-8: Give intrathecally to patients who were CNS 3 at study entry on day 1 of each course.

    • 16 mg for patients age 1-1.99
    • 20 mg for patients age 2-2.99
    • 24 mg for patients 3-8.99 years of age
    • 30 mg for patients >9 years of age
    Other Names:
    • Cytosine arabinoside
    • Ara-C
    • Cytosar
Detailed Description:

Studies have shown that mTOR inhibitors (MTI) inhibit growth of pre-B and T-cell ALL cell lines in vitro and in ALL xenograft models. The MTI temsirolimus was chosen for use in this study due to its weekly intravenous dosing, its more predictable blood levels, and availability of a single-agent pediatric MTD and its sustained biologic effect due to conversion to sirolimus. This study will determine the maximum tolerated dose of temsirolimus that can given in combination with dexamethasone, cyclophosphamide and etoposide in relapsed ALL, LL or PTL. A standard 3-patient cohort dose-escalation design will be used. Response to treatment will be evaluated. Biology tests will be done to evaluate minimal residual disease (MRD), temsirolimus' effect on glucocorticoid resistance, and mTOR inhibition.

  Eligibility

Ages Eligible for Study:   1 Year to 21 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA

-Patients must be greater than or equal to 12 months and ≤ 21 years of age at the time of study enrollment.

Patients must have one of the following:

Leukemia

  • Patients must have relapsed or refractory acute lymphoblastic leukemia (ALL) with greater than or equal to 25% blasts in the bone marrow (M3). OR
  • Patients may have an M2 marrow (greater than or equal to 5% to < 25% blasts) with an extramedullary site of relapse; including CNS 2 and CNS 3.
  • Patients may not have isolated CNS relapse.

Lymphoma

  • Patient must have relapsed or refractory lymphoblastic lymphoma or peripheral T-cell lymphoma.
  • Patient must have histologic verification of disease at original diagnosis.
  • Patient must have evaluable or measurable disease documented by clinical or radiographic criteria or bone marrow disease present at study entry.
  • Patients may have CNS 2 or 3 disease, if other sites of involvement.
  • Karnofsky greater than or equal to 50% for patients > 16 years of age and Lansky greater than or equal to 50 for patients ≤ 16 years of age.
  • Patients must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy.
  • Patients must have had 2 or more prior therapeutic attempts defined as:

    1. Relapse after going into remission from re-induction for the first or subsequent relapse (ie: 2nd , 3rd, 4th…relapse), or
    2. Refractory disease after first or greater relapse and a single re-induction attempt.
    3. Patients who are refractory to 2 or more frontline induction attempts are eligible.
  • Patients with leukemia or lymphoma who relapse while receiving maintenance chemotherapy will not be required to have a waiting period before enrollment onto this study.
  • Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given up to one week prior to the initiation of the dexamethasone.
  • At least 14 days must have elapsed after the completion of cytotoxic therapy, with the exception of hydroxyurea.
  • 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. 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.
  • Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of a monoclonal antibody. (ie: Rituximab = 66 days, Epratuzumab = 69 days).
  • XRT: At least 14 days after local palliative XRT (small port); At least 84 days must have elapsed if prior TBI, craniospinal XRT or if greater than or equal to 50% radiation of pelvis; At least 42 days must have elapsed if other substantial marrow radiation.
  • 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 received therapy with an mTOR inhibitor.
  • Patients with avascular necrosis may enroll on study but must receive the full dose dexamethasone prophase in Cycle 1.
  • Adequate Bone Marrow Function Defined as: Blood counts are not required to be normal prior to enrollment on trial. However, platelet count must be greater than or equal to 20,000/mm3 to initiate therapy (may receive platelet transfusions). Patients should not be known to be refractory to red blood cell or platelet transfusions.

Adequate Renal Function Defined as:

  • Creatinine clearance or radioisotope GFR greater than or equal to 70ml/min/1.73 m2 or
  • Normal serum creatinine based on age and gender.

Adequate Liver Function Defined as:

  • Total bilirubin (sum of conjugated + unconjugated) must be less than or equal to normal per institutional normal values for age.
  • SGPT (ALT) and SGOT (AST) must be less than 3 x institutional upper limit of normal (Grade 1 or less per CTCAE 4).
  • Serum albumin greater than or equal to 2 g/dL.
  • The hepatic requirements may be waived for patients with elevations clearly due to leukemic infiltration after consultation with the Study Chair or Vice Chair.
  • Fasting or non-fasting serum triglyceride level ≤ 300 mg/dL and serum cholesterol level ≤ 300 mg/dL.

Adequate Cardiac Function Defined As:

  • Shortening fraction of ≥ 27% by echocardiogram, or
  • Ejection fraction of ≥ 50% by gated radionuclide study.

Adequate Pulmonary Function Defined as:

  • Pulse oximetry > 94% on room air (> 90% if at high altitude)
  • No evidence of dyspnea at rest and no exercise intolerance.
  • Baseline chest x-ray with no evidence of active infectious disease or pneumonitis.

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 this 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.
  • Random or fasting glucose within the upper limits of normal for age. If the initial blood glucose is non-fasting and above normal limits a fasting glucose can be obtained and must be within the upper limits of normal for age.

EXCLUSION CRITERIA

  • 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.
  • 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, Health Canada or the Therapeutic Goods Administration to be sold in the countries they govern. (United States, Canada and Australia)
  • 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 receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy]. Intrathecal chemotherapy (at the discretion of the primary oncologist) may be given up to one week prior to the initiation of the dexamethasone.
  • 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.
  • Anticoagulants: Patients who are currently receiving therapeutic anticoagulants (including aspirin, low molecular weight heparin, and others) are not eligible.
  • 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 temsirolimus + ACE inhibitors.
  • Enzyme inducing Anti-convulsants: Patients who are currently receiving enzyme inducing anticonvulsants (ie 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.
  • Patients receiving treatment with azoles such as fluconazole or voriconazole which are potent inhibitors of temsirolimus metabolism.

Infection Criteria

Patients are excluded if they have:

  • 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.
  • Patients with Down syndrome and Fanconi Anemia are excluded.
  • Patients will be excluded if they have 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.
  • Patients with known optic nerve and/or retinal involvement (because it may not be possible to safely delay irradiation) are not eligible. Patients presenting with visual disturbances by history or physical exam should have an ophthalmological exam and, if indicated, an MRI to determine optic nerve or retinal involvement.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01614197

  Show 32 Study Locations
Sponsors and Collaborators
Therapeutic Advances in Childhood Leukemia Consortium
Pfizer
Investigators
Study Chair: Susan Rheingold, MD Children's Hospital of Philadelphia
  More Information

No publications provided

Responsible Party: Therapeutic Advances in Childhood Leukemia Consortium
ClinicalTrials.gov Identifier: NCT01614197     History of Changes
Other Study ID Numbers: T2008-004
Study First Received: May 18, 2012
Last Updated: January 31, 2014
Health Authority: United States: Food and Drug Administration
Canada: Health Canada

Keywords provided by Therapeutic Advances in Childhood Leukemia Consortium:
Relapse
Lymphoblastic
Leukemia
Refractory
Temsirolimus
Acute
Childhood
Pediatric
ALL
NHL
LL
PTL

Additional relevant MeSH terms:
Leukemia
Leukemia, Lymphoid
Lymphoma
Lymphoma, Non-Hodgkin
Lymphoma, T-Cell
Lymphoma, T-Cell, Peripheral
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Immune System Diseases
Immunoproliferative Disorders
Lymphatic Diseases
Lymphoproliferative Disorders
Neoplasms
Neoplasms by Histologic Type
BB 1101
Cortisol succinate
Cyclophosphamide
Cytarabine
Dexamethasone
Dexamethasone 21-phosphate
Dexamethasone acetate
Etoposide
Etoposide phosphate
Everolimus
Hydrocortisone
Hydrocortisone 17-butyrate 21-propionate
Hydrocortisone acetate
Hydrocortisone-17-butyrate
Methotrexate
Sirolimus
Abortifacient Agents

ClinicalTrials.gov processed this record on October 22, 2014