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

Study Description

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Brief Summary:

In this research study the investigators want to learn more about the safety of the study drug, PTC596 has when taken during radiation. The investigators also want to learn about the effects, if any, these drugs have on children and young adults with brain tumors.

The investigators are asking people to be in this research study who have been diagnosed with a high grade glioma (HGG) including diffuse intrinsic pontine glioma (DIPG) to be in the research, because they have scheduled to have radiation to treat their cancer.

The study is divided into two parts. The goal of the first part is to find the dose of PTC596 that can be given with radiation without causing serious side effects. The purpose of this surgical study is to test the amount of a study drug that may be found in the tumor and blood when given prior to and during a planned surgery for removal of the recurrent tumor.

The goals of the first part:

• Find the highest safe dose of PTC596 that can be given together with radiation therapy without causing severe side effects;
• Learn what kind of side effects can be caused by PTC596 with radiation therapy;
• Learn more about the pharmacology of PTC596;
• Learn more about the biological effects of PTC596 on the cells in their body including any changes to the tumor DNA;
• Determine whether PTC596 with radiation therapy is a beneficial treatment for their tumor;
• Determine if there are any changes to participants quality of life when taking PTC596.

The goals of the surgical part are:

• Learn if PTC596 is able to reach the tumor in the brain;
• Learn what kind of side effects can be caused by PTC596 with radiation therapy;
• Learn more about the pharmacology of PTC596;
• Learn more about the biological effects of PTC596 on the cells in their body including any changes to the tumor DNA;
• Determine whether PTC596 with radiation therapy is a beneficial treatment for their tumor;
• Determine if there are any changes to their quality of life when taking PTC596.

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

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Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	30 participants
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, 2022
Estimated Study Completion Date :	July 1, 2027

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Treatment (PTC596); PTC596 administered orally twice weekly (M/Th or T/F schedule) concomitantly with radiotherapy. One cycle is defined as 28 days. Post RT patients will continue to receive PTC596 twice weekly for up to 25 cycles.	Drug: PTC596; Oral Capsules; Radiation: Radiotherapy; Course 1

Outcome Measures

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Primary Outcome Measures :

1. Estimate maximum tolerated dose and/or recommended Phase 2 dose of PTC596 administered concurrently with radiation. [ Time Frame: Up to 49 days ]
   Number of dose limiting toxicities experienced during radiation
2. Estimate number of adverse events of PTC596 administered concurrently with radiation [ Time Frame: 6 months ]
   Number of individual toxicities and incidence
3. Pharmacokinetics of PTC596 [ Time Frame: 4 days ]
   Plasma concentration of PTC596

Secondary Outcome Measures :

1. Time from diagnosis to death - Overall survival [ Time Frame: 5 years ]
   Time (number of days/months) from diagnosis to death.
2. Time from diagnosis to disease progression - Progression Free survival [ Time Frame: 5 years ]
   Time (number of days/months) from diagnosis to disease progression

Eligibility Criteria

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Ages Eligible for Study:	36 Months to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age: Patients must be ≥36 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.

   Patient 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 >10 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
   • creatinine within normal institutional limits OR creatinine clearance ≥60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
   • Serum albumin ≥ 2g/dL

   Adequate Cardiac Function Defined As:

   - Shortening fraction of ≥ 27% by echocardiogram, or

   - Ejection fraction of ≥ 50% by gated radionuclide study.

   - 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.

   Adequate Clotting time as Defined as:

   - PT and APTT (activated partial thromboplastin time) within ≤ 1.5 times upper limit of normal or in the therapeutic range if on anticoagulation. NOTE: Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate.

   - No evidence or history of bleeding diathesis or coagulopathy.

   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.

   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.

Contacts and Locations

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Locations

United States, Ohio
Cincinnati Children's Hospital Medical Center	Recruiting
Cincinnati, Ohio, United States, 45229
Contact: Maryam Fouladi, MD 513-803-0721 Maryam.Fouladi@cchmc.org
Contact: Laura Fossett 513-636-9419 Laura.Fossett@cchmc.org

Sponsors and Collaborators

Children's Hospital Medical Center, Cincinnati

PTC Therapeutics

More Information

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Responsible Party:	Children's Hospital Medical Center, Cincinnati
ClinicalTrials.gov Identifier:	NCT03605550 History of Changes
Other Study ID Numbers:	CONNECT1702
First Posted:	July 30, 2018
Last Update Posted:	November 28, 2018
Last Verified:	November 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided
Plan Description:	IPD would only be shared following publication of the study.

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Children's Hospital Medical Center, Cincinnati:

DIPG; High Grade Glioma

Additional relevant MeSH terms:

Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal	Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue