Clinical Trials /

Nanoparticle Albumin-Bound Rapamycin, Temozolomide, and Irinotecan Hydrochloride in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors

NCT02975882

Description:

This phase I trial studies the side effects and best dose of nanoparticle albumin-bound rapamycin when given together with temozolomide and irinotecan hydrochloride in treating pediatric patients with solid tumors that have come back after a period of time during which the tumor could not be detected or has not responded to treatment. Nanoparticle albumin-bound rapamycin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nanoparticle albumin-bound rapamycin, temozolomide, and irinotecan hydrochloride may work better in treating pediatric patients with solid tumors.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Nanoparticle Albumin-Bound Rapamycin, Temozolomide, and Irinotecan Hydrochloride in Treating Pediatric Patients With Recurrent or Refractory Solid Tumors
  • Official Title: A Phase 1 Study of ABI-009 (NAB-RAPAMYCIN) in Pediatric Patients With Recurrent or Refractory Solid Tumors, Including CNS Tumors as a Single Agent and in Combination With Temozolomide and Irinotecan

Clinical Trial IDs

  • ORG STUDY ID: ADVL1514
  • SECONDARY ID: NCI-2016-01412
  • SECONDARY ID: ADVL1514
  • SECONDARY ID: ADVL1514
  • SECONDARY ID: UM1CA097452
  • NCT ID: NCT02975882

Conditions

  • Childhood Solid Neoplasm
  • Recurrent Central Nervous System Neoplasm
  • Recurrent Solid Neoplasm
  • Refractory Central Nervous System Neoplasm

Interventions

DrugSynonymsArms
Irinotecan HydrochlorideCampto, Camptosar, Camptothecin 11, Camptothecin-11, CPT 11, CPT-11, Irinomedac, U-101440ETreatment (nab-rapamycin, temozolomide, irinotecan)
Nanoparticle Albumin-Bound RapamycinABI-009, Nab-RapamycinTreatment (nab-rapamycin, temozolomide, irinotecan)
TemozolomideCCRG-81045, Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo-, M & B 39831, M and B 39831, Methazolastone, RP-46161, SCH 52365, Temcad, Temodal, Temodar, TemomedacTreatment (nab-rapamycin, temozolomide, irinotecan)

Purpose

This phase I trial studies the side effects and best dose of nanoparticle albumin-bound rapamycin when given together with temozolomide and irinotecan hydrochloride in treating pediatric patients with solid tumors that have come back after a period of time during which the tumor could not be detected or has not responded to treatment. Nanoparticle albumin-bound rapamycin may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as temozolomide and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nanoparticle albumin-bound rapamycin, temozolomide, and irinotecan hydrochloride may work better in treating pediatric patients with solid tumors.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of
      nanoparticle albumin-bound rapamycin (ABI-009) administered as an intravenous infusion over
      30 minutes on days 1 and 8 of a 21-day cycle, in combination with temozolomide and
      irinotecan hydrochloride (irinotecan) (administered on days 1-5) in pediatric patients with
      recurrent or refractory solid tumors, including central nervous system (CNS) tumors.

      II. To define and describe the toxicities of single-agent ABI-009 administered as an
      intravenous infusion over 30 minutes on days 1 and 8 of a 21-day cycle in pediatric patients
      with recurrent or refractory solid tumors, including CNS tumors.

      III. To define and describe the toxicities of ABI-009 administered as an intravenous
      infusion over 30 minutes on days 1 and 8 of a 21-day cycle in combination with temozolomide
      and irinotecan (administered on days 1-5) in pediatric patients with recurrent or refractory
      solid tumors, including CNS tumors.

      IV. To characterize the pharmacokinetics of ABI-009 in pediatric patients with recurrent or
      refractory solid tumors, including CNS tumors.

      SECONDARY OBJECTIVES:

      I. To preliminarily define the antitumor activity of ABI-009 in combination with
      temozolomide and irinotecan within the confines of a phase 1 study.

      II. To assess the biologic activity of ABI-009 by examining S6K1 and 4E-BP1 expression
      status in archival tumor tissue from solid tumor pediatric patients using
      immunohistochemistry.

      OUTLINE: This is a dose-escalation study of nanoparticle albumin-bound rapamycin.

      Patients receive nanoparticle albumin-bound rapamycin intravenously (IV) over 30 minutes on
      days 1 and 8 beginning on course 1. Patients also receive temozolomide orally (PO) and
      irinotecan hydrochloride PO on days 1-5 beginning on course 2. Treatment repeats every 21
      days for up to 35 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up periodically.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (nab-rapamycin, temozolomide, irinotecan)ExperimentalPatients receive nanoparticle albumin-bound rapamycin IV over 30 minutes on days 1 and 8 beginning on course 1. Patients also receive temozolomide PO and irinotecan hydrochloride PO on days 1-5 beginning on course 2. Treatment repeats every 21 days for up to 35 courses in the absence of disease progression or unacceptable toxicity.
  • Irinotecan Hydrochloride
  • Nanoparticle Albumin-Bound Rapamycin
  • Temozolomide

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have a body surface area (BSA) of >= 0.2 m^2 at the time of study
             enrollment

          -  Patients with recurrent or refractory solid tumors, including CNS tumors, are
             eligible; patients must have had histologic verification of malignancy at original
             diagnosis or relapse except in patients with intrinsic brain stem tumors, optic
             pathway gliomas, or patients with pineal tumors and elevations of cerebrospinal fluid
             (CSF) or serum tumor markers including alpha-fetoprotein or beta-human chorionic
             gonadotropin (HCG)

          -  Patients must have either measurable or evaluable disease

          -  Patient's current disease state must be one for which there is no known curative
             therapy

          -  Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16
             years of age

               -  Note: Neurologic deficits in patients with CNS tumors must have been relatively
                  stable for at least 7 days prior to study enrollment; patients 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

          -  Patients must have fully recovered from the acute toxic effects of all prior
             anti-cancer therapy and must meet the following minimum duration from prior
             anti-cancer directed therapy prior to enrollment; if after the required timeframe,
             the numerical eligibility criteria are met, e.g. blood count criteria, the patient is
             considered to have recovered adequately

          -  Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive; the
             duration of this interval must be discussed with the study chair and the
             study-assigned research coordinator prior to enrollment

               -  >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42
                  days if prior nitrosourea)

          -  Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced
             platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of
             agent; the duration of this interval must be discussed with the study chair and the
             study-assigned research coordinator prior to enrollment

          -  Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and
             toxicity related to prior antibody therapy must be recovered to grade =< 1

          -  Corticosteroids: If used to modify immune adverse events related to prior therapy, >=
             14 days must have elapsed since last dose of corticosteroid

          -  Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth
             factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; 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 and the
             study-assigned research coordinator

          -  Interleukins, interferons and cytokines (other than hematopoietic growth factors): >=
             21 days after the completion of interleukins, interferon or cytokines (other than
             hematopoietic growth factors)

          -  Stem cell infusions (with or without total body irradiation [TBI]):

               -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
                  cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84
                  days after infusion, and no evidence of graft-versus-host disease (GVHD)

               -  Autologous stem cell infusion including boost infusion: >= 42 days

          -  Cellular therapy: >= 42 days after the completion of any type of cellular therapy
             (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)

          -  X ray (XRT)/external beam irradiation including protons: >= 14 days after local XRT;
             >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >=
             42 days if other substantial bone marrow (BM) radiation

          -  Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131 iodine
             metaiodobenzylguanidine [131I-MIBG]): >= 42 days after systemically administered
             radiopharmaceutical therapy

          -  Irinotecan, temozolomide and mammalian target of rapamycin (mTOR) inhibitor exposure:

               -  Patients who have received prior single agent therapy with irinotecan,
                  temozolomide, or an mTOR inhibitor, excluding ABI-009, are eligible

               -  Patients who have received prior combination therapy with two of the three
                  agents, excluding ABI-009, are eligible

               -  Patients who have received prior therapy with all three agents in combination
                  (i.e. irinotecan, temozolomide, and an mTOR inhibitor) are not eligible

               -  Patients who have previously received irinotecan and temozolomide and had
                  significant toxicity with these two drugs are not eligible

          -  For patients with solid tumors without known bone marrow involvement:

               -  Peripheral absolute neutrophil count (ANC) >= 1000/mm^3

               -  Platelet count >= 100,000/mm^3 (transfusion independent, defined as not
                  receiving platelet transfusions for at least 7 days prior to enrollment)

               -  Hemoglobin >= 8.0 g/dl at baseline (may receive red blood cell [RBC]
                  transfusions)

          -  Patients with known bone marrow metastatic disease will be eligible for the study if
             they have an ANC >= 750/mm^3 and platelet count >= 50,000/mm^3 (may receive
             transfusions provided they are not known to be refractory to red cell or platelet
             transfusions); these patients will not be evaluable for hematologic toxicity; at
             least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for
             the dose-escalation part of the study; if dose-limiting hematologic toxicity is
             observed, all subsequent patients enrolled must be evaluable for hematologic toxicity

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             ml/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

               -  Age: maximum serum creatinine (mg/dL)

               -  1 to < 2 years: 0.6 (male and female)

               -  2 to < 6 years: 0.8 (male and female)

               -  6 to < 10 years: 1 (male and female)

               -  10 to < 13 years: 1.2 (male and female)

               -  13 to < 16 years: 1.5 (male), 1.4 (female)

               -  >= 16 years: 1.7 (male), 1.4 (female)

          -  Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for
             age

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 110
             U/L; for the purpose of this study, the ULN for SGPT is 45 U/L

          -  Serum albumin >= 2 g/dL

          -  Pulse oximetry > 94% on room air if there is clinical indication for determination
             (e.g. dyspnea at rest)

          -  Patients with seizure disorder may be enrolled if on non-enzyme inducing
             anticonvulsants and well controlled

          -  Nervous system disorders (National Cancer Institute Common Terminology Criteria for
             Adverse Events [NCI CTCAE]) resulting from prior therapy must be =< grade 2

          -  Serum triglyceride level =< 300 mg/dL

          -  Serum cholesterol level =< 300 mg/dL

          -  Random or fasting blood glucose within the upper normal limits for age; if the
             initial blood glucose is a random sample that is outside of the normal limits, then
             follow-up fasting blood glucose can be obtained and must be within the upper normal
             limits for age

          -  A blood pressure (BP) =< the 95th percentile for age, height, and gender, and not
             receiving medication for treatment of hypertension; please note that 3 serial blood
             pressures should be obtained and averaged to determine baseline BP

          -  International normalized ratio (INR) =< 1.5

          -  Not currently receiving anticoagulation therapy

          -  All patients and/or their parents or legally authorized representatives must sign a
             written informed consent; assent, when appropriate, will be obtained according to
             institutional guidelines

        Exclusion Criteria:

          -  Pregnant or breast-feeding women will not be entered on this study; pregnancy tests
             must be obtained in girls who are post-menarchal; males or females of reproductive
             potential may not participate unless they have agreed to use an effective
             contraceptive method both during and for 6 months after participation in this study;
             abstinence is an acceptable method of contraception

          -  Patients receiving corticosteroids must have been on a stable or decreasing dose of
             corticosteroid for at least 7 days prior to enrollment; if used to modify immune
             adverse events related to prior therapy, >= 14 days must have elapsed since last dose
             of corticosteroid

          -  Patients who are currently receiving another investigational drug are not eligible

          -  Patients who are currently receiving other anti-cancer agents are not eligible

          -  Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
             graft-versus-host disease post bone marrow transplant are not eligible for this trial

          -  Patients must not have received enzyme-inducing anticonvulsants for at least 7 days
             prior to enrollment

          -  Patients who are currently receiving therapeutic anticoagulants (including aspirin,
             low molecular weight heparin, and others) are not eligible

          -  Patients must not be receiving any strong CYP3A4 or P-glycoprotein (P-gp) inducers or
             inhibitors within 7 days prior to enrollment; moderate inducers or inhibitors of
             CYP3A4 and P-gp should also be avoided during ABI-009 treatment, if possible

          -  Patients with interstitial lung disease and/or pneumonitis are not eligible

          -  Patients with a history of allergic reactions attributed to compounds of similar
             composition, including macrolide and ketolide antibiotics, temsirolimus/other mTOR
             inhibitors, temozolomide or irinotecan are not eligible

          -  Patients with hypersensitivity to albumin are not eligible

          -  Patients who have had or are planning to have the following invasive procedures are
             not eligible:

               -  Major surgical procedure, laparoscopic procedure, open biopsy or significant
                  traumatic injury within 28 days prior to enrollment

               -  Subcutaneous port placement or central line placement is not considered major
                  surgery; external central lines must be placed at least 3 days prior to
                  enrollment and subcutaneous ports must be placed at least 7 days prior to
                  enrollment

               -  Core biopsy within 7 days prior to enrollment

               -  Fine needle aspirate within 7 days prior to enrollment

               -  NOTE: For purposes of this study, bone marrow aspirate and biopsy are not
                  considered surgical procedures and therefore are permitted within 14 days prior
                  to start of protocol therapy

          -  Patients with current deep vein thrombosis or deep vein thrombosis within the past 6
             months are not eligible

          -  Patients who have an uncontrolled infection are not eligible

          -  Patients who have received a prior solid organ transplantation are not eligible

          -  Patients who in the opinion of the investigator may not be able to comply with the
             safety monitoring requirements of the study are not eligible
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events according to NCI CTCAE version 4.0
Time Frame:Up to 21 days
Safety Issue:
Description:Blood samples (2 ml) will be collected in heparinized tubes at a site distant from the infusion for pharmacokinetic evaluation. The PK profile will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit.)

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Children's Oncology Group

Last Updated

November 23, 2016