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

STATUS

Recruiting
End date

Jul 1, 2028
participants needed

64
sponsor

Nationwide Children's Hospital

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Updated on 7 October 2022

See if I qualify

platelet count

renal function

cancer

anticonvulsants

epilepsy

neutrophil count

blood transfusion

seizure

glioblastoma multiforme

astrocytoma

malignant glioma

brain tumor

anaplastic astrocytoma

recurrent tumor

dipg

diffuse intrinsic pontine glioma

brainstem tumor

total resection

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

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,

2. We will enroll an expansion cohort of up to 16 patients at the RP2D (Part C expansion, and Part D)

3. We will enroll a surgical cohort of patients with either:

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.

Details

Condition	High Grade Glioma, Diffuse Intrinsic Pontine Glioma
Treatment	Radiotherapy, PTC596
Clinical Study Identifier	NCT03605550
Sponsor	Nationwide Children's Hospital
Last Modified on	7 October 2022

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Eligibility		Yes	No	Not Sure
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
	Newly-diagnosed DIPG who are amenable to undergo biopsy at the recommendation of their
	treating physician
	Patients eligible for the surgical stratum include patients with
	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
	Prior Therapy: Patients must not have received any prior anticancer therapy. Prior
	Patients enrolling on Part A (phase I, capsule formulation) must be able to swallow
	dexamethasone and/or surgery are permissible
	whole capsules
	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)
	Adequate Renal Function Defined as
	• Hemoglobin >8 g/dL (may be transfused)
	to < 2 years: 0.6 (Male) 0.6 (Female)
	• Creatinine clearance or radioisotope GFR ≥ 70ml/min/1.73 m2 or
	to < 6 years: 0.8 (Male) 0.8 (Female)
	• A serum creatinine based on age/gender as follows
	to < 10 years: 1 (Male) 1 (Female)
	to < 13 years: 1.2 (Male) 1.2 (Female)
	to < 16 years: 1.5 (Male) 1.4 (Female)
	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
	Adequate Neurologic Function Defined as
	clinical indication for determination
	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 must be reported
	Anti-cancer Agents: Patients who are currently receiving other anti-cancer agents
	Corticosteroids: Patients receiving corticosteroids are eligible. The use of
	Patients who are receiving rifampin are not eligible
	Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants as
	listed in appendix II, are not eligible
	Investigational Drugs: Patients who are currently receiving another
	investigational drug are not eligible
	Patients on beta-blockers 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
	Nasogastric or G tube administration of PTC596 is not permissible
	inhibitors) are not eligible
	Infection: Patients who have an uncontrolled infection 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
	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
	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
	are not eligible
	testing is not required unless clinically indicated in patients without a known
	Patients with any prior solid organ transplant are not eligible
	history
	exertion are not eligible. Pulmonary conditions include (but are not limited to) COPD
	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

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glioblastoma multiforme

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malignant glioma

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anaplastic astrocytoma

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diffuse intrinsic pontine glioma

brainstem tumor

total resection

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