Capivasertib, Venetoclax, and Low-Intensity Chemotherapy for the Treatment of Acute Lymphoblastic Leukemia/Lymphoblastic Lymphoma, CAVALRY Trial
This phase I/II trial studies the side effects and best dose of capivasertib when given together with venetoclax and low-intensity chemotherapy (cyclophosphamide, vincristine, dexamethasone, methotrexate, cytarabine) and to see how well it works in treating patients with acute lymphoblastic leukemia (ALL)/lymphoblastic lymphoma (LBL). Capivasertib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Chemotherapy drugs, such as cyclophosphamide, vincristine, methotrexate, and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving capivasertib with venetoclax and low-intensity chemotherapy may be safe, tolerable, and/or effective in treating patients with ALL/LBL.
Inclusion Criteria
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Patients with acute leukemia with lymphoid lineage (B acute lymphoblastic leukemia [B-ALL], T acute lymphoblastic leukemia [T-ALL], early T precursor acute lymphoblastic leukemia [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
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Age ≥ 18 years old
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Creatinine clearance ≥ 50 mL/min, determined by the Cockroft-Gault formula, or measured by a 24-hour urine collection
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 x upper limit of normal (ULN) (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement)
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Total bilirubin ≤ 3 x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement). For patients with Gilbert`s syndrome, total bilirubin ≤ 3 x of their baseline bilirubin level and direct bilirubin ≤ 2x ULN will be required
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Direct bilirubin ≤ 2x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement). For patients with Gilbert`s syndrome, total bilirubin ≤ 3 x of their baseline bilirubin level and direct bilirubin ≤ 2x ULN will be required. For patients with leukemic involvement of liver, direct bilirubin ≤ 3 mg/dL will be required
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): 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, determined according to the current National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade of less than 2
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Patients must voluntarily sign and date an informed consent prior to the initiation of any screening or study-specific procedures
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): 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. A patient is of childbearing potential if, in the opinion of the treating investigator, he/she is biologically capable of having children and is sexually active. Female patients who are not of childbearing potential (ie, meet at least one of the following criteria): * Have undergone hysterectomy or bilateral oophorectomy; or have medically confirmed ovarian failure; or are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause)
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): 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
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Age ≥ 18 years old
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): ECOG performance status 0-2
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Creatinine clearance ≥ 50 mL/min, determined by the Cockroft-Gault formula, or measured by a 24-hour urine collection
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): AST and ALT ≤ 3 x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement)
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Total bilirubin ≤ 3 x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement). For patients with Gilbert`s syndrome, total bilirubin ≤ 3 x of their baseline bilirubin level and direct bilirubin ≤ 2x ULN will be required
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Direct bilirubin ≤ 2x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement). For patients with Gilbert`s syndrome, total bilirubin ≤ 3 x of their baseline bilirubin level and direct bilirubin ≤ 2x ULN will be required. For patients with leukemic involvement of liver, direct bilirubin ≤ 3 mg/dL will be required
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): 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, determined according to the current NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade of less than 2
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Patients must voluntarily sign and date an informed consent prior to the initiation of any screening or study-specific procedures
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): 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. A patient is of childbearing potential if, in the opinion of the treating investigator, he/she is biologically capable of having children and is sexually active. Female patients who are not of childbearing potential (ie, meet at least one of the following criteria): * Have undergone hysterectomy or bilateral oophorectomy; or have medically confirmed ovarian failure; or are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause)
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): 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
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Age ≥ 40 years old
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): ECOG performance status 0-2
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Creatinine clearance ≥ 50 mL/min, determined by the Cockroft-Gault formula, or measured by a 24-hour urine collection
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): AST and ALT ≤ 3 x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement)
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Total bilirubin ≤ 3 x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement). For patients with Gilbert`s syndrome, total bilirubin ≤ 3 x of their baseline bilirubin level and direct bilirubin ≤ 2x ULN will be required
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Direct bilirubin ≤ 2x ULN (unless considered due to Gilbert’s syndrome or of non-hepatic origin i.e,, leukemic involvement). For patients with Gilbert`s syndrome, total bilirubin ≤ 3 x of their baseline bilirubin level and direct bilirubin ≤ 2x ULN will be required. For patients with leukemic involvement of liver, direct bilirubin ≤ 3 mg/dL will be required
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Patients must be at least 2 weeks from major surgery
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Patients must voluntarily sign and date an informed consent prior to the initiation of any screening or study-specific procedures
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): 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. A patient is of childbearing potential if, in the opinion of the treating investigator, he/she is biologically capable of having children and is sexually active. Female patients who are not of childbearing potential (ie, meet at least one of the following criteria): * Have undergone hysterectomy or bilateral oophorectomy; or have medically confirmed ovarian failure; or are medically confirmed to be post-menopausal (cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause)
Exclusion Criteria
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Philadelphia chromosome-positive (Ph-positive) ALL, Burkitt`s leukemia/lymphoma
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Patient is pregnant or breastfeeding
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Patients with uncontrolled infection. Patients with infections that have been controlled for ≥ 7 days will be eligible
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): 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% CD20
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Major surgery or radiation therapy within 2 weeks prior to the first study dose
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Symptomatic central nervous system (CNS) disease or spinal cord compression
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): 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
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): Uncontrolled cardiac disease
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): 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. Hemoglobin A1c (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
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): 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
- COHORT 1 (PHASE 1 STUDY IN R/R ALL/LBL): 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 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Ph-positive ALL, Burkitt`s leukemia/lymphoma
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Patient is pregnant or breastfeeding
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Patients with uncontrolled infection. Patients with infections that have been controlled for ≥ 7 days will be eligible
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): 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% CD20
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Major surgery or radiation therapy within 2 weeks prior to the first study dose
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Symptomatic central nervous system (CNS) disease or spinal cord compression
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): 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
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Uncontrolled cardiac disease
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): 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
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): 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
- COHORT 2 (PHASE 2 DOSE EXPANSION IN R/R ALL/LBL): Patients who cannot discontinue strong CYP3A inducers, grapefruit, grapefruit products, Seville oranges, or star fruit within the 3 days prior to starting venetoclax
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Ph-positive ALL, Burkitt`s leukemia/lymphoma
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Patient is pregnant or breastfeeding
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Patients with uncontrolled infection. Patients with infections that have been controlled for ≥ 7 days will be eligible
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): 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% CD20
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Major surgery or radiation therapy within 2 weeks prior to the first study dose
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Symptomatic central nervous system (CNS) disease or spinal cord compression
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): 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
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Uncontrolled cardiac disease
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): 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
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): 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
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Any prior systemic chemotherapy or radiotherapy for treatment of ALL/LBL is an exclusion with the exception of hydroxyurea, steroids, tretinoin (ATRA) and/or intrathecal chemotherapy. No more than 2 weeks of steroids is permitted
- COHORT 3 (PHASE 2 RANDOMIZED STUDY IN NEWLY DIAGNOSED ALL/LBL): Patients who cannot discontinue strong CYP3A inducers, grapefruit, grapefruit products, Seville oranges, or star fruit within the 3 days prior to starting venetoclax
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07294677.
Locations matching your search criteria
United States
Illinois
Chicago
PRIMARY OBJECTIVES:
I. To demonstrate the safety and to identify the recommended phase II dose (RP2D) for the combination of dose-attenuated hyperfractionated cyclophosphamide, vincristine and dexamethasone alternating with methotrexate and cytarabine plus venetoclax (mini-hyperCVD-venetoclax) plus capivasertib. (Cohort 1 [Phase 1 study in relapsed/refractory (R/R) ALL/LBL])
II. To investigate the efficacy of mini-hyperCVD-venetoclax plus capivasertib combination therapy in relapsed/refractory (R/R) ALL/LBL ≥ 18 years. (Cohort 2 [Phase 2 dose expansion in R/R ALL/LBL])
III. To investigate the efficacy of dose-attenuated hyperfractionated cyclophosphamide, vincristine and dexamethasone alternating with methotrexate and cytarabine plus venetoclax (mini-CVD + venetoclax) + capivasertib combination therapy over standard of care mini-CVD + venetoclax regimen in newly diagnosed ALL/LBL ≥ 40 years. (Cohort 3 [Phase 2 randomized study in newly diagnosed ALL/LBL])
SECONDARY OBJECTIVES:
I. To estimate the rate of complete clinical remission (CR), CR with incomplete count recovery (CRi), and CR with measurable residual disease (MRD) negativity for patients treated at different dose levels. (Cohort 1 [Phase 1 study in R/R ALL/LBL])
II. To estimate the overall survival (OS) and progression-free survival (PFS) for patients treated with the combination therapy at the RP2D dose level. (Cohort 1 [Phase 1 study in R/R ALL/LBL])
III. To estimate the overall survival (OS) and progression-free survival (PFS) for patients treated with the combination therapy at the RP2D dose level. (Cohort 2 [Phase 2 dose expansion in R/R ALL/LBL])
IV. To determine the safety of combination therapy. (Cohort 2 [Phase 2 dose expansion in R/R ALL/LBL])
V. To estimate the difference in overall survival (OS) and progression-free survival (PFS) between standard of care and experimental arms. (Cohort 3 [Phase 2 randomized study in newly diagnosed ALL/LBL])
VI. To compare the toxicities observed in patients treated on experimental arm versus (vs) standard of care arm. (Cohort 3 [Phase 2 randomized study in newly diagnosed ALL/LBL])
OUTLINE: This is a phase I, dose-escalation study of capivasertib in combination with mini-hyperCVD-venetoclax, followed by a phase II study. Patients are assigned to 1 of 3 cohorts.
COHORT 1:
MINI-HYPER-CVD-VENETOCLAX PLUS CAPIVASERTIB: Patients receive venetoclax orally (PO) on days 1-21 of each cycle, capivasertib PO twice daily (BID) on days 4-7, 11-14, 18-21, and 25-28 of cycle 1 and days 1-4, 8-11, 15-18, and 22-25 thereafter, cyclophosphamide intravenously (IV) BID on days 4-6 of cycle 1 and days 1-3 of cycles 3, 5, and 7, vincristine IV on days 4 and 11 of cycle 1 and days 1 and 8 of cycles 3, 5, and 7, dexamethasone PO or IV on days 4-7 and 14-17 of cycle 1 and days 1-4 and 11-14 of cycles 3, 5, and 7, methotrexate IV on day 1 of cycles 2, 4, 6, and 8, cytarabine IV BID on days 2-3 of cycles 2, 4, 6, and 8, and methotrexate or cytarabine intrathecally (IT) on days 5 and 11 of cycle 1 and days 2 and 8 of cycles 2-4. Patients whose leukemic blasts express CD20 (> 1% of blasts) also receive rituximab IV on days 5 and 11 of cycle 1 and days 2 and 8 of cycles 2-4. Cycles repeat every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with CD19+ B-lineage ALL in CR after cycle 2 may receive up to 4 cycles of blinatumomab consolidation per local standard of care. Patients with T-lineage ALL may receive nelarabine after cycles 2 and 4 at the discretion of treating physician and overall principal investigator (PI) as per institutional practices.
MAINTENANCE THERAPY: Patients receive venetoclax PO on days 1-14, methotrexate PO weekly, mercaptopurine PO BID on days 1-28, prednisone PO once daily (QD) on days 1-5, and vincristine IV on day 1 of each cycle. Cycles repeat every 28 days for up to 2 years from the date of first complete remission.
COHORT 2:
MINI-HYPER-CVD-VENETOCLAX PLUS CAPIVASERTIB: Patients receive mini-hyperCVD-venetoclax plus capivasertib combination therapy as in cohort 1 at the RP2D in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive maintenance therapy as in cohort 1 in the absence of disease progression or unacceptable toxicity.
COHORT 3: Patients are randomized to 1 of 2 arms.
ARM I:
MINI-HYPER-CVD-VENETOCLAX PLUS CAPIVASERTIB: Patients receive mini-hyperCVD-venetoclax plus capivasertib combination therapy as in cohort 1 in the absence of disease progression or unacceptable toxicity.
MAINTENANCE THERAPY: Patients receive maintenance therapy as in cohort 1 in the absence of disease progression or unacceptable toxicity.
ARM II:
MINI-HYPER-CVD-VENETOCLAX: Patients receive venetoclax PO on days 1-21 of each cycle, cyclophosphamide IV BID on days 4-6 of cycle 1 and days 1-3 of cycles 3, 5, and 7, vincristine IV on days 4 and 11 of cycle 1 and days 1 and 8 of cycles 3, 5, and 7, dexamethasone PO or IV on days 4-7 and 14-17 of cycle 1 and days 1-4 and 11-14 of cycles 3, 5, and 7, methotrexate IV on day 1 of cycles 2, 4, 6, and 8, cytarabine IV BID on days 2-3 of cycles 2, 4, 6, and 8, and methotrexate or cytarabine IT on days 5 and 11 of cycle 1 and days 2 and 8 of cycles 2-4. Patients whose leukemic blasts express CD20 (> 1% of blasts) also receive rituximab IV on days 5 and 11 of cycle 1 and days 2 and 8 of cycles 2-4. Cycles repeat every 28 days for up to 8 cycles in the absence of disease progression or unacceptable toxicity. Patients with CD19+ B-lineage ALL in CR after cycle 2 may receive up to 4 cycles of blinatumomab consolidation per local standard of care. Patients with T-lineage ALL may receive nelarabine after cycles 2 and 4 at the discretion of treating physician and overall PI as per institutional practices.
MAINTENANCE THERAPY: Patients receive maintenance therapy as in cohort 1 in the absence of disease progression or unacceptable toxicity.
Additionally, all patients undergo positron emission tomography (PET) or computed tomography (CT) and echocardiography (ECHO) or multigated acquisition scan (MUGA) during screening and bone marrow aspiration and biopsy and blood sample collection throughout the study. Patients may also undergo PET or CT on study.
After completion of study treatment, patients are followed up within 14 days, every 3 months until death or for up to 12 months, and then for up to 10 years or until disease progression or death, whichever occurs first.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationUniversity of Chicago Comprehensive Cancer Center
Principal InvestigatorCaner Saygin
- Primary IDIRB25-1773
- Secondary IDsNCI-2026-01627
- ClinicalTrials.gov IDNCT07294677