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
Updated on 7 October 2022
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:

  1. 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:

  1. 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:

  1. Newly-diagnosed DIPG patients who are amenable to undergo biopsy per the recommendation of their treating physician OR
  2. 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:

  1. 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
  2. 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 IdentifierNCT03605550
SponsorNationwide Children's Hospital
Last Modified on7 October 2022

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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