Selinexor and Venetoclax in Combination with Chemotherapy for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Leukemia of Ambiguous Lineage
Selinexor and Venetoclax in Combination with Chemotherapy for the Treatment of Relapsed or Refractory Acute Myeloid Leukemia or Acute Leukemia of Ambiguous Lineage
This phase I trial evaluates the side effects and best dose of selinexor and venetoclax in combination with chemotherapy in treating patients with acute myeloid leukemia or acute leukemia of ambiguous linage that has come back (relapsed) or does not respond to treatment. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Selinexor may stop the growth of cancer cells by blocking CRM1, which help the body's immune system to find and kill cancer cells. Chemotherapy drugs, such as fludarabine 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. Colony-stimulating factors, such as granulocyte colony-stimulating factor, may increase the production of blood cells and may help the immune system recover from the side effects of chemotherapy. Giving venetoclax and selinexor with chemotherapy may help control the disease in patients with acute myeloid leukemia or acute leukemia of ambiguous lineage.
Leukemia,
Pediatric Leukemia,
Pediatrics,
Phase I
Phase I
Both
Chemotherapy - cytotoxic,
Mol. targeted/Immunotherapy/Biologics,
Supportive Care
Cytarabine (ARA-C),
Filgrastim (GCSF),
Fludarabine,
Fludarabine (Fludara),
Selinexor (KPT-330),
Venetoclax
Smith, Brianna
National
Vanderbilt University
05-23-2023
Eligibility
2 Years
BOTH
NO
Inclusion Criteria:
Participants must have a diagnosis of AML or ALAL and meet the criteria below: * Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, OR * Early relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission and within one year of diagnosis, OR * Relapsed leukemia that is refractory to at least one course of salvage therapy (i.e., therapy given after the relapse has occurred), OR * Relapsed leukemia following hematopoietic cell transplantation (HCT), OR * Second or greater relapse * Patients with late first relapses, defined as the re-appearance of leukemia after the achievement of remission and greater than one year of diagnosis, may be enrolled in the dose expansion portion of the study after safety data from the dose escalation portion is available * Patients must have >= 5% blasts in the bone marrow as assessed by morphology or flow cytometry. However, if flow cytometry cannot be performed or if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with >= 5% blasts in the blood * In addition, patients in all categories must not be eligible to undergo curative therapy, such as immediate HCT, because of disease burden, time to identify a stem cell donor, or other reasons
Direct bilirubin = 1.5 x institutional upper limit of normal (ULN)
Normal creatinine for age or a calculated creatinine clearance >= 30 mL/min/1.73 m^2
Left ventricular ejection fraction >= 40% or shortening fraction >= 25%
Patients must be >=2 years of age and = 30 years old. The upper age limit may be defined by each institution, but may not exceed 30 years. Patients treated at St. Jude Childrens Research Hospital must be = 24 years old
Performance status: Lansky >= 50 for patients who are = 16 years old and Karnofsky >= 50% for patients who are > 16 years old
At least 14 days must have elapsed since the completion of myelosuppressive therapy or hypomethylating agents and the first doses of venetoclax and selinexor
At least 24 hours must have elapsed since the completion of low-dose or nonmyelosuppressive therapy, such as hydroxyurea or low-dose cytarabine (up to 100 mg/m^2/day), or leukapheresis, and the first doses of venetoclax and selinexor
For patients who have received prior HCT, there can be no evidence of graft versus host disease (GVHD) and greater than 60 days must have elapsed since the HCT
At least 14 days must have elapsed since the completion of any calcineurin inhibitors (e.g. tacrolimus, cyclosporine)
Patients may not receive strong or moderate CYP3A inducers, such as rifampin, within 3 days of the first dose of venetoclax or during the administration of venetoclax. During the dose-escalation portion of the trial, we discourage the use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) within 3 days of the first dose of venetoclax or during the administration of venetoclax. However, if an azole is required for the treatment or prevention of fungal infection during any phase of the trial, venetoclax dosing will be reduced to 60 mg/m^2 (100 mg max) in patients who require treatment with voriconazole and reduced to 40 mg/m^2 (70 mg max) in patients who require posaconazole
Exclusion Criteria:
Must not be pregnant or breastfeeding. Male or female of reproductive potential must agree to use effective contraception for the duration of study participation
Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible
Uncontrolled infection. Patients with infections that are controlled on concurrent anti-microbial agents are eligible
Impairment of gastrointestinal (GI) function or GI disease that, in the opinion of the treating physician, may significantly alter the absorption of venetoclax or selinexor
History of cerebellar toxicity or cerebellar neurological findings on exam
Previous toxicity or hypersensitivity directly attributed to venetoclax
Participants must have a diagnosis of AML or ALAL and meet the criteria below: * Refractory leukemia, defined as persistent leukemia after at least two courses of induction chemotherapy, OR * Early relapsed leukemia, defined as the re-appearance of leukemia after the achievement of remission and within one year of diagnosis, OR * Relapsed leukemia that is refractory to at least one course of salvage therapy (i.e., therapy given after the relapse has occurred), OR * Relapsed leukemia following hematopoietic cell transplantation (HCT), OR * Second or greater relapse * Patients with late first relapses, defined as the re-appearance of leukemia after the achievement of remission and greater than one year of diagnosis, may be enrolled in the dose expansion portion of the study after safety data from the dose escalation portion is available * Patients must have >= 5% blasts in the bone marrow as assessed by morphology or flow cytometry. However, if flow cytometry cannot be performed or if an adequate bone marrow sample cannot be obtained (e.g., in a patient with acute megakaryoblastic leukemia with marrow fibrosis), patients may be enrolled if there is unequivocal evidence of leukemia with >= 5% blasts in the blood * In addition, patients in all categories must not be eligible to undergo curative therapy, such as immediate HCT, because of disease burden, time to identify a stem cell donor, or other reasons
Direct bilirubin = 1.5 x institutional upper limit of normal (ULN)
Normal creatinine for age or a calculated creatinine clearance >= 30 mL/min/1.73 m^2
Left ventricular ejection fraction >= 40% or shortening fraction >= 25%
Patients must be >=2 years of age and = 30 years old. The upper age limit may be defined by each institution, but may not exceed 30 years. Patients treated at St. Jude Childrens Research Hospital must be = 24 years old
Performance status: Lansky >= 50 for patients who are = 16 years old and Karnofsky >= 50% for patients who are > 16 years old
At least 14 days must have elapsed since the completion of myelosuppressive therapy or hypomethylating agents and the first doses of venetoclax and selinexor
At least 24 hours must have elapsed since the completion of low-dose or nonmyelosuppressive therapy, such as hydroxyurea or low-dose cytarabine (up to 100 mg/m^2/day), or leukapheresis, and the first doses of venetoclax and selinexor
For patients who have received prior HCT, there can be no evidence of graft versus host disease (GVHD) and greater than 60 days must have elapsed since the HCT
At least 14 days must have elapsed since the completion of any calcineurin inhibitors (e.g. tacrolimus, cyclosporine)
Patients may not receive strong or moderate CYP3A inducers, such as rifampin, within 3 days of the first dose of venetoclax or during the administration of venetoclax. During the dose-escalation portion of the trial, we discourage the use of strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, voriconazole, posaconazole) within 3 days of the first dose of venetoclax or during the administration of venetoclax. However, if an azole is required for the treatment or prevention of fungal infection during any phase of the trial, venetoclax dosing will be reduced to 60 mg/m^2 (100 mg max) in patients who require treatment with voriconazole and reduced to 40 mg/m^2 (70 mg max) in patients who require posaconazole
Exclusion Criteria:
Must not be pregnant or breastfeeding. Male or female of reproductive potential must agree to use effective contraception for the duration of study participation
Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, or bone marrow failure syndromes are not eligible
Uncontrolled infection. Patients with infections that are controlled on concurrent anti-microbial agents are eligible
Impairment of gastrointestinal (GI) function or GI disease that, in the opinion of the treating physician, may significantly alter the absorption of venetoclax or selinexor
History of cerebellar toxicity or cerebellar neurological findings on exam
Previous toxicity or hypersensitivity directly attributed to venetoclax
