Selinexor, Fludarabine Phosphate, and Cytarabine in Treating Younger Patients with Refractory or Relapsed Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, or Myelodysplastic Syndromes
- Phase I (completed): Participants must have a diagnosis of AML, MDS, ALL or MPAL and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic stem cell transplantation (HSCT) * Refractory disease is defined as persistent disease after at least two courses of induction chemotherapy * Patients with AML, MPAL or MDS are eligible at first or subsequent relapse, whereas patients with ALL are eligible at second or subsequent relapse or any relapse that is refractory to salvage chemotherapy * Patients with AML or ALL must have >= 5% leukemic blasts in the bone marrow or increasing levels of MRD in the bone marrow as assessed by flow cytometry; if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood
- Phase II: Participants must have a diagnosis of AML and must have disease that has relapsed or is refractory to chemotherapy, or that has relapsed after hematopoietic stem cell transplantation (HSCT) * Refractory disease is defined as persistent disease after at least two courses of induction chemotherapy * Patients are eligible at first or subsequent relapse or any relapse that is refractory to salvage chemotherapy
- Patients must have >= 5% leukemic blasts in the bone marrow and/or increasing levels of MRD in the bone marrow as assessed by flow cytometry; if an adequate bone marrow sample cannot be obtained, patients may be enrolled if there is unequivocal evidence of leukemia in the peripheral blood
- Direct bilirubin =< 1.5 x institutional upper limit of normal (IULN)
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) < 3 x IULN
- Creatinine within normal institutional limits for age
- Prothrombin time (PT) and partial thromboplastin (PTT) =< 1.5 x IULN
- Patients treated at collaborating sites and current St. Jude patients who are on therapy or within 3 years of completion of therapy must be =< 24 years old; all other St. Jude patients must be =< 21 years old
- Patients must be able to swallow tablets
- Performance status: Lansky >= 50 for patients who are =< 16 years old and Karnofsky >= 50% for patients who are > 16 years old
- Patients must have fully recovered from the acute effects of all prior therapy
- For patients who have received prior HSCT, there can be no evidence of graft versus host disease (GVHD) and greater than 60 days must have elapsed since the HSCT
- History of cerebellar toxicity or cerebellar neurological findings on exam
- Must not be pregnant or breastfeeding; female patients who are sexually active and of child-bearing potential must agree to use dual methods of contraception and have a negative serum pregnancy test at screening, and male patients must use an effective barrier method of contraception if sexually active with a female of child-bearing potential; acceptable methods of contraception are condoms with contraceptive foam, oral, implantable or injectable contraceptives, contraceptive patch, intrauterine device, diaphragm with spermicidal gel, or a sexual partner who is surgically sterilized or post-menopausal; for both male and female patients who are sexually active, effective methods of contraception must be used throughout the study and for three months following the last dose; abstinence is an acceptable form of contraception
- Patients with Down syndrome, acute promyelocytic leukemia, juvenile myelomonocytic leukemia, Fanconi anemia, Kostmann syndrome, Shwachman syndrome, or other bone marrow failure syndromes are not eligible
- Use of investigational agents, with the exception of gemtuzumab ozogamicin, within 30 days
- Any significant concurrent disease, illness, or psychiatric disorder that would compromise patient safety or compliance, study participation, follow up, or interpretation of study research
- Unstable cardiovascular function: * Symptomatic ischemia * Congestive heart failure New York Heart Association (NYHA) class > 3 * Myocardial infarction (MI) within 3 months
- Uncontrolled infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to first dose; infections controlled on concurrent anti-microbial agents are acceptable, and anti-microbial prophylaxis per institutional guidelines are acceptable
- Known human immunodeficiency virus (HIV) infection (pre-study testing not required)
- Patients with malabsorption syndrome, or any other disease significantly affecting gastrointestinal function
- Prior treatment with selinexor
I. To determine a tolerable combination of selinexor, fludarabine phosphate (fludarabine), and cytarabine in pediatric patients with relapsed or refractory hematologic malignancies including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), mixed phenotype acute leukemia (MPAL), and myelodysplastic syndrome (MDS) in the phase I portion of this study. (COMPLETED)
II. To estimate the overall response rate, as defined by complete response or complete response with incomplete count recovery, of selinexor in combination with fludarabine and cytarabine for patients with relapsed or refractory AML in the phase II portion of the study.
I. To characterize the pharmacokinetics of selinexor, when administered in tablet form, after the first dose and at steady-state, as well as in combination with fludarabine and cytarabine.
I. To characterize the pharmacodynamic and biological effects of selinexor and to search for biological predictors of response.
OUTLINE: This is a phase I (COMPLETED), dose-escalation study of selinexor followed by a phase II study.
Patients receive selinexor orally (PO) on days 1, 3, 8, 10, 22, and 24. Patients also receive fludarabine phosphate intravenously (IV) over 30 minutes and cytarabine IV over 4 hours on days 16-20. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Patients achieving complete response (CR) or complete remission with incomplete blood count recovery (CRi) on day 15 may proceed directly to hematopoietic stem cell transplant (HSCT) at the discretion of the treating physician. Patients achieving CR or CRi with negative minimal residual disease (MRD) or with MRD that has decreased at day 15 of course 1 may continue to receive selinexor PO alone on days 1, 3, 8, 10, 15, 17, 22, and 24. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for 4 weeks.
Trial Phase Phase I/II
Trial Type Treatment
Saint Jude Children's Research Hospital
Jeffrey E. Rubnitz
- Primary ID SELHEM
- Secondary IDs NCI-2014-01704
- Clinicaltrials.gov ID NCT03071276