A pilot trial testing the clinical benefit of using molecular profiling to determine an individualized treatment plan in children and young adults with newly diagnosed DIPG

Trial Requirements and Treatment

Patients with newly diagnosed diffuse intrinsic pontine glioma (DIPG) who undergo a biopsy as part of their standard of care will be eligible for this study. Part of the tissue will be sent to TGEN for detailed profiling. After the biopsy, patients will be treated with focal irradiation per institutional guidelines. After completion of radiation therapy, patients will follow the specialized tumor board recommendation. The treatment will be based on each child’s individual tumor profile and will include up to 4 medications. Depending on the individual treatment plan, the tumor board will also recommend required study observations to assure safety for the patient.

Rationale for Study

This study will use a new treatment approach based on each patient’s tumor gene expression and whole exome sequencing. The study will test the feasibility of a specialized tumor board assigning a treatment plan based on gene expression analysis, whole exome sequencing, and predictive modeling to establish a molecular-based-therapy approach at initial diagnosis. The treatment plan will take into consideration each patient’s tumor expression profile, gene mutations, and predictive modeling, as well as prior history and treatment(s), other medical conditions, and the age of the patient.

Primary Objectives

To determine the overall survival at 12 months of children with newly diagnosed DIPG that have been treated based on a personalized treatment recommendation based on WES and RNA seq analysis of the tumor.

Secondary Objectives 

  1. To determine the safety and describe the toxicity of using a molecularly based treatment approach and specialized tumor board recommendation in children and young adults with newly diagnosed DIPG.
  2. To evaluate the safety of performing biopsy and obtaining tissue for molecular and genomic profiling in children and young adults with newly diagnosed DIPG.

Exploratory Objectives 

  1. To assess if information derived from WGS, or use of WGS findings to detect circulating tumor DNA, would have changed the treatment recommendations from the molecular tumor board. 
  2. To determine the frequency of success and genomic fidelity (to the patient’s original tumor) in patient derived xenograft models from these patients at initial diagnosis as well as at time of progression or recurrence when sufficient tissue is available.
  3. To archive tumor and normal DNA from each patient at time of initial diagnosis along with serial blood draw following therapies as biospecimens for later studies to determine whether ctDNA sequences in the patient’s blood serve as biomarkers of tumor burden, response to therapy, or development of drug resistance.

Eligibility Criteria

Patients must have baseline evaluations performed prior to start of treatment and must meet all inclusion and none of the exclusion criteria. In addition, the patient must be thoroughly informed about all aspects of the study, including the study visit schedule, required evaluations and all regulatory requirements. The written informed consent must be obtained from the patient or their legal guardian prior to enrollment. The following criteria apply to all patients enrolled onto the study unless otherwise specified.

Inclusion Criteria for Patients with Newly Diagnosed DIPG

  1. Diagnosis: Patients with newly diagnosed DIPG, who undergo a biopsy, are eligible. Patients with disseminated disease are not eligible, and MRI of the spine must be performed if disseminated disease is suspected by the treating physician.
  2. Enrollment within 28 days of the date of radiographic diagnosis.
  3. Age ≤ 25 years
  4. Karnofsky score ≥ 50 for patients ≥ 16 years of age and Lansky score ≥ 50 for patients ≤15 years of age. 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.
  5. Adequate bone marrow defined as: 
  • Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3
  • Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  • Hemoglobin ≥ 8 g/dl (can be transfusion dependent)

5. Adequate Renal function defined as:

    • Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 OR a serum creatinine within normal limits based on age and gender as follows:
      • Age 3 to <6 years: 0.8 (male); 0.8 (female)
      • Age 6 to < 10 years: 1 (male); 1 (female)
      • Age 10 to <13 years: 1.2 (male); 1.2 (female)
      • Age 13 to <16 years: 1.5 (male); 1.4 (female)
      • Age ≥ 16 years: 1.7 (male); 1.4 (female)

    6. Adequate liver function defined as:

      • Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for age
      • SGPT (ALT) ≤ 110 U/L.  For the purpose of this study, the ULN for SGPT is 45 U/L.
      • Serum albumin ≥ 2 g/dL

      7. The effects of the current treatment paradigm on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception: hormonal or barrier method of birth control; abstinence prior to study entry and for the duration of study participation, and 30 days after completion of study drug administration. Should a female become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 30 days after completion of study drug administration.

      8. Adequate neurological function defined as:

      • Patients with seizure disorder may be enrolled if seizures are well controlled
      • Ability by patient or parent/legal guardian (for patients under 18 years of age) to understand a written informed consent document, and the willingness to sign it.

      Exclusion Criteria for Patients with Newly Diagnosed DIPG

          1. Patients who are currently taking any anti-cancer directed therapy. Steroids are not considered anti-cancer therapy
          2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
          3. Female patients of childbearing potential must not be pregnant or breast-feeding. Female patients of childbearing potential must have a negative serum or urine pregnancy test prior to the start of therapy.
          4. Patients with inability to return for follow-up visits or obtain follow-up studies required to assess toxicity to therapy.
          5. Patients who are currently enrolled on another clinical trial.

      Important Note: The eligibility criteria listed above are interpreted literally and cannot be waived.