Clinical Trials /

Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma

NCT02596828

Description:

Children, adolescents and young adults with relapsed or treatment refractory pineoblastoma (rPB) represent a group of patients with dismal prognosis for whom a recommended standard salvage therapy is currently not available.

Related Conditions:
  • Pineoblastoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma
  • Official Title: Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma

Clinical Trial IDs

  • ORG STUDY ID: RIST-rPB-2015-P
  • NCT ID: NCT02596828

Conditions

  • Pineoblastoma

Interventions

DrugSynonymsArms
TemozolomideTemomedacRIST
IrinotecanIrinomedacRIST
DasatinibSprycelRIST
RapamycinRapamuneRIST

Purpose

Children, adolescents and young adults with relapsed or treatment refractory pineoblastoma (rPB) represent a group of patients with dismal prognosis for whom a recommended standard salvage therapy is currently not available.

Detailed Description

      The multimodal metronomic approach combining molecular targeted drugs (rapamycin and
      dasatinib) with conventional chemotherapy (irinotecan and temozolomide) will be investigated
      in a randomized fashion as new treatment strategy for patients with rPB. The intention is to
      assess the therapeutic benefit of molecular targeted drugs for the treatment of rPB.

      The combination of irinotecan and temozolomide showed activity in the treatment of several
      solid organ tumors, brain tumors and neuroblastoma. In one study relapsed neuroblastoma (rNB)
      patients received a median of 5 courses of 5 days irinotecan and temozolomide every 3 to 4
      weeks with a cumulative dose of 35% lower than in the RIST design. 33% had disease regression
      with 8% CR or PR. A phase II study in rNB also using irinotecan and temozolomide with a
      substantially lower intensity showed a response rate of 15%.

      The combination of a mTOR inhibitor with a multi-kinase inhibitor demonstrated in preclinical
      studies a synergistic effect on cell cycle arrest, apoptosis and sensitization for radio- and
      chemotherapy. It is assumed that this combination of molecular targeted drugs with a
      tolerable conventional chemotherapy consisting of irinotecan and temozolomide can
      substantially improve the outcome of this patient population. A group of 20 rNB patients
      treated with the RIST therapy approach in a compassionate use setting showed an overall
      survival of 55% at a median of 80 weeks with a tolerable adverse event profile.
    

Trial Arms

NameTypeDescriptionInterventions
RISTExperimental
  • Temozolomide
  • Irinotecan
  • Dasatinib
  • Rapamycin

Eligibility Criteria

        Inclusion Criteria:

        Patients with relapsed and refractory high-grade pineoblastome (=rPB) and all of the
        following criteria will be considered for admission to the clinical trial:

          -  Children, adolescents and young adults 0 months to 25 years

          -  Signed written informed consent (patient or his/her parents/legal guardian)

          -  Females of childbearing age must have a negative urine pregnancy test prior to
             starting the study drug. The first pregnancy test must be performed within 10-14 days
             prior to the start of the study drug and the second pregnancy test must be performed
             within 24 hours prior to the start of study drug. The subject may not receive the
             study drug until the investigator has verified that the results of these pregnancy
             tests are negative.

          -  Females of childbearing age must comply with the institutional standards of birth
             control with a pearl index <1%. Contraception must be started at least four weeks
             before the start of the investigational therapy.

          -  Females of childbearing age must be willing to abstain from breastfeeding for the
             duration of the clinical trial and for at least 30 days after discontinuation of the
             clinical trial.

          -  Males must agree not to father a child and must use latex condom during any sexual
             contact with women of childbearing age during and for 6 months after therapy ends or
             is stopped, even if they have undergone successful vasectomy.

          -  Willing and able to complete the clinical trial procedures, as described in the
             protocol

          -  Non-smoker for at least the previous 3 months. Smoking is not allowed during the
             entire study period

          -  Abstain from alcohol within the last 24 hours before screening and before admission to
             the clinical trial center as well as during the entire clinical trial. The regular
             daily ethanol intake has to be less than 20g/day for at least the previous three
             months.

          -  Patients are required to have an absolute neutrophil count (ANC) ≥500/µL, hemoglobin
             ≥8g/dL (transfusion permitted), and an unsupported platelet count ≥30,000/µL unless:

               -  patient is refractory or relapsed early after primary therapy

        Exclusion Criteria:

        Patients presenting with any of the following criteria will not be included in this
        clinical trial:

          -  Pregnancy, nursing

          -  Patients who suffered from a thrombotic event and need anticoagulation (i.e. coumadine
             derivatives or low molecular weight heparin derivatives, LMWH)

          -  Patients with cardiac arrhythmias especially prolonged QT

          -  Patients with chronic inflammatory bowel diseases and/or bowel obstruction

          -  Patients with bilirubin serum levels 1,5 fold above the upper normal limit

          -  Vaccination with a live virus vaccine during the clinical trial

          -  Impaired liver function and/or impaired renal function (hepatic and renal index
             parameter two times above normal range; see below)

          -  Potentially unreliable subjects, probably non compliant subjects and those judged by
             the investigator to be unsuitable for the study

          -  Doubts about the patient's cooperation

          -  Any contraindications or known hypersensitivity to the IMPs or to any of the other
             components: (see SPC "Fachinformation")

          -  Known allergic reactions to the treatment medication

          -  Patients who were treated with radiation and/or chemotherapy for any other oncological
             condition

          -  Participation in any other interventional phase I to III trial

          -  Sexually active patients who refuse to use contraception according to the
             institutional requirements

          -  Patients with extremely poor general condition (Karnofsky or Lansky score <50%)

          -  Neutrophil count (ANC) <500/µL, hemoglobin <8g/dL (transfusion permitted), and an
             unsupported platelet count <30 000/µL

          -  12-lead ECG with QTc>500 msec / QTc>60 msec baseline

               -  Patients with hepatitis B reactivation
      
Maximum Eligible Age:25 Years
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The primary endpoint is progression-free survival (PFS)
Time Frame:Time interval from date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 52 weeks
Safety Issue:
Description:According to: Imaging criteria to MRI, CT or CSF evaluations or date of death of any cause

Secondary Outcome Measures

Measure:Overall survival (OS)
Time Frame:From the first course of the investigational treatment up to the end of the trial assessed to 52 weeks
Safety Issue:
Description:According to: questionnaire
Measure:Response to the investigational treatment after 4 and 8 courses of I/T and 1-year-follow-up in the RIST treatment arm
Time Frame:From the first course of the investigational treatment up to the end of the trial assessed to 52 weeks
Safety Issue:
Description:According to: • Imaging criteria to MRI, CT or CSF evaluations
Measure:Duration until adequate response to this treatment regimen
Time Frame:From the first course of the investigational treatment up to the end of the trial assessed to 52 weeks
Safety Issue:
Description:According to: • Imaging criteria to MRI, CT or CSF evaluations
Measure:Assessment of quality of life (Lansky and Karnofsky Scores)
Time Frame:From the first course of the investigational treatment up to the end of the trial assessed to 52 weeks
Safety Issue:
Description:According to: Lansky and Karnofsky Scores
Measure:Toxicity of this combination of drugs in children, adolescents and young adults with rNB - Assessment according to the latest version of the CTC criteria
Time Frame:From the first course of the investigational treatment up to the end of the trial assessed to 52 weeks
Safety Issue:
Description:Assessment according to the latest version of the CTC criteria. In particular due to the expected AE Profile: Myelosuppressive measures (RBC, PLT units) Infectious complications Gastrointestinal problems
Measure:Safety and tolerability of the investigational treatment - Assessment according to the latest version of the CTC criteria
Time Frame:From the first course of the investigational treatment up to the end of the trial assessed to 52 weeks
Safety Issue:
Description:Assessment according to the latest version of the CTC criteria. In particular due to the expected AE Profile: Myelosuppressive measures (RBC, PLT units) Infectious complications Gastrointestinal problems

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Regensburg

Trial Keywords

  • molecular targeted therapy
  • protein kinase inhibitor
  • mTOR Inhibitor
  • cytostatic topoisomerase-I-inhibitor
  • temozolomide
  • irinotecan
  • dasatinib
  • rapamycin

Last Updated

September 26, 2019