CApivasertib, Venetoclax And Low-intensity chemotheRapY for Adults With ALL/LBL
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 104
- 试验地点
- 1
- 主要终点
- Safety of the combination of mini-hyperCVD and venetoclax plus capivasertib [Cohort 1]
研究概览
简要总结
This is a 3-part study to assess the safety of adding capivasertib to a standard of care treatment regimen consisting of venetoclax and low-intensity chemotherapy. This chemotherapy regimen called mini-hyperCVD consists of the chemotherapy drugs, cyclophosphamide, vincristine, dexamethasone; (part A) alternating with high-dose methotrexate and cytarabine (part B) administered approximately every 28 days.
In the first part of the study (Cohort 1), the study seeks to determine the recommended dose of capivasertib that can be safely given with venetoclax and chemotherapy. Several doses of capivasertib may be tested in small groups of subjects in this part of the study. The dose tested will be increased or lowered depending on types and frequency of side effects seen until the best, safe dose is found.
Once the recommended, safe dose of capivasertib is found, the study will move on to the second part (Cohort 2) and will treat additional participants to learn more about the safety of giving these drugs together.
If the combination is determined to be safe overall, the study will move on to the third part (Cohort 3). In this part of the study, participants will be randomized to receive the mini-hyperCVD and venetoclax alone or with capivasertib.
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
- •COHORT 1 Inclusion Criteria
- •Patients with acute leukemia with lymphoid lineage (B-ALL, T-ALL, ETP-ALL, mixed phenotype or bi-phenotypic) or lymphoblastic lymphoma (B- or T-lineage) that is relapsed or refractory
- •Bone marrow or peripheral blood involvement with ≥5% leukemic blasts. Patients with isolated extramedullary disease that is measurable by CT scan are also eligible.
- •18 years or older
- •ECOG performance status 0-2
- •Adequate organ function meeting protocol criteria
- •Patients must be at least 2 weeks from major surgery or radiation therapy. A wash-out period of 5 half-lives is required for patients who participated in other investigational trials. These patients must have recovered from clinically significant toxicities related to these prior treatments.
- •Patients must voluntarily sign and date an informed consent prior to the initiation of any screening or study-specific procedures.
- •Females of childbearing potential will use effective contraception during protocol treatment and for at least 8 months after the last dose. Males with female partners of reproductive potential will use effective contraception during protocol treatment and for at least 5 months after the last dose.
排除标准
- •Ph-positive ALL, Burkitt's leukemia/lymphoma
- •Patient is pregnant or breastfeeding
- •Patients with uncontrolled infection.
- •Known active hepatitis B or C infection, or uncontrolled human immunodeficiency virus (HIV) infection. Patients with HIV infection, whose disease is controlled with anti-retroviral therapy are eligible, but their highly active antiretroviral therapy (HAART) should be modified to minimize drug interactions. Due to the increased risk of hepatitis B reactivation, all patients with active, previously treated or resolved hepatitis B infection will not be eligible for rituximab treatment if their leukemia expresses >1% CD
- •Major surgery or radiation therapy within 2 weeks prior to the first study dose
- •Symptomatic central nervous system (CNS) disease or spinal cord compression
- •Concurrent active malignancy requiring treatment with potential to influence the endpoint of the clinical trial. Patients with non-melanoma skin cancer, carcinoma in situ of the cervix, localized prostate cancer, past history of malignancy that has been definitively treated, and patients treated with hormonal therapies for solid tumors are eligible. Patients with history of multiple myeloma that does not need active treatment are also eligible.
- •Uncontrolled cardiac disease
- •Uncontrolled diabetes mellitus, defined as fasting blood glucose >160 mg/dL or random blood glucose >250 mg/dL. Patients with type 1 diabetes mellitus or insulin-dependent diabetes are also excluded. A1c measurements are less reliable in leukemia patients due to anemia and/or need for red cell transfusions. Patients with well-controlled, non-insulin-dependent diabetes are eligible, but their blood glucose must be monitored closely during the study period in consultation with Diabetes specialists.
- •Other severe acute, chronic medical, psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the treating physician, would make the patient inappropriate for entry into this study.
- •Patients who cannot discontinue strong CYP3A inducers, grapefruit, grapefruit products, Seville oranges, or star fruit within the 3 days prior to starting venetoclax.
- •COHORT 2 Inclusion criteria
- •Relapsed or refractory patients with acute leukemia with lymphoid lineage (B-ALL, T-ALL, ETP-ALL, mixed phenotype or bi-phenotypic) or lymphoblastic lymphoma (B- or T-lineage)
- •Bone marrow or peripheral blood involvement with ≥5% leukemic blasts. Patients with isolated extramedullary disease that is measurable by CT scan are also eligible.
- •18 years or older
- •ECOG performance status 0-2
- •Adequate organ function meeting protocol criteria
- •Patients must be at least 2 weeks from major surgery or radiation therapy. A wash-out period of 5 half-lives is required for patients who participated in other investigational trials. These patients must have recovered from clinically significant toxicities related to these prior treatments.
- •Patients must voluntarily sign and date an informed consent prior to the initiation of any screening or study-specific procedures.
- •Females of childbearing potential will use effective contraception during protocol treatment and for at least 8 months after the last dose. Males with female partners of reproductive potential will use effective contraception during protocol treatment and for at least 5 months after the last dose.
- •Exclusion criteria
- •Ph-positive ALL, Burkitt's leukemia/lymphoma
- •Patient is pregnant or breastfeeding
- •Patients with uncontrolled infection. Patients with infections that have been controlled for ≥7 days will be eligible.
- •Known active hepatitis B or C infection, or uncontrolled human immunodeficiency virus (HIV) infection. Patients with HIV infection, whose disease is controlled with anti-retroviral therapy are eligible, but their highly active antiretroviral therapy (HAART) should be modified to minimize drug interactions. Due to the increased risk of hepatitis B reactivation, all patients with active, previously treated or resolved hepatitis B infection will not be eligible for rituximab treatment if their leukemia expresses >1% CD
- •Major surgery or radiation therapy within 2 weeks prior to the first study dose
- •Symptomatic central nervous system (CNS) disease or spinal cord compression
- •Concurrent active malignancy requiring treatment with potential to influence the endpoint of the clinical trial. Patients with non-melanoma skin cancer, carcinoma in situ of the cervix, localized prostate cancer, past history of malignancy that has been definitively treated, and patients treated with hormonal therapies for solid tumors are eligible. Patients with history of multiple myeloma that does not need active treatment are also eligible.
- •Uncontrolled cardiac disease
- •Uncontrolled diabetes mellitus, defined as fasting blood glucose >160 mg/dL or random blood glucose >250 mg/dL. Patients with type 1 diabetes mellitus or insulin-dependent diabetes are also excluded. A1c measurements are less reliable in leukemia patients due to anemia and/or need for red cell transfusions. Patients with well-controlled, non-insulin-dependent diabetes are eligible, but their blood glucose must be monitored closely during the study period in consultation with Diabetes specialists.
- •Other severe acute, chronic medical, psychiatric condition, or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the treating physician, would make the patient inappropriate for entry into this study.
- •Patients who cannot discontinue strong CYP3A inducers, grapefruit, grapefruit products, Seville oranges, or star fruit within the 3 days prior to starting venetoclax.
- •Inclusion criteria
- •Previously untreated patients with acute leukemia with lymphoid lineage (B-ALL, T-ALL, ETP-ALL, mixed phenotype or bi-phenotypic) or lymphoblastic lymphoma (B- or T-lineage)
- •Bone marrow or peripheral blood involvement with ≥20% leukemic blasts. Patients with isolated extramedullary disease that is measurable by CT scan are also eligible.
- •Previous therapy with dexamethasone or hydroxyurea given for cytoreductive purposes is allowed.
- •40 years old or older
- •ECOG performance status 0-2
- •Adequate organ function per protocol criteria
- •Patients must be at least 2 weeks from major surgery.
- •Patients must voluntarily sign and date an informed consent prior to the initiation of any screening or study-specific procedures.
- •Females of childbearing potential will use effective contraception during protocol treatment and for at least 8 months after the last dose. Males with female partners of reproductive potential will use effective contraception during protocol treatment and for at least 5 months after the last dose.
- •Exclusion criteria
- •Ph-positive ALL, Burkitt's leukemia/lymphoma
- •Patient is pregnant or breastfeeding
- •Patients with uncontrolled infection. Patients with infections that have been controlled for ≥7 days will be eligible.
- •Known active hepatitis B or C infection, or uncontrolled human immunodeficiency virus (HIV) infection. Patients with HIV infection, whose disease is controlled with anti-retroviral therapy are eligible, but their highly active antiretroviral therapy (HAART) should be modified to minimize drug interactions. Due to the increased risk of hepatitis B reactivation, all patients with active, previously treated or resolved hepatitis B infection will not be eligible for rituximab treatment if their leukemia expresses >1% CD
- •Major surgery or radiation therapy within 2 weeks prior to the first study dose
- •Symptomatic central nervous system (CNS) disease or spinal cord compression
- •Concurrent active malignancy requiring treatment with potential to influence the endpoint of the clinical trial. Patients with non-melanoma skin cancer, carcinoma in situ of the cervix, localized prostate cancer, past history of malignancy that has been definitively treated, and patients treated with hormonal therapies for solid tumors are eligible. Patients with history of multiple myeloma that does not need active treatment are also eligible.
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研究组 & 干预措施
Cohort 1 - Dose Escalation (Dose Level 1)
In this arm, a dose of 320 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Capivasertib (Drug)
Cohort 1 - Dose Escalation (Dose Level 1)
In this arm, a dose of 320 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Venetoclax (Drug)
Cohort 1 - Dose Escalation (Dose Level 1)
In this arm, a dose of 320 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Rituximab (Drug)
Cohort 1 - Dose Escalation (Dose Level 1)
In this arm, a dose of 320 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Blinatumomab (Drug)
Cohort 1 - Dose Escalation (Dose Level 1)
In this arm, a dose of 320 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Nelarabine (Drug)
Cohort 1 - Dose Escalation (Dose Level 1)
In this arm, a dose of 320 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: mini-hyperCVD (Drug)
Cohort 1 - Dose Escalation (Dose Level 2)
In this arm, a dose of 400 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Capivasertib (Drug)
Cohort 1 - Dose Escalation (Dose Level 2)
In this arm, a dose of 400 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Venetoclax (Drug)
Cohort 1 - Dose Escalation (Dose Level 2)
In this arm, a dose of 400 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Rituximab (Drug)
Cohort 1 - Dose Escalation (Dose Level 2)
In this arm, a dose of 400 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Blinatumomab (Drug)
Cohort 1 - Dose Escalation (Dose Level 2)
In this arm, a dose of 400 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Nelarabine (Drug)
Cohort 1 - Dose Escalation (Dose Level 2)
In this arm, a dose of 400 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: mini-hyperCVD (Drug)
Cohort 1 - Dose Escalation (Dose Level -1)
In this arm, a dose of 200 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Capivasertib (Drug)
Cohort 1 - Dose Escalation (Dose Level -1)
In this arm, a dose of 200 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Venetoclax (Drug)
Cohort 1 - Dose Escalation (Dose Level -1)
In this arm, a dose of 200 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Rituximab (Drug)
Cohort 1 - Dose Escalation (Dose Level -1)
In this arm, a dose of 200 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Blinatumomab (Drug)
Cohort 1 - Dose Escalation (Dose Level -1)
In this arm, a dose of 200 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Nelarabine (Drug)
Cohort 1 - Dose Escalation (Dose Level -1)
In this arm, a dose of 200 mg dose of capivasertib will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: mini-hyperCVD (Drug)
Cohort 2 (Expansion)
In this arm, the best, safe dose of capivasertib found after completion of enrollment to dose escalation (cohort 1) arms, will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Capivasertib (Drug)
Cohort 2 (Expansion)
In this arm, the best, safe dose of capivasertib found after completion of enrollment to dose escalation (cohort 1) arms, will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Venetoclax (Drug)
Cohort 2 (Expansion)
In this arm, the best, safe dose of capivasertib found after completion of enrollment to dose escalation (cohort 1) arms, will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Rituximab (Drug)
Cohort 2 (Expansion)
In this arm, the best, safe dose of capivasertib found after completion of enrollment to dose escalation (cohort 1) arms, will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Blinatumomab (Drug)
Cohort 2 (Expansion)
In this arm, the best, safe dose of capivasertib found after completion of enrollment to dose escalation (cohort 1) arms, will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: Nelarabine (Drug)
Cohort 2 (Expansion)
In this arm, the best, safe dose of capivasertib found after completion of enrollment to dose escalation (cohort 1) arms, will be tested in combination with venetoclax and mini-hyperCVD chemotherapy regimen.
干预措施: mini-hyperCVD (Drug)
Cohort 3 -- Arm 1 -- mini-hyperCVD + venetoclax (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax.
干预措施: Venetoclax (Drug)
Cohort 3 -- Arm 1 -- mini-hyperCVD + venetoclax (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax.
干预措施: Rituximab (Drug)
Cohort 3 -- Arm 1 -- mini-hyperCVD + venetoclax (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax.
干预措施: Blinatumomab (Drug)
Cohort 3 -- Arm 1 -- mini-hyperCVD + venetoclax (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax.
干预措施: Nelarabine (Drug)
Cohort 3 -- Arm 1 -- mini-hyperCVD + venetoclax (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax.
干预措施: mini-hyperCVD (Drug)
Cohort 3 -- Arm 2 -- mini-hyperCVD + venetoclax + capivasertib (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax and capivasertib.
干预措施: Capivasertib (Drug)
Cohort 3 -- Arm 2 -- mini-hyperCVD + venetoclax + capivasertib (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax and capivasertib.
干预措施: Venetoclax (Drug)
Cohort 3 -- Arm 2 -- mini-hyperCVD + venetoclax + capivasertib (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax and capivasertib.
干预措施: Rituximab (Drug)
Cohort 3 -- Arm 2 -- mini-hyperCVD + venetoclax + capivasertib (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax and capivasertib.
干预措施: Blinatumomab (Drug)
Cohort 3 -- Arm 2 -- mini-hyperCVD + venetoclax + capivasertib (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax and capivasertib.
干预措施: Nelarabine (Drug)
Cohort 3 -- Arm 2 -- mini-hyperCVD + venetoclax + capivasertib (Randomized)
Participants randomized to this arm will receive mini-hyperCVD + venetoclax and capivasertib.
干预措施: mini-hyperCVD (Drug)
结局指标
主要结局
Safety of the combination of mini-hyperCVD and venetoclax plus capivasertib [Cohort 1]
时间窗: After all cohort 1 participants have completed 2 28-day cycles of study treatment
Summary of dose limiting toxicities as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5.
Recommended Phase 2 Dose (RP2D) of capivasertib in combination with mini-hyperCVD and venetoclax [Cohort 1]
时间窗: This will be assessed after all cohort 1 participants have completed 2 28-day cycles of study treatment
The dose that dose not cause dose limiting toxicities as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 5 will be identified as the RP2D.
Efficacy of capivasertib in combination with mini-hyperCVD and venetoclax [Cohort 2 and 3]
时间窗: This will be assessed after all participants have completed treatment (an average of about 8 months)
Number of participants with complete remission (CR) with measurable residual disease (MRD) negativity
次要结局
- Rate of clinical remission (CR) [Cohort 1](This will be assessed after all participants have completed treatment (an average of about 8 months))
- Rate of clinical remission with incomplete count recovering (CRi) [Cohort 1](This will be assessed after all participants have completed treatment (an average of about 8 months))
- Rate of CR with measurable residual disease (MRD) negativity [Cohort 1](This will be assessed after all participants have completed treatment (an average of about 8 months))
- Progression free survival [All Cohorts](up to 10 years after treatment completion)
- Overall survival [Cohort 2 and 3](up to 10 years after treatment completion)
- Side effects of the combination of mini-hyperCVD and venetoclax plus capivasertib [Cohort 2 and 3](This will be assessed after all participants have completed treatment (an average of about 8 months))