2024-514791-40-00招募中2 期
AcSé-ESMART: European Proof-of-Concept Therapeutic Stratification Trial of Molecular Anomalies in Relapsed or Refractory Tumors
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 398
- 试验地点
- 18
- 主要终点
- The recommended phase II dose (RP2D) will be defined as the adult recommended dose (adjusted for weight or BSA) if toxicity and PK profiling are similar in children and in adults, or a higher dose, providing it is below or equal to the maximum tolerated dose (MTD).
研究概览
简要总结
Based on results from a comparative review (Paoletti 2013), we hypothesize that if the toxicity profile and the PK parameters observed in children treated at the adult RP2D are similar to those in adults; escalating to the MTD is not necessarily required, unless a dose-activity relationship has been documented in adults. Therefore, for each agent or combination of agents being investigated, there will be two co-primary objectives:
- Phase I: To define or validate that the adult RP2D of the selected drug or combination of drugs is safe in children/adolescents and equivalent to that seen in adults, in pediatric/adolescent patients with malignancies which are recurrent or refractory to standard therapy.
- Phase II: To determine the preliminary activity (as measured by objective tumor response) of these agents in patients harboring specific molecular alterations or tumor types that may be associated with the mechanism of action of these drugs (i.e. molecularly enriched patient cohorts, where possible) and non-enriched patients (if included in the arm design).
入排标准
- 年龄范围
- 0 years 至 17 years（0-17 Years）
- 接受健康志愿者
- 是
入选标准
- •Patients must be diagnosed with hematologic or solid tumor malignancy that has progressed or relapsed despite standard therapy, or for which no effective standard therapy exists.
- •For all oral medications patients must be able to comfortably swallow whole capsules or tablets (except for those for which an oral solution is available); nasogastric or gastrostomy feeding tube administration is allowed only if indicated.
- •Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening procedures are conducted according to local, regional or national guidelines.
- •Patient affiliated to a social security regimen or beneficiary of the same according to local requirements.
- •For a complete list of eligibility criteria, see the sections corresponding to inclusion and exclusion criteria in the protocol.
- •Age <18 years at inclusion.
- •Patient must have had advanced molecular profiling (i.e. WES/WGS +/- RNAseq) of their recurrent or refractory tumor i.e. at the time of disease progression/relapse; exceptionally patients with advanced molecular profiling at diagnosis may be allowed.
- •Evaluable or measurable disease as defined by standard imaging criteria for the patient’s tumor type.
- •Performance status: Karnofsky performance status (for patients >12 years of age) or Lansky Play score (for patients ≤12 years of age) ≥70%.
- •Life expectancy ≥3 months.
- •Adequate organ function as defined in section 3.1.1 of the protocol.
- •Able to comply with scheduled follow-up and with management of toxicity.
- •Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment. Sexually active patients must agree to use highly effective method of contraception.
排除标准
- •Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease.
- •Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection.
- •Presence of any ≥CTCAE grade 2 treatment-related toxicity with the exception of lymphopenia G3, alopecia, ototoxicity or peripheral neuropathy.
- •Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less.
- •Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose
- •Allogeneic stem cell transplant within 3 months prior to the first study drug dose. Patients receiving any agent to treat or prevent graft-versus host disease (GVHD) post bone marrow transplant are not eligible for this trial.
- •Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within 6 weeks for therapeutic doses of MIBG or craniospinal irradiation).
- •Increasiong dose of Steroids over the last 7 days and with a maximum of 0.5 mg/kg /days
- •Major surgery within 21 days of the first dose.
- •Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes.
- •Known hypersensitivity to any study drug or component of the formulation.
- •Pregnant or nursing (lactating) females
- •Vaccinated with live, attenuated vaccines,including yellow fever, within 4 weeks of the first dose of study drug.
- •For a complete list of eligibility criteria, see the sections corresponding to inclusion and exclusion criteria in the protocol. Additional inclusion and enrichment and exclusion criteria for each treatment arm are specified separately in protocol section 3.
- •Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome).
- •Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias).
结局指标
主要结局
The recommended phase II dose (RP2D) will be defined as the adult recommended dose (adjusted for weight or BSA) if toxicity and PK profiling are similar in children and in adults, or a higher dose, providing it is below or equal to the maximum tolerated dose (MTD).
The recommended phase II dose (RP2D) will be defined as the adult recommended dose (adjusted for weight or BSA) if toxicity and PK profiling are similar in children and in adults, or a higher dose, providing it is below or equal to the maximum tolerated dose (MTD).
次要结局
- The maximum tolerated dose (MTD) will be defined as the dose associated with or closest to 25% of DLTs in cycle 1.
- Dose Limiting Toxicities (DLT) will be defined using NCI CTCAE v4.03.
- Overall response rate (ORR) will be defined as percentage of patients achieving confirmed CR or confirmed PR as per standard methods for the underlying disease.
- Duration of response (DOR) will be defined as the time period between the first documented response (PR or CR) and the time of first documented progression (clinically or radiologically – Appendix 3 to 7) or death from any cause, whichever comes first. Duration of response for patients free of progression at the cut-off date will be censored at the last assessment date.
- Progression-free survival (PFS) will be defined as the time from treatment initiation until the date of first documented progression or death from any cause, whichever comes first. Patients alive and free of progression at the cut-off date will be censored at the last assessment date.
- Overall survival (OS) will be defined as the time from treatment initiation until the date of death from any cause. Patients alive at the cut-off date will be censored at the date of last news.
- Adverse events according to the NCI CTCAE V4.03 in all cycles of treatment.
- PK parameters, including but not limited to plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, Clearance, Half-life time.
- Relationship between the molecular profile of the tumor samples, circulating tumor DNA and tumor growth.
研究者
Regulatory Affairs Officer
Scientific
Institut Gustave Roussy
研究点 (18)
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