A Phase I Study of WP1066 in Children With Refractory and Progressive or Recurrent Malignant Brain Tumors (AflacST1901)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 10
- 试验地点
- 1
- 主要终点
- Change in safety and tolerability of WP1066: Maximum tolerated dose (MTD) and Dose limiting toxicities (DLT)
研究概览
简要总结
In this Phase I clinical study, the investigators plan to offer investigational treatment with the novel JAK2/STAT3 inhibitor WP1066 (Moleculin Biotech, Inc.) to pediatric patients with any progressive or recurrent malignant brain tumor that is refractory to standard treatment and is without known cure.
详细描述
The goal of this clinical research study is to find the highest tolerable dose of WP1066 that can be given to pediatric patients with recurrent (has returned after treatment) cancerous brain tumors or melanoma that has gotten worse and spread to the brain. The safety of this drug will also be studied.
WP1066 is designed to target the STAT3 pathway in cancer cells, which makes these cells divide, increases new blood vessels to the tumor, causes the cancer cells to move throughout the body and brain, and avoids them being detected by the immune system. Targeting this pathway may cause the immune system to kill the cancer cells. The investigators will administer five escalating doses of WP1066, starting at lowest dose currently found to be safe and tolerable in adults.
WP1066 is not FDA approved or commercially available. It is currently being used for research purposes only.
Up to 36 participants will be enrolled in this study. All will take part at Children's Healthcare of Atlanta (CHOA).
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
- 3 Years 至 25 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must have histologically confirmed progressive medulloblastoma, malignant glioma or any other recurrent/progressive malignant brain tumor, for which curative measures do not exist. Primary spinal tumors are eligible. DIPG and DMG H3K27M do not require histological confirmation.
- •Patients with DIPG and DMG with H3K27M who are post-radiation but have not exhibited tumor progression are also eligible.
- •Patients must have previously undergone standard-of-care treatment including surgery, radiation, and/or first line adjuvant chemotherapy prior to the experimental treatment (WP1066).
- •Patients must have recovered from the acute treatment related toxicities (defined as < grade 1 if not defined in eligibility criteria) of all prior chemotherapy, immunotherapy or radiotherapy prior to entering this study. There is no upper limit to the number of prior therapies that is allowed.
- •Age > 3 to 25 years.
- •Karnofsky or Lansky Performance Scale score > 60%.
- •Patients must have normal organ and marrow function as defined below:
- •Absolute neutrophil count> 1,000/mcL
- •Platelets> 100,000/mcL
- •Total bilirubin within normal institutional limits
- •AST(SGOT)/ALT(SGPT)< 5 x (<10 x if taking steroids) institutional upper limit of normal
- •creatinine within normal institutional limits for age OR creatinine clearance> 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
- •PT/PTT< 1.5 x normal institutional standard
- •Patients with stable seizures (e.g., no seizures for ≥ 14 days and not requiring escalation or addition of anti-epileptic drugs) will be eligible.
- •Signed informed written consent obtained from patient if 18 years of age or older, or from guardian/legal representative if patient is less than 18 years of age
排除标准
- •Patients must have received their last dose of known myelosuppressive anticancer therapy at least three (3) weeks prior to study enrollment or at least six (6) weeks if prior nitrosourea.
- •Biologic or investigational agent (anti-neoplastic): Patient must have received their last dose of the investigational or biologic agent ≥ 7 days prior to study enrollment. Antibodies: ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to Grade ≤
- •Agents with prolonged half-lives: At least three half-lives must have elapsed prior to enrollment.
- •Immunotherapy: Patient must have completed immunotherapy (e.g. tumor vaccines, oncolytic viruses. etc.) at least 42 days prior to enrollment.
- •Radiation: Patients must have had their last fraction of:
- •Craniospinal irradiation ≥ 3 months prior to enrollment.
- •Other substantial bone marrow irradiation ≥ 6 weeks prior to enrollment
- •Local palliative XRT (small port) ≥2 weeks.
- •Stem Cell Transplant: Patient must be ≥ 12 weeks since autologous bone marrow/stem cell transplant prior to enrollment.
- •Surgery Patients must be fully recovered from all acute effects of prior surgical intervention.
- •History of allergic reactions attributed to compounds of similar chemical or biologic composition to WP
- •The enzymatic metabolism profile of WP1066 is unknown. Patients who are receiving drugs that significantly interact with the CYP450 enzyme(s) are ineligible. However, if they are switched to other medications with a 2-week washout window, they will be eligible. Patients are also excluded if they have been exposed within 7 days of planned first study treatment day to medications that are predominantly CYP2D6, 2C9 or 2C19 substrates, strong inhibitors or inducers, and sensitive substrates of CYP3A4 with narrow therapeutic range.
- •Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
- •No single lesion can be larger than 5 cm in maximal diameter. There may not be clinically significant midline shift or hydrocephalus.
- •The effects of WP1066 on the developing human fetus are unknown. Pregnant women are excluded from this study because WP1066 could potentially be teratogenic or have abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with WP1066, breastfeeding should be discontinued if the mother is treated with WP
- •Female subjects of childbearing potential should be willing to use 2 methods of birth control prior to study entry, during the study, and for 2 months after the last dose of the study drug or be surgically sterile. Subjects of childbearing potential are those who have not been surgically sterilized or have not been free from menses for > 1 year. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of WP1066 administration.
- •HIV-positive patients receiving combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with WP
- •The potential for further hemorrhaging with the use of WP1066 is unknown. It will be at the PIs discretion to enroll a patient who has a small, asymptomatic brain hemorrhage, but patients who have had symptomatic hemorrhages will be excluded.
- •Patients requiring escalation of the corticosteroid dose will be excluded, but patients receiving a stable or decreasing dose for at least one week prior to registration will be eligible.
- •The cardiac toxicities of WP1066 are unknown. Thus, patients who have a mean QTc interval >450 ms at baseline will be excluded. Concomitant use of agents that prolong the QT interval will be avoided.
- •Patients with uncontrolled seizures or seizure requiring escalation or addition of anti-epileptic drugs will be excluded.
- •The use of medical cannabis and CBD oil is prohibited during the first 2 cycles of this protocol. Patients must be off cannabis oil for 3 days prior to enrollment
研究组 & 干预措施
WP1066
There will be 5 groups based on the enrollment timing. The first group of participants will receive the lowest dose level of WP1066. Each subject within a group will receive an assigned dose of the investigational drug. The dose levels are 4, 6, 8 and 16 mg/kg of the investigational drug given twice a day. The first group will receive the lowest dose level, 4mg/kg twice a day, and subsequent groups will escalate to the next higher dose level. All groups will be treated identically, except for the dose of drug administered, with the liquid formulation of the drug.
干预措施: WP1066 (Drug)
结局指标
主要结局
Change in safety and tolerability of WP1066: Maximum tolerated dose (MTD) and Dose limiting toxicities (DLT)
时间窗: Up to 2 months after the last study drug dose
The trial will investigate the maximum tolerated dose (MTD) and record the dose limiting toxicities (DLTs) at least possibly related to the investigational drug, as well as all toxicities related or unrelated that occur. MTD is defined as the dose level at which 0/6 or 1/6 subjects experience a DLT with at least 2 subjects experiencing DLT at the next higher dose level. A minimum of 6 subjects must be treated at the MTD. DLT is defined as a graded adverse event or abnormal lab value at least possibly related to the investigational drug that occurred within 28 days after the first dose of the drug was administered. All toxicities will be recorded and graded throughout the study.
Maximum tolerated dose (MTD) of WP1066
时间窗: 28 Days post-intervention
Maximum tolerated dose (MTD) of WP1066 in pediatric patients with recurrent or refractory and progressive malignant brain tumors for which there is no known treatment with clinical benefit. Maximum tolerated dose (MTD) is determined as the dose level at which 0/6 or 1/6 patients experience a dose-limiting toxicity (DLT) with at least 2 patients experiencing DLT at the next higher dose level. DLT is defined as an adverse event or an abnormal laboratory value assessed as being at least possibly related to the investigational agent that occurs during the first 28 days after administration of the first dose of WP1066.
次要结局
- Pharmacokinetic analysis of WP1066: Apparent volume of distribution(Days 1, 2, 14, and 15 of course 1)
- Pharmacokinetic of WP1066: Area Under the Plasma Concentration-time Curve from time zero to 24 hours (AUC0-24)(Days 1, 2, 14, and 15 of course 1)
- Pharmacokinetic analysis of WP1066: Clearance from plasma (CL) following drug administration(Days 1, 2, 14, and 15 of course 1)
- Pharmacokinetic analysis of WP1066: change in accumulation ratio of WP1066(Day 1 of cycle 1 (each cycle is 28 days) and Day 7 of cycle 1)
- Change in overall response rate (ORR) of WP1066 treatment(Up to 2 months after the last study drug dose)
- Pharmacokinetic analysis of WP1066: Elimination half life (t1/2)(Days 1, 2, 14, and 15 of course 1)
- Pharmacodynamic analysis of WP1066: level of activated Stat3(Hours 0, 4, 24 of Day 1 and Hours 0, 4, 24 of Day 7)
- Change in Immunological response(Up to 2 months after the last study drug dose)
- Change in progression-free survival (PFS)(Up to 2 months after the last study drug dose)
- Pharmacokinetic of WP1066: Peak plasma concentration (Cmax)(Days 1, 2, 14, and 15 of course 1)
- Pharmacokinetic of WP1066: Time to peak concentration (Tmax)(Days 1, 2, 14, and 15 of course 1)
- Time to radiographically assessed progression and/or response to treatment with WP1066.(Up to 2 months post-intervention)
- Change in overall survival (OS)(Up to 2 months after the last study drug dose)