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

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ClinicalTrials.gov Identifier: NCT03605550

Recruitment Status : Recruiting

First Posted : July 30, 2018

Last Update Posted : June 28, 2022

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Sponsor:

Collaborator:

PTC Therapeutics

Information provided by (Responsible Party):

Nationwide Children's Hospital

Study Description

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.

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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Detailed Description:

This study consists of three parts:

The Phase I, dose-finding component of the trial, to estimate the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of PTC596 in combination with radiation therapy followed by maintenance therapy with PTC596, in children with newly-diagnosed DIPG and HGG.

Once the RP2D has been determined,
We will enroll an expansion cohort of up to 16 patients at the RP2D (Part C expansion, and Part D)
We will enroll a surgical cohort of patients with either:

a. newly-diagnosed DIPG who are amenable to undergo biopsy per recommendation of their treating physician OR b. 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.

The primary objectives of the Phase I (Part A and Part C) study will be to determine the MTD or RP2D of PTC596 in combination with radiation therapy. Dose-modifying toxicities for maintenance therapy will also be monitored.

For Cohorts A and C, PK studies will be collected on Days 1, 2, 3, and 4 (doses 1 and 2) of Cycle 1 and Day 1 of Cycle 2. For Cohort D, plasma PK studies will be collected on Days 1 and 2 of Cycle 1 and Day 1 of Cycle 2.

PTC596 will be given twice weekly on Monday and Thursday or Tuesday and Friday, for 6-7 weeks, during daily radiation therapy. Once radiation therapy with concomitant PTC596 is completed, all patients will continue with maintenance therapy which will begin immediately after completion of RT for up to 25 cycles.

Once the RP2D has been established, up to 12 patients will be enrolled on the surgical study. Patients eligible for the Surgical Stratum include:

Newly-diagnosed DIPG patients who are amenable to undergo biopsy per the recommendation of their treating physician OR
Newly-diagnosed HGG patients 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.

The objectives of the Surgical Cohort Stratum are to:

Assess the ability of PTC596 to inhibit BMI-1 activity in tumor and peripheral blood mononuclear cells (PBMNCs) of children with newly-diagnosed DIPG or HGG
To characterize the pharmacokinetics of PTC596 in plasma, cerebrospinal fluid (CSF), and tumor tissue of children with newly-diagnosed DIPG or HGG Once the RP2D has been established, up to 12 patients will be enrolled on the surgical study.

Patients on the surgical cohort study will commence treatment with the surgical cycle. During the surgical cycle, patients will be treated with two doses of PTC596, on days 1 and 4 of the surgical cycle prior to biopsy or re-resection; the second dose of PTC596 should ideally be administered 3-6 hours before surgery (but may be up to 12 hours prior to surgery). The concentration of PTC596 will then be measured in the tumor and accompanying blood sample by mass spectrometry. BMI-1 expression and the effects of BMI-1 inhibition in DIPG and HGG on gene regulation through gene expression profiling and epigenetic studies will be assessed in tissue and plasma. The PK and PD studies on the surgical cohort study are mandatory. The surgical cycle will end when patients begin RT.

Patients must begin RT at least two weeks after the date of surgery and may restart PTC596 on Mondays and Thursdays or Tuesdays and Fridays (twice weekly) after starting RT. Following completion of radiotherapy, patients will immediately start maintenance therapy on a Monday and Thursday or Tuesday and Friday schedule. Patients can continue to receive therapy with PTC596 for up to 25 cycles.

Study Design

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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, 2022
Estimated Study Completion Date :	July 1, 2027

Resource links provided by the National Library of Medicine

Genetic and Rare Diseases Information Center resources: Glioma Diffuse Intrinsic Pontine Glioma Neuroepithelioma

U.S. FDA Resources

Arms and Interventions

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 tablets Radiation: Radiotherapy Course 1

Outcome Measures

Primary Outcome Measures :

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
Estimate number of adverse events of PTC596 administered concurrently with radiation [ Time Frame: 6 months ]
Number of individual toxicities and incidence
Pharmacokinetics of PTC596 [ Time Frame: 4 days ]
Plasma concentration of PTC596

Secondary Outcome Measures :

Time from diagnosis to death - Overall survival [ Time Frame: 5 years ]
Time (number of days/months) from diagnosis to death.
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:	12 Months to 21 Years (Child, Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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:

Newly-diagnosed DIPG who are amenable to undergo biopsy at the recommendation of their treating physician
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

Contacts and Locations

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 ClinicalTrials.gov identifier (NCT number): NCT03605550

Contacts

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Contact: Dorothy Crabtree	614-722-8693	Dorothy.Crabtree@nationwidechildrens.org

Locations

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United States, Colorado
Children's Hospital Colorado	Recruiting
Aurora, Colorado, United States, 80045
Contact: Kathleen Dorris, MD 720-777-8314 kathleen.dorris@childrenscolorado.org
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 ehwang@childrensnational.org
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 aplant@luriechildrens.org
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 KarenD_wright@dfci.harvard.edu
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 david.ashley@duke.edu
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 Natasha.pillay-smiley@cchmc.org
Contact: Lori Backus 513-636-9419 Lori.backus@cchmc.org
Nationwide Children's Hospital	Recruiting
Columbus, Ohio, United States, 43205
Contact: Melinda Triplet, RN 614-722-6039 Melinda.Triplet@nationwidechildrens.org
Principal Investigator: Maryam Fouladi, MD
United States, Pennsylvania
The Children's Hospital of Philadelphia	Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Michael J Fisher, MD 215-590-5188 fisherm@email.chop.edu
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 pabaxter@txch.org
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 Sarah.Leary@seattlechildrens.org
Principal Investigator: Sarah Leary, MD

Sponsors and Collaborators

Nationwide Children's Hospital

PTC Therapeutics

Investigators

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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

More Information

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Responsible Party:	Nationwide Children's Hospital
ClinicalTrials.gov Identifier:	NCT03605550
Other Study ID Numbers:	CONNECT1702 #FD-R-6352 ( Other Grant/Funding Number: FDA OOPD )
First Posted:	July 30, 2018 Key Record Dates
Last Update Posted:	June 28, 2022
Last Verified:	June 2022
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:


DIPG High Grade Glioma

Additional relevant MeSH terms:

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Glioma Diffuse Intrinsic Pontine Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms 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

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