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PI3K/mTOR Inhibitor LY3023414 in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)

NCT03213678

Description:

This phase II Pediatric MATCH trial studies how well PI3K/mTOR inhibitor LY3023414 works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with TSC or PI3K/MTOR mutations that have spread to other places in the body and have come back or do not respond to treatment. PI3K/mTOR inhibitor LY3023414 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Related Conditions:
  • Histiocytic and Dendritic Cell Neoplasm
  • Malignant Solid Tumor
  • Non-Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Pediatric MATCH: PI3K/mTOR Inhibitor LY3023414 in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations
  • Official Title: NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)- Phase 2 Subprotocol of LY3023414 in Patients With Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-01249
  • SECONDARY ID: NCI-2017-01249
  • SECONDARY ID: APEC1621D
  • SECONDARY ID: APEC1621D
  • SECONDARY ID: APEC1621D
  • SECONDARY ID: U10CA180886
  • NCT ID: NCT03213678

Conditions

  • Advanced Malignant Solid Neoplasm
  • 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
  • Refractory Central Nervous System Neoplasm
  • Refractory Childhood Malignant Germ Cell Tumor
  • Refractory Langerhans Cell Histiocytosis
  • Refractory Malignant Solid Neoplasm
  • Refractory Neuroblastoma
  • Refractory Non-Hodgkin Lymphoma
  • Rhabdoid Tumor
  • Stage III Childhood Non-Hodgkin Lymphoma
  • Stage III Osteosarcoma AJCC v7
  • Stage III Soft Tissue Sarcoma AJCC v7
  • Stage IV Childhood Non-Hodgkin Lymphoma
  • Stage IV Osteosarcoma AJCC v7
  • Stage IV Soft Tissue Sarcoma AJCC v7
  • Stage IVA Osteosarcoma AJCC v7
  • Stage IVB Osteosarcoma AJCC v7
  • TSC1 Gene Mutation
  • TSC2 Gene Mutation
  • Wilms Tumor

Interventions

DrugSynonymsArms
PI3K/mTOR Inhibitor LY3023414LY 3023414, LY-3023414, LY3023414Treatment (PI3K/mTOR inhibitor LY3023414)

Purpose

This phase II trial studies how well PI3K/mTOR inhibitor LY3023414 works in treating patients with solid tumors, non-Hodgkin lymphoma, or histiocytic disorders with TSC or PI3K/MTOR mutations that have spread to other places in the body and have come back or do not respond to treatment. PI3K/mTOR inhibitor LY3023414 may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the objective response rate (ORR; complete response + partial response) in
      pediatric patients treated with PI3K/mTOR inhibitor LY3023414 (LY3023414) with advanced solid
      tumors, non-Hodgkin lymphomas or central nervous system (CNS) tumors that harbor TSC loss of
      function mutations, that harbor other PI3K/MTOR activating mutations, and if efficacy is
      observed in a MATCHed cohort, in patients that lack mutations in the PI3K/MTOR pathway.

      SECONDARY OBJECTIVES:

      I. To estimate the progression free survival in pediatric patients treated with LY3023414
      with advanced solid tumors, non-Hodgkin lymphomas or CNS tumors that harbor TSC loss of
      function mutations, that harbor other PI3K/MTOR activating mutations, or if efficacy is
      observed in a MATCHed cohort, that lack mutations in the PI3K/MTOR pathway.

      II. To obtain information about the tolerability of LY3023414 in children with relapsed or
      refractory cancer.

      III. To characterize the pharmacokinetics of LY3023414 in children with recurrent or
      refractory cancer.

      IV. If efficacy is observed in a MATCHed cohort, to obtain preliminary information on the
      response rate to LY3023414 in patients that lack mutations in the PI3K/MTOR pathway.

      TERTIARY OBJECTIVES:

      I. To increase knowledge of the genomic landscape of relapsed pediatric solid tumors and
      lymphomas and identify potential predictive biomarkers (other than the genomic alteration for
      which study treatment was assigned) using additional genomic, transcriptomic, and proteomic
      testing platforms.

      II. To explore approaches to profiling changes in tumor genomics over time through evaluation
      of circulating tumor deoxyribonucleic acid (DNA).

      III. To evaluate the frequency and mechanism of biallelic loss of function, and evaluate the
      expression of TSC1, TSC2, and PTEN in subjects who enroll with a loss of function mutation in
      one of these genes.

      OUTLINE: This is a dose-escalation study.

      Patients receive PI3K/mTOR inhibitor LY3023414 orally (PO) twice daily (BID) on days 1-28.
      Courses repeat every 28 days for up to 2 years in the absence of disease progression or
      unexpected toxicity.

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

Trial Arms

NameTypeDescriptionInterventions
Treatment (PI3K/mTOR inhibitor LY3023414)ExperimentalPatients receive PI3K/mTOR inhibitor LY3023414 PO BID on days 1-28. Courses repeat every 28 days for up to 2 years in the absence of disease progression or unexpected toxicity.
  • PI3K/mTOR Inhibitor LY3023414

Eligibility Criteria

        Inclusion Criteria:

          -  Patient must have enrolled onto APEC1621SC and must have been given a treatment
             assignment to Molecular Analysis for Therapy Choice (MATCH) to APEC1621D based on the
             presence of an actionable mutation; note that treatment assignment may be to primary
             cohort A for patients with TSC1 or TSC2 loss of function mutations, primary cohort B
             for patients with other PI3K/MTOR pathway mutations, a histology specific biomarker
             positive expansion cohort if the criteria to open such a cohort are met, or a
             biomarker negative expansion cohort if the criteria to open such a cohort are met

          -  Patients accruing to dose level 1 must have a body surface area >= 0.52 m^2 at the
             time of study enrollment; patients accruing to dose level 2 must have a body surface
             area >= 0.37 m^2 at the time of study enrollment; patients accruing to dose level -1
             must have a body surface area >= 0.75 m^2 at the time of study enrollment

          -  Patients must have radiographically measurable disease at the time of study
             enrollment; patients with neuroblastoma who do not have measurable disease but have
             metaiodobenzylguanidine (MIBG) positive (+) evaluable disease 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 cerebrospinal fluid (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

                    -  Bone lesions without an associated soft tissue mass >= 10 mm in greatest
                       diameter; bone lesions with an associated soft tissue mass >= 10 mm in
                       greatest diameter imaged by computed tomography (CT) or MRI are considered
                       measurable

          -  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

          -  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;
                  >= 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

               -  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
                  growth factors 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.)

               -  Radiation 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, iobenguane I-131
                  [131I-MIBG]): >= 42 days after systemically administered radiopharmaceutical
                  therapy

               -  Patients must not have received prior exposure to LY3023414

               -  Patients must not have received prior exposure to an agent specifically directed
                  at the PI3K/MTOR pathway (a PI3K inhibitor, an AKT inhibitor, an MTOR inhibitor,
                  including rapalogs, or a combined PI3K/MTOR inhibitor)

          -  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)

          -  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

          -  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: 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

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

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135
             U/L; (for the purpose of this study, the ULN for SGPT is 45 U/L)

          -  Serum albumin >= 2 g/dL

          -  Patients must have a normal blood sugar level for age; if an initial random draw (i.e.
             non-fasting) blood glucose value is out of range, it is acceptable to repeat this test
             as a fasting draw

          -  Patients must have a serum triglyceride level =< 300 mg/dL and serum cholesterol level
             =< 300 mg/dL; if an initial random draw (i.e. non-fasting) is out of range, it is
             acceptable to repeat this test as a fasting draw

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

          -  Nervous system disorders (by Common Terminology Criteria for Adverse Events version
             4.0 [CTCAE V 4.0]) resulting from prior therapy must be =< grade 2

          -  Corrected QT (QTc) interval =< 480 milliseconds

          -  Patients must be able to swallow intact tablets

          -  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 while receiving study treatment and for 3 months after the last
             dose of LY3023414

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

               -  Investigational drugs: patients who are currently receiving another
                  investigational drug are not eligible

               -  Anti-cancer agents: patients who are currently receiving other anti-cancer agents
                  are not eligible

               -  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 for this trial

          -  Patients who have an uncontrolled infection are not eligible

          -  Patients who have insulin dependent diabetes are not eligible

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

          -  Patients with subependymal giant cell astrocytomas (SEGAs) 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:Response rate
Time Frame:3 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 adverse events graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0
Time Frame:Up to 3 years
Safety Issue:
Description:Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the worst grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.
Measure:Pharmacokinetic (PK) parameters
Time Frame:At baseline, 30 minutes, 1, 2, 4, 4, 6-8 hours, and 24 hours after the morning dose on day 1 course 1, pre-dose and at 1-2 hours after the morning dose on day 15 course 1
Safety Issue:
Description:A descriptive analysis of pharmacokinetic (PK) parameters will be performed to define systemic exposure, drug clearance, and other pharmacokinetic parameters. The PK parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
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 3 years
Safety Issue:
Description:PFS along with the confidence intervals will be estimated using the Kaplan-Meier method.

Details

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

Last Updated

September 4, 2017