human stem cell derived neurons

Adavosertib and Local Radiation Therapy in Treating Children With Newly Diagnosed Diffuse Intrinsic Pontine Gliomas

This phase I clinical trial studies the side effects and best dose of adavosertib in combination with radiation therapy in treating children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). 

Adavosertib is a small molecule drug that blocks WEE1, a protein involved in cell cycle regulation. By blocking WEE1, adavosertib may make cells more vulnerable to cytotoxic agents like chemotherapy and radiation therapy, helping to facilitate cell death in tumors exposed those agents. In this study, adavosertib will be given in combination with radiation therapy, which may work better than radiation therapy alone in treating DIPG. 

This study will evaluate the combination of adavosertib and radiation therapy, in treating children and young adults with newly diagnosed DIPG. All eligible participants will receive the following treatment:

  • Experimental Group: adavosertib + radiation therapy

 

Inclusion Criteria
  1. Patients with newly diagnosed DIPGs, defined as tumors with a pontine epicenter and diffuse involvement of the pons, are eligible without histologic confirmation
    1. Patients with brainstem tumors that do not meet these criteria or are not considered to be typical intrinsic pontine gliomas will only be eligible if the tumors are biopsied and proven to be an anaplastic astrocytoma, glioblastoma, gliosarcoma, diffuse midline glioma with histone H3 K27M mutation, or anaplastic mixed glioma; patients with pilocytic astrocytoma, fibrillary astrocytoma, gangliogliomas, or other mixed gliomas without anaplasia are not eligible
    2. Patients with disseminated disease are not eligible, and magnetic resonance imaging (MRI) of spine must be performed if disseminated disease is suspected by the treating physician
    3. Enrollment must be no later than 28 days after the date of radiographic diagnosis or surgery, whichever is the later date
  2. Patients must have a body surface area >= 0.35 m^2 at the time of study enrollment
  3. Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 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
  4. Patients must not have received any prior chemotherapy, radiation therapy, immunotherapy or bone marrow transplant for the treatment of DIPG; prior dexamethasone and/or surgery are allowed
  5. Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
  6. Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
  7. Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or
  8. A serum creatinine based on age/gender as follows:
    1. 0.8 mg/dL (3 to < 6 years of age)
    2. 1.0 mg/dL (6 to < 10 years of age)
    3. 1.2 mg/dL (10 to < 13 years of age)
    4. 1.5 mg/dL (male) or 1.4 mg/dl (female) (13 to < 16 years of age)
    5. 1.7 mg/dL (male) or 1.4 mg/dl (female) (>= 16 years of age)
  9. Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
  10. Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN = 135 units per liter (U/L); for the purpose of this study, the ULN for SGPT is 45 U/L
  11. Serum glutamic oxaloacetic transaminase (SGOT) aspartate aminotransferase [AST] =< 3 x ULN = 150 U/L; for the purpose of this study, the ULN for SGOT is 50 U/L
  12. Serum albumin >= 2 g/dL
  13. Patients with seizure disorder may be enrolled if on non-enzyme inducing anticonvulsants and well controlled
  14. Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5) resulting from prior therapy must be =< grade 2 with the exception of tendon reflex (deep tendon reflex [DTR]); any grade of DTR is eligible
  15. Corrected QT interval (QTc) =< 480 msec
  16. 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

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Exclusion Criteria
  1. Pregnant or breast-feeding women may not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; negative serum or urine pregnancy test within 3 days prior to enrollment
  2. Males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive methods as follows: fertile females of childbearing potential who agree to use adequate contraceptive measures from 2 weeks prior to the study and until 1 month after study treatment discontinuation; male patients willing to abstain or use barrier contraception (i.e. condoms) for the duration of the study and for 3 months after treatment stops
  3. Patients receiving corticosteroids are eligible for this trial
  4. Patients who are currently receiving another investigational drug are not eligible
  5. Patients who are currently receiving other anti-cancer agents are not eligible
  6. Patients must not currently be receiving enzyme inducing anticonvulsants
  7. Patients should avoid concomitant medication known or suspected to prolong QTc interval or cause Torsades De Pointes; if possible, alternative agents should be considered; patients who are receiving drugs that prolong the QTc are eligible if the drug is necessary and no alternatives are available
  8. Patients who are currently receiving drugs that are strong or moderate inhibitors and/or inducers of CYP3A4, sensitive CYP3A4 substrates and CYP3A4 substrates with a narrow therapeutic range are not eligible; the use of aprepitant or fosaprepitant as an antiemetic is prohibited due to early drug interaction data demonstrating increased exposure to AZD1775; the use of hydroxymethylglutary (HMG) coenzyme-A (Co-A) inhibitors such as atorvastatin is prohibited
  9. Herbal preparations are not allowed throughout the study; these herbal medications include but are not limited to: St. John's wort, kava, ephedra (ma hung), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto and ginseng; patients should stop using these herbal medications 7 days prior to study enrollment
  10. Any known hypersensitivity or contraindication to the components of the study drug AZD1775
  11. Patients must not receive metformin for at least 5 days prior to enrollment and for the duration of study treatment
  12. Patients must be able to swallow capsules; nasogastric or gastrostomy feeding (G) tube administration is not allowed
  13. Patients who have an uncontrolled infection are not eligible
  14. Patients who have received a prior solid organ transplantation are not eligible
  15. Patients with cardiac diseases ongoing or in the past 6 months (e.g. congestive heart failure, acute myocardial infarction, significant uncontrolled arrhythmias) are not eligible for this trial
  16. Major surgical procedures =< 28 days of beginning study treatment, or minor surgical procedures (including ventriculoperitoneal [VP] shunt placement or stereotactic biopsy of the tumor) =< 7 days; no waiting period required following port-a-cath or other central venous access placement
  17. 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
     

For the most up-to-date list of criteria, please visit clinicaltrials.gov.

Investigator(s)

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