A Phase 1b Study of PTC596 in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma and High Grade Glioma
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 入组人数
- 64
- 试验地点
- 10
- 主要终点
- Establish MTD and RP2D of PTC596
研究概览
简要总结
The goal of this study is to evaluate the safety of the study drug PTC596 (Unesbulin) taken in combination with radiotherapy (RT) when given to pediatric patients newly diagnosed with High-Grade Glioma (HGG) including diffuse intrinsic pontine glioma (DIPG).
The main aims of the study are to:
- Find the safe dose of the study drug PTC596that can be given without causing serious side effects.
- Find out the amount of drug that enters blood (in all patients) and tumor (in patients who receive drug prior to a planned surgery for removal of their brain tumor)
During the first cycle (6-7weeks), patients will receive drug orally twice a week in combination with daily RT. During subsequent cycles (4 weeks each), they will receive only the study drug orally twice a week.
Funding Source - FDA OOPD
详细描述
This study consists of 3 parts:
- The Phase I (Parts A and C), dose-finding component of the trial, to estimate the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) of PTC596 in combination with RT followed by maintenance therapy with PTC596, in children with newly-diagnosed DIPG and HGG.
Once the RP2D has been determined, 2. An early efficacy expansion cohort of up to 17 patients at the RP2D (Part C expansion, and Part D) 3. A surgical cohort (part B) of 12 patients with newly diagnosed DIPG who are amenable to undergo biopsy or HGG for whom a second surgical resection is warranted
For patients on cohorts A, C and D, PTC596 will be given orally twice weekly for 6-7 weeks along with daily RT for the first cycle. In subsequent cycles (4 weeks each), all patients will continue with maintenance therapy which will begin immediately after completion of RT for up to 26 cycles (2 years).
For the surgical cohort, patients will be treated with 2 doses of PTC596, on days 1 and 4 prior to biopsy or re-resection; the second dose of PTC596 should ideally be administered 3-6 hrs before surgery. The surgical cycle will end when patients begin RT which should take place at least two weeks after the date of surgery and may restart PTC596 (twice weekly) after starting RT. Following completion of RT, patients will immediately start maintenance therapy with twice weekly PTC596 for up to 26 cycles.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 12 Months 至 21 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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
研究组 & 干预措施
Treatment (PTC596)
PTC596 administered orally twice weekly (M/Th or T/F schedule) concomitantly with RT for 6 -7 weeks. Each subsequent cycle is defined as 28 days. Post RT patients will continue to receive PTC596 twice weekly for up to 26 cycles at RP2D of 200mg/m2 with a maximum dose capped at 400mg for patients with BSA ≥2.0
干预措施: PTC596 (Drug)
Treatment (PTC596)
PTC596 administered orally twice weekly (M/Th or T/F schedule) concomitantly with RT for 6 -7 weeks. Each subsequent cycle is defined as 28 days. Post RT patients will continue to receive PTC596 twice weekly for up to 26 cycles at RP2D of 200mg/m2 with a maximum dose capped at 400mg for patients with BSA ≥2.0
干预措施: Radiotherapy (Radiation)
结局指标
主要结局
Establish MTD and RP2D of PTC596
时间窗: At the end of Cycle 1 (42-49 days)
To determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of PTC596 given concurrently with radiation in newly-diagnosed patients with DIPG or HGG (Parts A and C)
Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
时间窗: From Day 1 of treatment through 30 days following end of protocol treatment
To determine the toxicities of PTC596 given concurrently with radiotherapy and during maintenance therapy (Parts A, C) in newly diagnosed HGG and DIPG patients treated with PTC596 by calculating the number of participants with, as well as frequency and severity of, PTC596-related Adverse Events as assessed by CTCAE v5.0.
Maximum Plasma Concentration [Cmax] of PTC596 (A, B, C, D)
时间窗: Days1 through 29
To characterize the plasma pharmacokinetics of PTC596 in children with newly-diagnosed DIPG or HGG when given concurrently with radiotherapy and during maintenance (Parts A, C, D) by measuring the Maximum Concentration \[Cmax\] and Area Under the Curve (AUC) of PTC596 in plasma
Tumor Concentration of PTC596 (B)
时间窗: Day 4 of surgical cycle
To characterize the pharmacokinetics of PTC596 in tumor tissue of children with newly-diagnosed DIPG and HGG who are treated with PTC596 before undergoing a second resection
Protein levels of BMI1 in tumor
时间窗: Day 4 of surgical cycle
To test the ability of PTC596 to inhibit BMI-1 activity and downstream effectors by measuring protein levels in tumor and peripheral blood mononuclear cells (PBMCs) of children with newly-diagnosed HGG and DIPG who are treated with PTC596 before undergoing a second resection
次要结局
- Evaluate Overall survival(From date of treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months)
- Evaluate Progression Free survival(From date of treatment until date of progressive disease or death due to any cause or date of last follow-up, assessed up to 60 months)