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A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03605550
Recruitment Status : Recruiting
First Posted : July 30, 2018
Last Update Posted : February 21, 2023
PTC Therapeutics
Information provided by (Responsible Party):
Nationwide Children's Hospital

Brief Summary:

The goal of this study is to evaluate the safety of the study drug PTC596 (Unesbulin) taken in combination with radiotherapy (RT) when given to pediatric patients newly diagnosed with High-Grade Glioma (HGG) including diffuse intrinsic pontine glioma (DIPG).

The main aims of the study are to:

  • Find the safe dose of the study drug PTC596that can be given without causing serious side effects.
  • Find out the amount of drug that enters blood (in all patients) and tumor (in patients who receive drug prior to a planned surgery for removal of their brain tumor)

During the first cycle (6-7weeks), patients will receive drug orally twice a week in combination with daily RT. During subsequent cycles (4 weeks each), they will receive only the study drug orally twice a week.

Funding Source - FDA OOPD

Condition or disease Intervention/treatment Phase
High Grade Glioma Diffuse Intrinsic Pontine Glioma Drug: PTC596 Radiation: Radiotherapy Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma
Actual Study Start Date : August 1, 2018
Estimated Primary Completion Date : July 1, 2023
Estimated Study Completion Date : July 1, 2028

Arm Intervention/treatment
Experimental: Treatment (PTC596)
PTC596 administered orally twice weekly (M/Th or T/F schedule) concomitantly with RT for 6 -7 weeks. Each subsequent cycle is defined as 28 days. Post RT patients will continue to receive PTC596 twice weekly for up to 26 cycles at RP2D of 200mg/m2 with a maximum dose capped at 400mg for patients with BSA ≥2.0
Drug: PTC596
Oral tablets

Radiation: Radiotherapy

Primary Outcome Measures :
  1. Establish MTD and RP2D of PTC596 [ Time Frame: At the end of Cycle 1 (42-49 days) ]
    To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of PTC596 given concurrently with radiation in newly-diagnosed patients with DIPG or HGG (Parts A and C)

  2. Number of participants with treatment-related adverse events as assessed by CTCAE v5.0 [ Time Frame: From Day 1 of treatment through 30 days following end of protocol treatment ]
    To determine the toxicities of PTC596 given concurrently with radiotherapy and during maintenance therapy (Parts A, C) in newly diagnosed HGG and DIPG patients treated with PTC596 by calculating the number of participants with, as well as frequency and severity of, PTC596-related Adverse Events as assessed by CTCAE v5.0.

  3. Maximum Plasma Concentration [Cmax] of PTC596 (A, B, C, D) [ Time Frame: Days1 through 29 ]
    To characterize the plasma pharmacokinetics of PTC596 in children with newly-diagnosed DIPG or HGG when given concurrently with radiotherapy and during maintenance (Parts A, C, D) by measuring the Maximum Concentration [Cmax] and Area Under the Curve (AUC) of PTC596 in plasma

  4. Tumor Concentration of PTC596 (B) [ Time Frame: Day 4 of surgical cycle ]
    To characterize the pharmacokinetics of PTC596 in tumor tissue of children with newly-diagnosed DIPG and HGG who are treated with PTC596 before undergoing a second resection

  5. Protein levels of BMI1 in tumor [ Time Frame: Day 4 of surgical cycle ]
    To test the ability of PTC596 to inhibit BMI-1 activity and downstream effectors by measuring protein levels in tumor and peripheral blood mononuclear cells (PBMCs) of children with newly-diagnosed HGG and DIPG who are treated with PTC596 before undergoing a second resection

Secondary Outcome Measures :
  1. Evaluate Overall survival [ Time Frame: From date of treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months ]
    To estimate the overall survival distribution for newly-diagnosed patients with high-grade glioma treated with PTC596 during radiotherapy followed by PTC596 and compare to historical controls

  2. Evaluate Progression Free survival [ Time Frame: From date of treatment until date of progressive disease or death due to any cause or date of last follow-up, assessed up to 60 months ]
    To estimate the progression-free survival distribution for newly-diagnosed patients with high-grade glioma treated with PTC596 during radiotherapy followed by PTC596 and compare to historical controls

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   12 Months to 21 Years   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

Age: Patients must be ≥12 months and ≤ 21 years of age at the time of study enrollment.

Diagnosis: Patients with newly-diagnosed diffuse intrinsic pontine gliomas (DIPGs), defined as tumors with a pontine epicenter and diffuse involvement of at least 2/3 of the pons, are eligible without histologic confirmation.

Patients with brainstem tumors that do not meet radiographic criteria or are not considered to be typical diffuse intrinsic pontine gliomas will be eligible if the tumors are biopsied and proven to be high-grade gliomas (such as anaplastic astrocytoma, glioblastoma, H3K27-mutant diffuse midline glioma) or diffuse astrocytoma.

Patients with newly-diagnosed non-brainstem high-grade glioma (HGG) are eligible.

Patients must have had histologically verified high-grade glioma such as anaplastic astrocytoma, glioblastoma, H3 K27 mutant diffuse midline glioma etc.

Patients eligible for the surgical stratum include patients with:

  1. Newly-diagnosed DIPG who are amenable to undergo biopsy at the recommendation of their treating physician
  2. Newly-diagnosed HGG for whom a second surgical resection is warranted for further debulking or to achieve a near-total or gross total resection after initial diagnosis has been made but prior to start of therapy.

    Disease Status: Patients with disseminated DIPG or HGG are not eligible, and MRI of spine must be performed if disseminated disease is suspected clinically by the treating physician.

    Performance Level: 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.

    Neurologic Status: Patients must be able to swallow oral medications to be eligible for study enrollment.

    Patients enrolling on Part A (phase I, capsule formulation) must be able to swallow whole capsules.

    Prior Therapy: Patients must not have received any prior anticancer therapy. Prior dexamethasone and/or surgery are permissible.

    Organ Function Requirements:

    Adequate Bone Marrow Function 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 (may be transfused).

    Adequate Renal Function Defined as:

    • Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or

    • A serum creatinine based on age/gender as follows:

    • 1 to < 2 years: 0.6 (Male) 0.6 (Female)
    • 2 to < 6 years: 0.8 (Male) 0.8 (Female)
    • 6 to < 10 years: 1 (Male) 1 (Female)
    • 10 to < 13 years: 1.2 (Male) 1.2 (Female)
    • 13 to < 16 years: 1.5 (Male) 1.4 (Female)

      • 16 years: 1.7 (Male) 1.4 (Female)

    Adequate Liver Function Defined as:

    • Total bilirubin must be ≤ 1.5 times institutional upper limit of normal for age

    • AST(SGOT)/ALT(SGPT) < 3 times institutional upper limit of normal

    • Serum albumin ≥ 2g/dL

    Adequate Cardiac Function Defined As:

    - Ejection fraction of ≥ 55% by echocardiogram.

    - QTc ≤ 480 msec.

    Adequate Pulmonary Function Defined as

    - No evidence of dyspnea at rest, and a pulse oximetry > 94% in room air if there is clinical indication for determination

    Adequate Neurologic Function Defined as:

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

    Informed Consent: 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:

    Diagnosis: patients with a diagnosis of oligodendroglioma or oligoastrocytoma are not eligible. Patients with juvenile pilocytic astrocytoma, are not eligible.

    Patients with non-brainstem diffuse astrocytoma (grade 2) are not eligible for the HGG stratum of the study.

    Pregnancy or breast-feeding: Pregnant or breast-feeding women will not be entered on this study due to known or unknown risks of fetal and teratogenic adverse events as seen in animal/human studies. 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.

    Patients of childbearing or child fathering potential must agree to use adequate contraceptive methods (hormonal or barrier method of birth control; abstinence) while being treated on this study and for 3 months after completing therapy. Note: The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate.

    Concomitant Medications

    • Corticosteroids: Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported.
    • 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.
    • Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants as listed in appendix II, are not eligible
    • Patients who are receiving rifampin are not eligible.
    • Patients who are receiving medications known to prolong QTc interval as listed in appendix III are not eligible.
    • Patients who are receiving duloxetine, alosetron or theophylline (CYP1A2 inhibitors) are not eligible
    • Patients on beta-blockers are not eligible
    • Selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), Fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft) should be used with caution but are not contraindicated.
    • Anticoagulants: patients who are receiving therapeutic anticoagulants including warfarin, low-molecular weight heparin are not eligible

    Nasogastric or G tube administration of PTC596 is not permissible.

    Infection: Patients who have an uncontrolled infection 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.

    Patients with evidence of bowel obstruction, malabsorption, or other contraindication to oral medication are not eligible.

    Patients with GI disease or other condition that could affect absorption or predispose subject to gastrointestinal ulceration are not eligible.

    Patients with an active peptic ulcer disease or inflammatory bowel disease (including ulcerative colitis and Crohn's disease), diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis are not eligible.

    Patients with serious non-healing wounds, ulcers, or bone fractures are not eligible.

    Patients with moderate to severe pulmonary problems generally defined by need for medical intervention (e.g., oxygen, medications) and/or limiting activities of daily living (generally CTCAE Grade 2 or higher) or shortness of breath with limited exertion are not eligible. Pulmonary conditions include (but are not limited to) COPD, asthma, and hemi-pneumectomy.

    Patients with malignancy related to HIV or solid organ transplant: known history of HIV, HBV surface antigen positivity or positive HCV antibody are not eligible. Viral testing is not required unless clinically indicated in patients without a known history.

    Patient with prior or ongoing clinically significant illness, medical or psychiatric condition, medical history, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, could affect the safety of the subject, or alter the absorption, distribution, metabolism, or excretion of the study drugs, or could impair the assessment of study results are not eligible.

    Patients with any prior solid organ transplant are not eligible

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03605550

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Contact: Dorothy Crabtree 614-722-8693
Contact: Leonie Mikael, PhD 16147223284

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United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Kathleen Dorris, MD    720-777-8314   
Principal Investigator: Kathleen Dorris, MD         
United States, District of Columbia
Children's National Medical Center Recruiting
Washington, District of Columbia, United States, 20010
Contact: Eugene Hwang, MD    202-476-5046   
Principal Investigator: Eugene Hwang, MD         
United States, Illinois
Ann & Robert H. Lurie Children's Hospital of Chicago Recruiting
Chicago, Illinois, United States, 60611
Contact: Ashley Plant, MD    312-227-4090   
Principal Investigator: Ashley Plant, MD         
United States, Massachusetts
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Karen Wright, MD    617-632-4309   
Principal Investigator: Karen Wright, MD         
United States, North Carolina
Duke University Medical Center Recruiting
Durham, North Carolina, United States, 27710
Contact: David Ashley, MBBS, PhD    919-681-3824   
Principal Investigator: David Ashley, MBBS, PhD         
United States, Ohio
Cincinnati Children's Hospital Medical Center Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Natasha Pillay-Smiley, DO    513-636-0673   
Contact: Lori Backus    513-636-9419   
Nationwide Children's Hospital Recruiting
Columbus, Ohio, United States, 43205
Contact: Melinda Triplet, RN    614-722-6039   
Principal Investigator: Maryam Fouladi, MD         
United States, Pennsylvania
The Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Michael J Fisher, MD    215-590-5188   
Principal Investigator: Michael J Fisher, MD         
United States, Texas
Texas Children's Hospital Recruiting
Houston, Texas, United States, 77030
Contact: Patricia Baxter, MD    832-824-4681   
Principal Investigator: Patricia Baxter, MD         
United States, Washington
Seattle Children's Hospital Recruiting
Seattle, Washington, United States, 98105
Contact: Sarah Leary, MD    206-987-2106   
Principal Investigator: Sarah Leary, MD         
Sponsors and Collaborators
Nationwide Children's Hospital
PTC Therapeutics
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Study Chair: Maryam Fouladi, MD Nationwide Children's Hospital
Study Chair: Patricia Baxter, MD Baylor College of Medicine
Study Chair: Margot Lazow, MD Nationwide Children's Hospital
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Responsible Party: Nationwide Children's Hospital Identifier: NCT03605550    
Other Study ID Numbers: CONNECT1702
5R01FD006352-03 ( U.S. FDA Grant/Contract )
First Posted: July 30, 2018    Key Record Dates
Last Update Posted: February 21, 2023
Last Verified: February 2023
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided
Plan Description: IPD would only be shared following publication of the study.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Nationwide Children's Hospital:
High Grade Glioma
Additional relevant MeSH terms:
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Diffuse Intrinsic Pontine Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Brain Stem Neoplasms
Infratentorial Neoplasms
Brain Neoplasms
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases