Phase I/II, Open-Label, Multicenter Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of Durvalumab Monotherapy or Durvalumab in Combination with Tremelimumab in Pediatric Patients with Advanced Solid Tumors and Hematological Malignancies
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 11
- 试验地点
- 2
- 主要终点
- Based on PK parameters (including Cmax, Cmin, AUC, and others), identify the adult equivalent exposure/MTD of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, among children and young adults from birth to <18 years of age with advanced solid tumors using a q4w dosing schedule.
研究概览
简要总结
Dose-finding: -To determine the adult equivalent exposure/MTD/recommended Phase II pediatric dose of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy. -To determine the safety profile of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy Dose-expansion:
- To determine the preliminary antitumor activity of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy at the recommended dose, using cohortspecific response criteria (eg, RECIST 1.1).
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 have a histopathologic confirmation of malignancy. Patients must have progressed or are refractory to standard therapies, and for whom no standard of care treatments exist.
- •If available, patients must provide a diagnostic tumor sample taken ˂3 years prior to screening for evaluation of PD-L1 status.
- •Lansky play performance scale ≥50 for patients ≥1 and <16 years of age and Karnofsky performance status score ≥50 for patients ≥16 years of age (patients <1 year of age are exempt from this criterion)
- •Patients must have measurable/evaluable disease as defined by methods used in common clinical practice.
- •No prior exposure to immune checkpoint inhibitors or genetically engineered cellular therapies including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1, anti-PD-L2 antibodies and CAR-T or other cell therapies, excluding therapeutic anticancer vaccines. Exposure to other investigational agents may be permitted after discussion with the Sponsor or designee.
排除标准
- •History of allogeneic organ transplantation. Patients who have previously received an autologous bone marrow transplant may be eligible
- •Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis, celiac disease or other serious GI chronic conditions associated with diarrhea, systemic lupus erythematosus, Wegener syndrome; myasthenia gravis, Graves’ disease, rheumatoid arthritis, hypophysitis, uveitis, etc.), autoimmune myocarditis, and autoimmune pneumonitis. The following are exceptions to this criterion: − Patients with vitiligo or alopecia − Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement − Psoriasis that does not require systemic therapy − Patients with celiac disease controlled by diet alone.
- •Uncontrolled intercurrent illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, cardiac arrhythmia, ILD, or psychiatric illness or social situations that would limit compliance with study requirements, substantially increase risk of incurring AEs from IP, or compromise the ability of the patient to give written informed consent.
- •History of primary immunodeficiency.
- •Active infection including tuberculosis, hepatitis B, hepatitis C, or HIV. Patients with a past or resolved HBV infection are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV ribonucleic acid (RNA).
- •Any unresolved toxicity NCI CTCAE version 5.0 Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, lymphopenia and the laboratory values defined in the inclusion criteria − Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and may be included after consultation with the Study Physician. − Persistent toxicities (CTCAE Grade ≥2) caused by previous anticancer therapy, excluding alopecia. Patients with toxicity not reasonably expected to be exacerbated by treatment with durvalumab or tremelimumab in the opinion of the Investigator (eg, hearing loss, gastrostomy tube), may be included.
- •Patients with clinically active brain metastases (known or suspected), spinal cord compression, and choloromas are excluded, unless these conditions have been previously treated and are considered stable.
- •History of leptomeningeal carcinomatosis, or involvement of any other anatomic area that, in the opinion of the Investigator, may cause significant symptoms if an inflammatory reaction occurs
结局指标
主要结局
Based on PK parameters (including Cmax, Cmin, AUC, and others), identify the adult equivalent exposure/MTD of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, among children and young adults from birth to <18 years of age with advanced solid tumors using a q4w dosing schedule.
Based on PK parameters (including Cmax, Cmin, AUC, and others), identify the adult equivalent exposure/MTD of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, among children and young adults from birth to <18 years of age with advanced solid tumors using a q4w dosing schedule.
Identify the safety and tolerability of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, at the adult equivalent exposure/MTD among children and young adults from birth to <18 years of age with advanced solid tumor using a q4w dosing schedule. Endpoints include AEs, vital signs, physical examinations, ECGs, and laboratory evaluations
Identify the safety and tolerability of durvalumab in combination with tremelimumab and durvalumab as monotherapy following combination therapy, at the adult equivalent exposure/MTD among children and young adults from birth to <18 years of age with advanced solid tumor using a q4w dosing schedule. Endpoints include AEs, vital signs, physical examinations, ECGs, and laboratory evaluations
Objective response rate as determined by the Investigator assessed RECIST 1.1 or alternative pre-specified tumor-specific response rates for different scoring systems. -Assessment of antitumor activity will be specific to tumor cohort, eg, Investigator assessed RECIST 1.1 (other malignancies will be analyzed based on the best response assessed by the Investigator).
Objective response rate as determined by the Investigator assessed RECIST 1.1 or alternative pre-specified tumor-specific response rates for different scoring systems. -Assessment of antitumor activity will be specific to tumor cohort, eg, Investigator assessed RECIST 1.1 (other malignancies will be analyzed based on the best response assessed by the Investigator).
Additional efficacy endpoints that will be collected include DoR, BoR, DCR, PFS, APF12, and APF18 based on RECIST 1.1 assessed by the Investigator, and OS, OS12, and OS24 as appropriate
Additional efficacy endpoints that will be collected include DoR, BoR, DCR, PFS, APF12, and APF18 based on RECIST 1.1 assessed by the Investigator, and OS, OS12, and OS24 as appropriate
次要结局
- Individual durvalumab and tremelimumab concentrations in serum, and PK parameters including Cmax, Cmin, AUC.
- Number and percentage of patients who develop detectable ADAs.
- Individual antibody titer measurements before and after planned routine immunization during treatment and Cycle 4 or follow-up, whichever is earlier.
- Flow cytometry for CD4, CD8, B and NK cells, including T-cell activation with Ki67
研究者
AstraZeneca Clinical Study Information Center
Scientific
AstraZeneca AB