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

• ClinicalTrials.gov Identifier: NCT03605550
• Recruitment Status: Recruiting
• First Posted: July 30, 2018
• Last Update Posted: February 25, 2020
• Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborator: PTC Therapeutics
• Information provided by (Responsible Party): Children's Hospital Medical Center, Cincinnati

Tracking Information

• First Submitted Date: July 20, 2018
• First Posted Date: July 30, 2018
• Last Update Posted Date: February 25, 2020
• Actual Study Start Date: August 1, 2018
• Estimated Primary Completion Date: July 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 20, 2018)

• 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

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: July 20, 2018)

• 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

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma
• Official Title: A Phase 1b Study of PTC596 in Children With Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma

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.

Detailed Description

This study consists of two parts:

1. The phase I (Part A), 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.
2. Once the RP2D has been determined, the investigators will enroll a surgical cohort (Part B) 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) study will be to determine the MTD or RP2D of PTC596 in combination with radiation therapy and to assess pharmacokinetic (PK) and pharmacodynamics studies. Dose-modifying toxicities for maintenance therapy will also be monitored.

PK studies will be collected on days 1 and 4 (doses 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.

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 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.

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 Type: Interventional
• Study Phase: Phase 1
• Study Design: Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• High Grade Glioma
• Diffuse Intrinsic Pontine Glioma

Intervention

• Drug: PTC596
  Oral tablets
• Radiation: Radiotherapy
  Course 1

Study Arms

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.

Interventions:

• Drug: PTC596
• Radiation: Radiotherapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: July 20, 2018): 30
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: July 1, 2027
• Estimated Primary Completion Date: July 1, 2022 (Final data collection date for primary outcome measure)

Eligibility 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:

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 if enrolling in Part A.

   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

   • 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.

   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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Months to 21 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03605550
• Other Study ID Numbers: CONNECT1702
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

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

IPD Sharing Statement

• Plan to Share IPD: Undecided
• Plan Description: IPD would only be shared following publication of the study.

• Responsible Party: Children's Hospital Medical Center, Cincinnati
• Study Sponsor: Children's Hospital Medical Center, Cincinnati
• Collaborators: PTC Therapeutics
• Investigators: Not Provided
• PRS Account: Children's Hospital Medical Center, Cincinnati
• Verification Date: February 2020