Clinical Trials /

Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors

NCT02644460

Description:

This is a Phase I clinical trial evaluating abemaciclib (LY2835219), an inhibitor of cyclin dependent-kinases 4 and 6 (Cdk 4/6) in children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (Stratum A) and in relapsed/refractory/progressive malignant brain (Grade III/IV, including DIPG; MBT) and solid tumor (ST) patients (Stratum B).

Related Conditions:
  • Childhood Brain Stem Glioma
  • Diffuse Intrinsic Pontine Glioma
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Abemaciclib in Children With DIPG or Recurrent/Refractory Solid Tumors
  • Official Title: Abemaciclib in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma, and in Children With Recurrent and Refractory Solid Tumors Including Malignant Brain Tumors

Clinical Trial IDs

  • ORG STUDY ID: IRB00083793
  • NCT ID: NCT02644460

Conditions

  • Diffuse Intrinsic Pontine Glioma
  • Brain Tumor, Recurrent
  • Solid Tumor, Recurrent
  • Neuroblastoma, Recurrent, Refractory
  • Ewing Sarcoma, Recurrent, Refractory
  • Rhabdomyosarcoma, Recurrent, Refractory
  • Osteosarcoma, Recurrent, Refractory
  • Rhabdoid Tumor, Recurrent, Refractory

Interventions

DrugSynonymsArms
AbemaciclibLY2835219Stratum A

Purpose

This is a Phase I clinical trial evaluating abemaciclib (LY2835219), an inhibitor of cyclin dependent-kinases 4 and 6 (Cdk 4/6) in children and young adults with newly diagnosed diffuse intrinsic pontine glioma (DIPG) (Stratum A) and in relapsed/refractory/progressive malignant brain (Grade III/IV, including DIPG; MBT) and solid tumor (ST) patients (Stratum B).

Detailed Description

      Stratum A- Appropriate dose RT will be administered in 30-33 fractions over approximately 6
      weeks for Stratum A patients. Treatment with abemaciclib (LY2835219) will start on the same
      day as radiation therapy (RT) and continue twice daily during and after RT for a maximum
      treatment duration of 2 years. Investigators plan to treat a maximum of 4 cohorts of research
      participants (dosage levels 1, 2, 3, and 4) with escalating doses of abemaciclib (LY2835219)
      starting with dose level 1 (80% of adult dose). A cycle is defined as 28 days and the first 6
      weeks of therapy will constitute the dose-limiting toxicity (DLT)-evaluation period.
      Participants must take abemaciclib by mouth as intact capsules.

      Stratum B - Abemaciclib (LY2835219) will be administered orally on a twice daily basis
      continuously for 28 days, which defines one cycle. The maximum treatment duration will be 2
      years. Investigators plan to treat a maximum of 4 cohorts of research participants (dosage
      levels 1, 2, 3, and 4) with escalating doses of abemaciclib starting with dose level 1 (80%
      of adult dose). Dose escalation will be independent of Stratum A escalation. A cycle is
      defined as 28 days and the first 4 weeks of therapy will constitute the DLT-evaluation
      period. Participants must take abemaciclib by mouth as intact capsules.
    

Trial Arms

NameTypeDescriptionInterventions
Stratum AExperimentalAppropriate dose RT will be administered in 30-33 fractions over approximately 6 weeks for Stratum A patients. Treatment with abemaciclib (LY2835219) will start on the same day as RT and continue twice daily during and after RT for a maximum treatment duration of 2 years. Investigators plan to treat a maximum of 4 cohorts of research participants (dosage levels 1, 2, 3, and 4) with escalating doses of abemaciclib (LY2835219) starting with dose level 1 (80% of adult dose). A cycle is defined as 28 days and the first 6 weeks of therapy will constitute the dose-limiting toxicity (DLT)-evaluation period. Participants must take abemaciclib by mouth as intact capsules.
  • Abemaciclib
Stratum BExperimentalAbemaciclib (LY2835219) will be administered orally on a twice daily basis continuously for 28 days, which defines one cycle. The maximum treatment duration will be 2 years. Investigators plan to treat a maximum of 4 cohorts of research participants (dosage levels 1, 2, 3, and 4) with escalating doses of abemaciclib starting with dose level 1 (80% of adult dose). Dose escalation will be independent of Stratum A escalation. A cycle is defined as 28 days and the first 4 weeks of therapy will constitute the DLT-evaluation period. Participants must take abemaciclib by mouth as intact capsules.
  • Abemaciclib

Eligibility Criteria

        Inclusion Criteria for All Participants:

          -  Patient must have measurable or evaluable disease.

          -  Age must be ≥ 2 years and < 25 years

          -  Body surface area (BSA) ≥ 0.5 m^2

          -  Lansky (for participants ≤ 16 years) or Karnofsky (for participants > 16 years)
             performance score ≥ 40 at the time of study enrollment

          -  Adequate organ function at the time of study enrollment as follows:

               -  Bone marrow: Absolute neutrophil count (ANC) ≥ 1,000/μL, platelet count ≥
                  75,000/μL (transfusion independent for ≥ 7 days), hemoglobin concentration ≥
                  8g/dL (may be transfused)

               -  Patients with bone marrow metastatic disease who do not meet the above criteria
                  will be eligible to enroll in the study with the following count criteria. These
                  patients will not be evaluable for hematologic toxicity or hematologic DLT.

                    -  ANC > 750/μL within 7 days prior to first dose of abemaciclib

                    -  Platelet count > 50,000/μL (may receive platelet transfusions) within 7 days
                       prior to first dose of abemaciclib

                    -  Hemoglobin ≥ 7.5 g/dL (may receive red blood cell (RBC) transfusions) within
                       7 days prior to first dose of abemaciclib

               -  Renal: Normal serum creatinine concentration based on age or glomerular
                  filtration rate (GFR) > 70 ml/min/1.73m^2

               -  Hepatic: Total bilirubin concentration < 1.5x the institutional upper limit of
                  normal for age; serum glutamic pyruvic transaminase (SGPT) < 10x the
                  institutional upper limit of normal for patients on Stratum A. Stratum B patients
                  must have SGPT < 4x the institutional upper limit of normal.

               -  Cardiac: Adequate cardiac conductivity with corrected Q-T interval (QTC) of < 450
                  ms on screening ECG.

          -  Female research participants of childbearing age must not be pregnant as confirmed by
             a serum or urine pregnancy test within 1 week of start of treatment. Participants must
             not be breast-feeding.

          -  All patients should submit an archival tumor biopsy specimen (collected at diagnosis
             or relapse). Patients who have no tumor tissue available may be permitted to
             participate after discussion with the principal investigator.

          -  Males or females of reproductive potential may not participate unless they have agreed
             to use two effective contraceptive methods. Abstinence in a non-sexually active child
             will be sufficient birth control.

        Inclusion Criteria for Stratum A (Newly Diagnosed DIPG)

          -  Diagnosis of DIPG or high-grade glioma originating from the brainstem

          -  Participants have had no previous treatment except corticosteroid use.

        Inclusion Criteria for Stratum B (Recurrent/refractory/progressive MBT (including DIPG) or
        ST)

          -  Patients must have radiologic evidence of recurrent, refractory or progressive
             malignant central nervous system (WHO Grade III or IV) or solid tumor. For patients
             with radiologic features of DIPG histologic confirmation of diagnosis is not required
             though biopsy is suggested if clinically indicated.

          -  Patients with neurological deficits should have deficits that are stable for a minimum
             of 1 week prior to registration.

          -  Patients who are on dexamethasone must be on a stable or decreasing dose for at least
             one week prior to registration.

          -  Patients must have fully recovered from the acute toxic effects of chemotherapy,
             immunotherapy, or radiotherapy prior to entering this study.

          -  Myelosuppressive chemotherapy: Patients must have received their last dose of known
             myelosuppressive anticancer chemotherapy at least 21 days prior to study registration
             or at least six weeks if nitrosourea. At least two weeks must have lapsed if patients
             received lower dose oral etoposide (50 mg/2) without experiencing evidence of
             myelosuppression (i.e. neutropenia or requiring transfusion with blood products)

          -  Biologic agent: Patient must have recovered from any toxicity potentially related to
             the agent and received their last dose of the biologic agent ≥ 7 days prior to study
             registration.

          -  Monoclonal antibody treatment: At least three half-lives must have elapsed prior to
             registration.

          -  Radiation: Patient has received radiation therapy prior to study registration.
             Patients must have had their last fraction of local irradiation to the primary tumor ≥
             3 months prior to registration, their last fraction of craniospinal irradiation
             (>24Gy) or total body irradiation > 3 months prior to registration or > 6 wks for
             therapeutic doses of metaiodobenzylguanidine (MIBG). Patient has not received focal
             irradiation for symptomatic metastatic sites within 14 days prior to registration.

          -  Bone Marrow Transplant: Patient must be ≥ 3 months since high dose chemotherapy and
             peripheral blood stem cell rescue prior to registration.

          -  Autologous stem cell transplant following myeloablative therapy within 3 months prior
             to the first dose of abemaciclib or prior allogeneic stem cell transplant at any time.
             Patients who received stem cell reinfusion following non-myeloablative therapy are
             eligible once they meet peripheral blood count criteria.

          -  Growth factors: Patients must be off all colony forming growth factors(s) for at least
             1 week prior to registration (filgrastim, sargramostim, erythropoietin) and at least 2
             weeks for long-acting formulations (e.g. Neulasta).

        Exclusion Criteria:

          -  Patients with uncontrolled infection

          -  Patients with any concomitant significant medical illness that in the investigator's
             opinion cannot be adequately controlled with appropriate therapy, or that would impair
             the evaluation of side effects related to this treatment, alter drug metabolism or the
             tolerance to this treatment

          -  Patients receiving any other anticancer or investigational drug therapy

          -  Prior therapy with abemaciclib

          -  Known mutation of Rb in tumor tissue

          -  Prior history of QTC prolongation or QTC>450 ms on screening ECG.
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:2 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Abemaciclib Maximum Tolerated Dose (MTD) for Diffuse Intrinsic Pontine Glioma (DIPG)
Time Frame:Week 6
Safety Issue:
Description:The maximum dose of abemaciclib tolerated in participants with newly diagnosed diffuse intrinsic pontine glioma (DIPG).

Secondary Outcome Measures

Measure:Number of participants with adverse events
Time Frame:End of study (Up to two years)
Safety Issue:
Description:The number of participants who experience adverse events.
Measure:Number of hematological toxicities
Time Frame:End of study (Up to two years)
Safety Issue:
Description:The number of hematological toxicities observed throughout the study among participants.
Measure:Number of non-hematological toxicities
Time Frame:End of study (Up to two years)
Safety Issue:
Description:The number of non-hematological toxicities observed throughout the study among participants.

Details

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

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