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Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)

NCT03155620

Description:

This Pediatric MATCH screening and multi-sub-study phase II trial studies how well treatment that is directed by genetic testing works in pediatric patients with solid tumors, non-Hodgkin lymphomas, or histiocytic disorders that have progressed following at least one line of standard systemic therapy and/or for which no standard treatment exists that has been shown to prolong survival. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit more from treatment which targets their tumor's particular genetic mutation, and may help doctors plan better treatment for patients with solid tumors or non-Hodgkin lymphomas.

Related Conditions:
  • Malignant Solid Tumor
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
  • Official Title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice) Screening Protocol

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01251
  • SECONDARY ID: NCI-2017-01251
  • SECONDARY ID: APEC1621SC
  • SECONDARY ID: APEC1621SC
  • SECONDARY ID: APEC1621SC
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03155620

Conditions

  • Advanced Malignant Solid Neoplasm
  • Ann Arbor Stage III Childhood Non-Hodgkin Lymphoma
  • Ann Arbor Stage IV Childhood Non-Hodgkin Lymphoma
  • Childhood Langerhans Cell Histiocytosis
  • Histiocytic Sarcoma
  • Juvenile Xanthogranuloma
  • Malignant Glioma
  • Recurrent Central Nervous System Neoplasm
  • Recurrent Childhood Ependymoma
  • Recurrent Childhood Malignant Germ Cell Tumor
  • Recurrent Childhood Medulloblastoma
  • Recurrent Childhood Non-Hodgkin Lymphoma
  • Recurrent Childhood Rhabdomyosarcoma
  • Recurrent Childhood Soft Tissue Sarcoma
  • Recurrent Ewing Sarcoma
  • Recurrent Glioma
  • Recurrent Hepatoblastoma
  • Recurrent Langerhans Cell Histiocytosis
  • Recurrent Malignant Solid Neoplasm
  • Recurrent Neuroblastoma
  • Recurrent Osteosarcoma
  • Recurrent Peripheral Primitive Neuroectodermal Tumor
  • Recurrent Rhabdoid Tumor
  • Refractory Central Nervous System Neoplasm
  • Refractory Childhood Malignant Germ Cell Tumor
  • Refractory Ewing Sarcoma
  • Refractory Glioma
  • Refractory Hepatoblastoma
  • Refractory Langerhans Cell Histiocytosis
  • Refractory Malignant Solid Neoplasm
  • Refractory Medulloblastoma
  • Refractory Neuroblastoma
  • Refractory Non-Hodgkin Lymphoma
  • Refractory Osteosarcoma
  • Refractory Peripheral Primitive Neuroectodermal Tumor
  • Refractory Rhabdoid Tumor
  • Refractory Rhabdomyosarcoma
  • Rhabdoid Tumor
  • Stage III Osteosarcoma AJCC v7
  • Stage III Soft Tissue Sarcoma AJCC v7
  • Stage IV Osteosarcoma AJCC v7
  • Stage IV Soft Tissue Sarcoma AJCC v7
  • Stage IVA Osteosarcoma AJCC v7
  • Stage IVB Osteosarcoma AJCC v7
  • Wilms Tumor

Interventions

DrugSynonymsArms
EnsartinibX-396Subprotocol F (ALK or ROS1 gene alteration)
ErdafitinibJNJ-42756493Subprotocol B (FGFR1, FGFR2, FGFR3, or FGFR4 gene mutation)
LarotrectinibARRY 470, LOXO 101, LOXO-101Subprotocol A (NTRK1, NTRK2, or NTRK3 gene fusion)
OlaparibAZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Subprotocol H (ATM, BRCA1, BRCA2, RAD51C, RAD51D mutations)
PalbociclibIbrance, PD-0332991, PD-332991Subprotocol I (Rb positive, alterations in cell cycle genes)
PI3K/mTOR Inhibitor LY3023414LY 3023414, LY-3023414, LY3023414Subprotocol D (TSC1, TSC2, or PI3K/mTOR gene mutation)
Selumetinib SulfateAZD-6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulfate, AZD6244 Hydrogen Sulphate, Selumetinib SulphateSubprotocol E (activating MAPK pathway gene mutation)
TazemetostatE7438, EPZ-6438, EPZ6438Subprotocol C (EZH2, SMARCB1, or SMARCA4 gene mutation)
UlixertinibBVD-523, VRT752271Subprotocol J (MAPK pathway mutations)
VemurafenibBRAF (V600E) kinase inhibitor RO5185426, BRAF(V600E) Kinase Inhibitor RO5185426, PLX-4032, PLX4032, RG 7204, RG7204, RO 5185426, ZelborafSubprotocol G (BRAF V600 gene mutation)

Purpose

This Pediatric MATCH screening and multi-sub-study phase II trial studies how well treatment that is directed by genetic testing works in pediatric patients with solid tumors, non-Hodgkin lymphomas, or histiocytic disorders that have progressed following at least one line of standard systemic therapy and/or for which no standard treatment exists that has been shown to prolong survival. Genetic tests look at the unique genetic material (genes) of patients' tumor cells. Patients with genetic changes or abnormalities (mutations) may benefit more from treatment which targets their tumor's particular genetic mutation, and may help doctors plan better treatment for patients with solid tumors or non-Hodgkin lymphomas.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To utilize clinical and biological data to screen for eligibility to phase 2
      pathway-targeting specific subprotocols of pathway-targeting agents in pediatric patients
      with advanced solid tumors, non-Hodgkin lymphomas, and histiocytic disorders.

      II. To determine the proportion of pediatric patients whose advanced tumors have pathway
      alterations that can be targeted by select anti-cancer drugs.

      III. To determine the objective response rates (ORR; complete response + partial response) in
      pediatric patients with advanced solid tumors, non-Hodgkin lymphomas, and histiocytic
      disorders harboring a priori specified genomic alterations treated with pathway-targeting
      agents.

      SECONDARY OBJECTIVES:

      I. To estimate the progression free survival in pediatric patients receiving targeted
      therapies for advanced solid tumors, non-Hodgkin lymphomas, and histiocytic disorders.

      II. To obtain preliminary or additional information about the tolerability of targeted
      therapies in children with advanced cancers.

      III. To provide preliminary estimates of the pharmacokinetics of targeted therapies in
      children with advanced cancers.

      IV. To obtain preliminary information on the response rate to targeted therapy in patients
      whose tumors lack actionable alterations as defined for the molecular analysis for therapy
      choice (MATCH) study, for selected agents for which efficacy is observed in the primary
      matched cohort.

      TERTIARY OBJECTIVES:

      I. To increase knowledge of the genomic landscape of advanced pediatric solid tumors,
      non-Hodgkin lymphomas, and histiocytic disorders.

      II. To describe the genomic changes that occur in advanced pediatric cancers between the time
      of initial diagnosis and relapse, in cases for which paired tumor specimens are available.

      III. To explore approaches to diagnosing and profiling genomics of advanced pediatric cancers
      through evaluation of circulating tumor deoxyribonucleic acid (DNA).

      IV. To determine the frequency and spectrum of germline cancer susceptibility mutations in
      children with relapsed solid tumors and non-Hodgkin lymphomas and assess the feasibility of
      return of those results in the National Clinical Trial Network (NCTN) group setting.

      OUTLINE:

      STEP 1 (SCREENING): Patients undergo biopsy along with tumor mutational screening of the
      biopsy material for specific, pre-defined mutations, amplifications, or translocations of
      interest via tumor sequencing and immunohistochemistry. Patients also undergo collection of
      blood samples for research purposes.

      STEP 2 (TREATMENT): Patients with a mutation targeted by one or more of the investigational
      drugs used in this study or those without mutations are assigned to 1 of 10 treatment
      subprotocols.

      APEC1621A: Patients with a NTRK1, NTRK2, or NTRK3 gene fusion receive Trk inhibitor LOXO-101
      orally (PO) or via nasogastric- or gastric-tube twice daily (BID) on days 1-28. Courses
      repeat every 28 days for 2 years in the absence of disease progression or unacceptable
      toxicity.

      APEC1621B: Patients with a FGFR1, FGFR2, FGFR3, or FGFR4 gene mutation receive pan-FGFR
      tyrosine kinase inhibitor JNJ-42756493 PO once daily on days 1-28. Courses repeat every 28
      days for up to 2 years in the absence of disease progression or unacceptable toxicity.

      APEC1621C: Patients with an EZH2, SMARCB1, or SMARCA4 gene mutation receive tazemetostat PO
      BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease
      progression or unacceptable toxicity.

      APEC1621D: Patients with a TSC1, TSC2, or PI3K/mTOR gene mutations receive PI3K/mTOR
      inhibitor LY3023414 PO BID on days 1-28. Courses repeat every 28 days for 2 years in the
      absence of disease progression or unacceptable toxicity.

      APEC1621E: Patients with an activating MAPK pathway gene mutation receive selumetinib sulfate
      PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease
      progression or unacceptable toxicity.

      APEC1621F: Patients with an ALK or ROS1 gene alteration receive ensartinib (ALK Inhibitor
      X-396) PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of
      disease progression or unacceptable toxicity.

      APEC1621G: Patients with a BRAF V600 gene mutation receive vemurafenib PO BID on days 1-28.
      Courses repeat every 28 days for 2 years in the absence of disease progression or
      unacceptable toxicity.

      APEC1621H: Patients with deleterious ATM, BRCA1, BRCA2, RAD51C, or RAD51D gene mutations
      receive olaparib PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence
      of disease progression or unacceptable toxicity.

      APEC1621I: Patients with Rb positive advanced solid tumors, non-Hodgkin lymphoma, or
      histiocytic disorders with activating alterations in cell cycle genes receive palbociclib PO
      QD on days 1-21. Courses repeat every 28 days for up to 2 years in the absence of disease
      progression or unacceptable toxicity.

      APEC1621J: Patients with MAPK Pathway Mutations receive ulixertinib PO BID. Courses repeat
      every 28 days for up to 2 years in the absence of disease progression or unacceptable
      toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Subprotocol A (NTRK1, NTRK2, or NTRK3 gene fusion)ExperimentalPatients with a NTRK1, NTRK2, or NTRK3 gene fusion receive Trk inhibitor LOXO-101 PO or via nasogastric- or gastric-tube BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.
  • Larotrectinib
Subprotocol B (FGFR1, FGFR2, FGFR3, or FGFR4 gene mutation)ExperimentalPatients with a FGFR1, FGFR2, FGFR3, or FGFR4 gene mutation receive pan-FGFR tyrosine kinase inhibitor JNJ-42756493 PO once daily on days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Erdafitinib
Subprotocol C (EZH2, SMARCB1, or SMARCA4 gene mutation)ExperimentalPatients with an EZH2, SMARCB1, or SMARCA4 gene mutation receive tazemetostat PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.
  • Tazemetostat
Subprotocol D (TSC1, TSC2, or PI3K/mTOR gene mutation)ExperimentalPatients with a TSC1, TSC2, or PI3K/mTOR gene mutations receive PI3K/mTOR inhibitor LY3023414 PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.
  • PI3K/mTOR Inhibitor LY3023414
Subprotocol E (activating MAPK pathway gene mutation)ExperimentalPatients with an activating MAPK pathway gene mutation receive selumetinib sulfate PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.
  • Selumetinib Sulfate
Subprotocol F (ALK or ROS1 gene alteration)ExperimentalPatients with an ALK or ROS1 gene alteration receive ensartinib (ALK Inhibitor X-396) PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.
  • Ensartinib
Subprotocol G (BRAF V600 gene mutation)ExperimentalPatients with a BRAF V600 gene mutation receive vemurafenib PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.
  • Vemurafenib
Subprotocol H (ATM, BRCA1, BRCA2, RAD51C, RAD51D mutations)ExperimentalPatients deleterious ATM, BRCA1, BRCA2, RAD51C, or RAD51D gene mutations receive olaparib PO BID on days 1-28. Courses repeat every 28 days for 2 years in the absence of disease progression or unacceptable toxicity.
  • Olaparib
Subprotocol I (Rb positive, alterations in cell cycle genes)ExperimentalPatients with Rb positive advanced solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with activating alterations in cell cycle genes receive palbociclib PO QD on days 1-21. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Palbociclib
Subprotocol J (MAPK pathway mutations)ExperimentalPatients with MAPK pathway mutations receive ulixertinib PO BID. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unacceptable toxicity.
  • Ulixertinib

Eligibility Criteria

        Inclusion Criteria:

          -  ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients with recurrent or
             refractory solid tumors (including non-Hodgkin lymphomas, histiocytoses [e.g.
             Langerhans cell histiocytosis (LCH), juvenile xanthogranuloma (JXG), histiocytic
             sarcoma], and central nervous system [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-HCG

          -  ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: Patients must have a formalin
             fixed paraffin embedded (FFPE) tumor sample available for MATCH study testing from a
             biopsy or surgery that was performed at any point after initial tumor
             recurrence/progression, or be planned to have a procedure to obtain such a sample that
             is considered to be of potential benefit by the treating clinicians; a tumor sample
             from a clinically performed diagnostic (pre-treatment) biopsy will be acceptable for
             enrollment onto pediatric MATCH for children with diffuse intrinsic pontine gliomas
             (DIPG, brainstem gliomas)

          -  ELIGIBILITY CRITERIA FOR ENROLLMENT ONTO APEC1621SC: 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 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

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: NOTE: patient does not need to meet all
             subprotocol criteria at time of enrollment onto the APEC1621 screening protocol, but
             will need to meet all criteria prior to enrollment on any assigned treatment
             subprotocol; patients must be enrolled onto a subprotocol within 8 weeks (56 days) of
             treatment assignment

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: 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 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

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of treatment with subprotocol
             specified therapy, the patients must have radiographically measurable disease;
             patients with neuroblastoma who do not have measurable disease but have iobenguane
             (MIBG) positive (+) evaluable are eligible; measurable disease in patients with CNS
             involvement is defined as tumor that is measurable in two perpendicular diameters on
             magnetic resonance imaging (MRI) and visible on more than one slice

               -  Note: The following do not qualify as measurable disease:

                    -  Malignant fluid collections (e.g., ascites, pleural effusions)

                    -  Bone marrow infiltration except that detected by MIBG scan for neuroblastoma

                    -  Lesions only detected by nuclear medicine studies (e.g., bone, gallium or
                       positron emission tomography [PET] scans) except as noted for neuroblastoma

                    -  Elevated tumor markers in plasma or CSF

                    -  Previously radiated lesions that have not demonstrated clear progression
                       post radiation

                    -  Leptomeningeal lesions that do not meet the measurement requirements for
                       Response Evaluation Criteria in Solid Tumors (RECIST) 1.1

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: At the time of enrollment onto a
             subprotocol, the following general criteria for initiation of therapy will be
             required:

               -  Patients must have fully recovered from the acute toxic effects of all prior
                  anticancer therapy and must meet the following minimum duration from prior
                  anticancer directed therapy prior to enrollment to the subprotocol; 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 anticancer agents known to be
                       myelosuppressive: for agents not listed, 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)

                    -  Anticancer agents not known to be myelosuppressive (e.g. not associated with
                       reduced platelet or absolute neutrophil counts [ANC]): >= 7 days after the
                       last dose of agent; for agents not listed, 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. Neulasta) 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 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 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, NK cells, dendritic cells, etc.)

                    -  X-ray therapy (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; note: radiation may not be delivered to "measurable disease"
                       tumor site(s) being used to follow response to subprotocol treatment

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

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: 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

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients with known bone marrow
             metastatic disease will be eligible for study provided they meet the blood counts (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

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

               -  Age: 1 to < 2 years; maximum serum creatinine (mg/dL): male 0.6; female 0.6

               -  Age: 2 to < 6 years; maximum serum creatinine (mg/dL): male 0.8; female 0.8

               -  Age: 6 to < 10 years; maximum serum creatinine (mg/dL): male 1; female 1

               -  Age: 10 to < 13 years; maximum serum creatinine (mg/dL): male 1.2; female 1.2

               -  Age: 13 to < 16 years; maximum serum creatinine (mg/dL): male 1.5; female 1.4

               -  Age: >= 16 years; maximum serum creatinine (mg/dL): male 1.7; female 1.4

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Bilirubin (sum of conjugated +
             unconjugated) =< 1.5 x upper limit of normal (ULN) for age

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: serum glutamate pyruvate transaminase
             (SGPT) (alanine transferase [ALT]) =< 135 U/L (for the purpose of this study, the ULN
             for SGPT is 45 U/L)

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Patients must be able to swallow intact
             capsules/tablets, unless otherwise specified in the subprotocol to which they are
             assigned

          -  GENERAL INCLUSION CRITERIA FOR SUBPROTOCOLS: Agent specific limitations on prior
             therapy will be included with specific treatment subprotocols

        Exclusion Criteria:

          -  GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Pregnant or breast-feeding women will not
             be entered on this study; pregnancy tests must be obtained in females who are
             post-menarchal; males or females of reproductive potential may not participate unless
             they have agreed to use an effective contraceptive method

          -  GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Concomitant medications

               -  Corticosteroids: at the time of consent and enrollment to regimen specific
                  subprotocols, patients receiving corticosteroids who have not been on a stable or
                  decreasing dose of corticosteroid for at least 7 days prior to enrollment to the
                  subprotocol will not be eligible; if used to modify immune adverse events related
                  to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid

               -  Investigational drugs: patients must meet criteria for prior therapy at the time
                  of consent and enrollment to a subprotocol; other investigational agents may not
                  be administered to patients while they are receiving study drug as part of a
                  subprotocol

               -  Anticancer agents: patients must meet criteria for prior therapy at the time of
                  consent and enrollment to a subprotocol; other investigational agents may not be
                  administered to patients while they are receiving study drug as part of a
                  subprotocol

               -  Anti-GVHD agents post-transplant: patients who are receiving cyclosporine,
                  tacrolimus or other agents to prevent graft-versus-host disease post bone marrow
                  transplant are not eligible

          -  GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have an uncontrolled
             infection are not eligible

          -  GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Patients who have had a prior solid organ
             transplant are not eligible

          -  GENERAL EXCLUSION CRITERIA FOR SUBPROTOCOLS: Additional agent specific criteria will
             be included with specific treatment subprotocols
      
Maximum Eligible Age:21 Years
Minimum Eligible Age:12 Months
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (complete response/partial response) assessed according to Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up to 4 years
Safety Issue:
Description:Response rates will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed using the Wilson score interval method.

Secondary Outcome Measures

Measure:Incidence of toxicity assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 4 years
Safety Issue:
Description:Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.
Measure:Incidence of research biopsy related target toxicity
Time Frame:Up to 14 days
Safety Issue:
Description:Defined as any >= grade 3 toxicity or complication that is probably or definitely attributable to any biopsy-related anesthesia or imaging procedures that occurs within 14 days of research.
Measure:Progression free survival (PFS)
Time Frame:From the initiation of protocol treatment to the occurrence of any of the following events: disease progression or disease recurrence or death from any cause, assessed up to 4 years
Safety Issue:
Description:Will be estimated using the Kaplan-Meier method along with confidence intervals.
Measure:Pharmacokinetic (PK) parameters
Time Frame:Up to 4 years
Safety Issue:
Description:A descriptive analysis of PK parameters will be performed in specific subprotocols to define systemic exposure, drug clearance, and other pharmacokinetic parameters.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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