A Phase 1/2 Multicenter Open-label Study to Investigate Treatment of Hydroxyurea in Combination With Valproic Acid (VPA), or 6- Mercaptopurine in Combination With VPA in Patients With AML or HR-MDS Unfit for Standard Therapy
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 48
- 试验地点
- 1
- 主要终点
- Safety and tolerability of the treatment combinations of hydroxyurea + valproic acid, and 6-mercaptopurine + valproic acid administered at established clinical doses.
研究概览
简要总结
The purpose of this study is to investigate the safety, tolerability, and preliminary efficacy of the combination treatment of hydroxyurea capsules and valproic acid capsules, or the combination treatment of 6-mercaptopurine tablets and valproic acid capsules in male and female patients aged 18 years or older with acute myeloid leukemia or high- risk myelodysplastic syndrome.
The population to be studied is newly diagnosed AML patients who are considered unfit for standard induction chemotherapy, HR-MDS unfit/ineligible for standard treatment, and relapsed/refractory AML/HR-MDS patients who are considered unfit for standard therapy ,or are, for some reason, ineligible for another type of therapy. Clinically, hydroxyurea, valproic acid and 6-mercaptopurine are historically very well-known therapeutic agents with low toxicity profiles. The rationale for this study is that the combination of these drugs with low toxicity will be well tolerated in elderly AML patients with comorbidities, or lower performance status. This combination could have a beneficial therapeutic effect on overall survival and contribute to a better quality of life.
详细描述
This a two-part, open-label phase 1/2 study that will include clinical sites in Norway and other Nordic countries.
The study consists of part A and part B. Part A will run in Norway only. Part B will run in Norway and the Nordic countries.
Both part A and part B have two different treatment combinations (T), combination 1 and combination 2. Part B is a cohort expansion of part A (if part A proves to be positive).
Treatment combination 1 (T1): hydroxyurea + valproic acid. Treatment combination 2 (T2): 6-mercaptopurine + valproic acid.
Each patient enrolled in the trial will start and will receive at least one cycle with T1:
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Participants are eligible for the study only if all of the following criteria apply:
- •o Female or male, age 18 years or older
- •Written informed consent
- •Patients with Newly diagnosed AML, as defined by ELN 2022 criteria, or relapsed/refractory AML who: - are unfit, defined as HCT-CI ≥ 3, or - in the opinion of the investigator are not candidates for standard therapy or unlikely to tolerate or derive significant clinical benefit from standard therapy, or
- •the patient has declined standard therapy
- •Newly diagnosed HR-MDS, or relapsed/refractory HR-MDS who:
- •are unfit, defined as HCT-CI ≥ 3, or
- •in the opinion of the investigator are not candidates for standard therapy or unlikely to tolerate or derive significant clinical benefit from standard therapy, or
- •has declined standard therapy
- •Secondary AML (MDS-related/ therapy- induced), or
- •Acute promyelocytic leukemia not eligible for standard therapy and/or specific therapy.
- •Adequate renal and hepatic functions unless clearly disease related as indicated by the following laboratory values:
- •Serum creatinine ≤1.5 x ULN;
- •Estimated creatinine clearance ≥ 40 mL/min (Cockcroft-Gault equation);
- •Hepatic function;
- •i. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN); ii. Aspartate aminotransferase (AST)
- •≤5 × ULN for patients with liver metastases
- •iii. Alanine aminotransferase (ALT)
- •≤5 × ULN for patients with liver metastases
- •iv. Alkaline phosphatase (ALP)
- •European Cooperative Oncology Group (ECOG) performance status 0, 1, 2 or 3
- •Female patients of childbearing potential must have a negative serum pregnancy test within 3 days prior to taking their first dose of study medication. Male patients and female patients of reproductive potential must agree to practice highly effective methods of contraception (such as hormonal implants, combined oral contraceptives, injectable contraceptives, intrauterine device with hormone spirals, total sexual abstinence, vasectomy) throughout the study and for >3 months after the last dose of study medication. Female patients are considered NOT of childbearing potential if they have a history of surgical sterility or evidence of post-menopausal status defined as any of the following:
- •Natural menopause with last menses >1 year ago
- •Radiation induced oophorectomy with last menses >1 year ago
- •Chemotherapy induced menopause with last menses >1 year ago
排除标准
- •Participants are excluded from the study if any of the following criteria apply:
- •Patients on treatment for AML (any anti-leukemic therapy including investigational agents) or treated less than 2 weeks before inclusion.
- •Concurrent history of active malignancy in the past six months prior to diagnosis except for
- •basal and squamous cell carcinoma of the skin
- •in situ carcinoma of the cervix
- •Concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, pulmonary disease et cetera) at the investigators discretion.
- •Breastfeeding women
- •Cardiac dysfunction as defined by:
- •myocardial infarction within the last 3 months of study entry, or
- •congestive heart failure NYHA class IV or
- •unstable angina, or
- •unstable cardiac arrhythmias
- •SARS-CoV-2 infection < 7 days or Covid-19-vaccine < 7 days from study onset
- •Patients with a history of non-compliance to medical regimens or who are considered unreliable with respect to compliance.
- •Patients with any serious concomitant medical condition that could, in the opinion of the investigator, compromise participation in the study.
- •Patients with senile dementia, mental impairment or any other psychiatric disorder that prohibits the patient from understanding and giving informed consent.
- •Current concomitant chemotherapy, radiation therapy, or immunotherapy other than as specified in the protocol.
- •Known hypersensitivity to study medications or its excipients.
- •Any psychological, familial, sociological, and geographical condition potentially hampering compliance with the study protocol and follow-up schedule.
研究组 & 干预措施
Hydroxyurea (HU) + Valproic Acid (VPA) part 1
Combination treatment 1 (T1): hydroxyurea + valproic acid, combination treatment 2 (T2): 6-mercaptopurine + valproic acid.
Each patient enrolled will receive at least one cycle with T1: hydroxyurea and valproic acid. The 1st cycle in the study always constitutes of hydroxyurea (1000 mg twice a day) plus valproic acid (300 mg + 600 mg) for 14 days; then 14 days with no medication.
Each cycle duration is 28 days. Patients who do not experience clinical benefit after 1st cycle, or experience unacceptable and unmanageable toxicity after 1st cycle, will not be eligible to continue on this regimen and they will be allocated to treatment combination 2. T2 constitutes of 6-mercaptopurine ( 50 mg once a day) plus valproic acid 300 mg + 600 mg ) for 14 days; followed by 14 days with no medication. Each cycle duration is 28 days.
干预措施: Hydroxyurea, Hydroxycarbamide (Drug)
Hydroxyurea (HU) + Valproic Acid (VPA) part 1
Combination treatment 1 (T1): hydroxyurea + valproic acid, combination treatment 2 (T2): 6-mercaptopurine + valproic acid.
Each patient enrolled will receive at least one cycle with T1: hydroxyurea and valproic acid. The 1st cycle in the study always constitutes of hydroxyurea (1000 mg twice a day) plus valproic acid (300 mg + 600 mg) for 14 days; then 14 days with no medication.
Each cycle duration is 28 days. Patients who do not experience clinical benefit after 1st cycle, or experience unacceptable and unmanageable toxicity after 1st cycle, will not be eligible to continue on this regimen and they will be allocated to treatment combination 2. T2 constitutes of 6-mercaptopurine ( 50 mg once a day) plus valproic acid 300 mg + 600 mg ) for 14 days; followed by 14 days with no medication. Each cycle duration is 28 days.
干预措施: Valproic acid (Drug)
Hydroxyurea (HU) + Valproic Acid (VPA) part 1
Combination treatment 1 (T1): hydroxyurea + valproic acid, combination treatment 2 (T2): 6-mercaptopurine + valproic acid.
Each patient enrolled will receive at least one cycle with T1: hydroxyurea and valproic acid. The 1st cycle in the study always constitutes of hydroxyurea (1000 mg twice a day) plus valproic acid (300 mg + 600 mg) for 14 days; then 14 days with no medication.
Each cycle duration is 28 days. Patients who do not experience clinical benefit after 1st cycle, or experience unacceptable and unmanageable toxicity after 1st cycle, will not be eligible to continue on this regimen and they will be allocated to treatment combination 2. T2 constitutes of 6-mercaptopurine ( 50 mg once a day) plus valproic acid 300 mg + 600 mg ) for 14 days; followed by 14 days with no medication. Each cycle duration is 28 days.
干预措施: 6-Mercaptopurine (6-MP) (Drug)
Hydroxyurea (HU) + Valproic Acid (VPA) part 2
Part B consists of two cohort expansions where the setup is identical to part A: one for HU + VPA and one for 6-MP + VPA, 16 patients in each, in total 32 new patients.
In part B the same principles will apply for response, withdrawal and allocation from HU+ VPA to 6-MP + VPA. The treatment duration in all arms can last to up 6 cycles in total. Each cycle duration is 28 days.
干预措施: Hydroxyurea, Hydroxycarbamide (Drug)
Hydroxyurea (HU) + Valproic Acid (VPA) part 2
Part B consists of two cohort expansions where the setup is identical to part A: one for HU + VPA and one for 6-MP + VPA, 16 patients in each, in total 32 new patients.
In part B the same principles will apply for response, withdrawal and allocation from HU+ VPA to 6-MP + VPA. The treatment duration in all arms can last to up 6 cycles in total. Each cycle duration is 28 days.
干预措施: Valproic acid (Drug)
Hydroxyurea (HU) + Valproic Acid (VPA) part 2
Part B consists of two cohort expansions where the setup is identical to part A: one for HU + VPA and one for 6-MP + VPA, 16 patients in each, in total 32 new patients.
In part B the same principles will apply for response, withdrawal and allocation from HU+ VPA to 6-MP + VPA. The treatment duration in all arms can last to up 6 cycles in total. Each cycle duration is 28 days.
干预措施: 6-Mercaptopurine (6-MP) (Drug)
结局指标
主要结局
Safety and tolerability of the treatment combinations of hydroxyurea + valproic acid, and 6-mercaptopurine + valproic acid administered at established clinical doses.
时间窗: Evaluation every 4th week, i.e. after each treatment cycle.
Safety and tolerability assessed by monitoring the incidence, frequency, and severity of AEs by using CTCAE v5.0, including evaluation of the following: * DLTs * Physical examinations * Clinical laboratory blood samples
Preliminary efficacy of the treatment combination of hydroxyurea and valproic acid administered at established clinical doses.
时间窗: Evaluation every 4th week, i.e. after each treatment cycle.
Clinical benefit in patients receiving hydroxyurea in combination with valproic acid. Clinical benefit in patients receiving 6-mercaptopurine in combination with valproic acid. Clinical benefit, in this protocol, is defined as stable disease, partial response (decrease of bone marrow blast percentage to between 5% to 25% and decrease of pre-treatment bone marrow blast percentage by at least 50%), or better response \[European Leukemia Net (ELN) 2022 response criteria in AML\], and/or stable or improved ECOG performance status.
Changes in patients performance status from baseline and during the study period.
时间窗: Evaluation at baseline, i.e. before onset treatment, after 4 weeks on treatment (i.e.after first cycle), and every 4th week to a total of 24 weeks. (i.e. after each treatment cycle, up to a total of 6 cycles).
Baseline and longitudinal ECOG performance status of the patient (Eastern Cooperative Oncology Group). The ECOG performance status scale is best at 0 (fully active, able to carry on all pre-disease performance without restriction), and worst at 5 (dead).
次要结局
- Duration of clinical benefit.(During the treatment period of 6 months, and during follow-up, up to 6 months after end treatment.)
- Clinical benefit.(After 3 and 6 cycles (i.e. after 3 and 6 months from the treatment onset).)
- Time to progression.(From the treatment onset, during the treatment period of 6 months, and during follow-up, up to 6 months after end treatment.)
- Changes in reported Quality of Life (QoL) compared to baseline.(At baseline, i.e. before onset treatment, after 4 weeks on treatment (i.e.after first cycle), and after each treatment cycle (every 4th week).)
- Survival analyses, ORR.(After 3 and 6 cycles (i.e. after 3 and 6 months from the treatment onset).)
- Survival analyses, OS.(From the treatment onset, during the treatment period of 6 months, and during follow-up, up to 6 months after end-treatment.)
- Hospitalization rate per month per patient.(Before the treatment onset, during the treatment period of 6 months, and during follow-up, up to 6 months after end treatment.)
- Transfusion rate per month per patient.(Before the treatment onset, during the treatment period of 6 months, and during follow-up, up to 6 months after end treatment.)