Selinexor Combination Therapy for Acute Myeloid Leukemia
Recruiting in Palo Alto (17 mi)
+1 other location
Overseen byTimothy Pardee
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 2
Recruiting
Sponsor: Wake Forest University Health Sciences
Disqualifiers: Secondary AML, Active malignancy, CNS involvement, HIV, others
No Placebo Group
Prior Safety Data
Breakthrough Therapy
Trial Summary
What is the purpose of this trial?This pilot phase II trial studies how well selinexor works when given together with induction, consolidation, and maintenance therapy in treating older patients with acute myeloid leukemia. Selinexor may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as cytarabine and daunorubicin hydrochloride, 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. Selinexor with induction, consolidation, and maintenance therapy may kill more cancer cells in older patients with acute myeloid leukemia.
Do I need to stop my current medications to join the trial?
The trial does not specify if you need to stop taking your current medications. However, it allows the use of hydroxyurea, cytarabine, or ATRA before starting the trial treatment.
What data supports the effectiveness of the drug Selinexor in combination therapy for Acute Myeloid Leukemia?
Selinexor has shown promising activity in patients with acute myeloid leukemia (AML) both as a single agent and in combination with other treatments. In a phase 1 study, 43% of patients with relapsed or refractory AML responded to a combination of selinexor with other chemotherapy drugs, with some achieving complete remission. Additionally, selinexor has demonstrated anti-leukemia effects in preclinical studies, particularly when combined with other targeted therapies.
12345Is Selinexor combination therapy safe for humans?
Selinexor has been studied in patients with acute myeloid leukemia and has shown some safety concerns. Common side effects include low blood cell counts, fatigue, and low sodium levels, but these were generally manageable with care. No dose-limiting toxicities were reported, suggesting it is generally safe when used as a single agent or in combination with other treatments.
12345What makes the drug selinexor unique for treating acute myeloid leukemia?
Selinexor is unique because it is a first-in-class drug that works by blocking a protein called exportin 1, which helps cancer cells survive. This drug is used in combination with other treatments like cytarabine and daunorubicin to enhance its effectiveness against acute myeloid leukemia.
12346Eligibility Criteria
This trial is for adults over 18 with newly diagnosed Acute Myeloid Leukemia (non-APL) who haven't had AML treatment, except Hydrea and ATRA. It's not for those with certain genetic abnormalities or previous cancer treatments, HIV, hepatitis, CNS involvement, or other serious health issues. Participants must be physically able to undergo therapy and willing to use effective contraception.Inclusion Criteria
I have a new diagnosis of Acute Myeloid Leukemia and haven't started treatment, except possibly Hydrea or ATRA.
I am taking hydroxyurea or cytarabine for leukocytosis without severe side effects.
Ability to understand and the willingness to sign an IRB-approved informed consent document.
+7 more
Exclusion Criteria
Psychiatric illness/social situations that would limit compliance with study requirements.
I cannot swallow pills or have a condition affecting how my body absorbs medication.
I have another cancer that needs treatment, not including skin cancer.
+10 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Induction Therapy
Patients receive cytarabine IV on days 1-7, daunorubicin hydrochloride IV on days 1-3, and selinexor PO twice weekly from day 1. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
2 weeks
Re-Induction Therapy
Patients whose disease has not responded receive cytarabine IV on days 1-5, daunorubicin hydrochloride IV on days 1-2, and selinexor PO twice weekly. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
2 weeks
Consolidation Therapy
Patients in remission receive cytarabine IV every 12 hours on days 1-3, and selinexor PO twice weekly from day 1. Treatment repeats every 42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Up to 18 weeks
Follow-up
Participants are monitored for safety and effectiveness after treatment
Up to 1 year
Participant Groups
The trial tests Selinexor combined with chemotherapy drugs cytarabine and daunorubicin hydrochloride in older patients. The goal is to see if this mix can better kill leukemia cells by blocking enzymes needed for cell growth while stopping the cells from dividing or spreading.
2Treatment groups
Experimental Treatment
Active Control
Group I: Arm 2 (Selinexor) cytarabine, daunorubicin and selinexorExperimental Treatment3 Interventions
INDUCTION: Cytarabine IV on days 1-7, daunorubicin hydrochloride IV on days 1-3, and selinexor PO twice weekly from day 1. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
RE-INDUCTION: Disease has not responded receive cytarabine IV on days 1-5, daunorubicin hydrochloride IV on days 1-2, and selinexor PO twice weekly. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: In remission receive cytarabine IV every 12 hours for a total 6 doses days 1-3, and selinexor PO twice weekly from day 1. Treatment repeats every 42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Group II: Standard of Care - Cytarabine and daunorubicinActive Control2 Interventions
INDUCTION: Cytarabine IV on days 1-7, daunorubicin hydrochloride IV on days 1-3. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
RE-INDUCTION: Disease has not responded receive cytarabine IV on days 1-5, daunorubicin hydrochloride IV on days 1-2. Treatment continues for 14 days in the absence of disease progression or unacceptable toxicity.
CONSOLIDATION: In remission receive cytarabine IV every 12 hours for a total 6 doses days 1-3. Treatment repeats every 42 days for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Cytarabine is already approved in United States, European Union, Canada for the following indications:
🇺🇸 Approved in United States as Cytosar-U for:
- Acute myeloid leukemia
- Acute lymphocytic leukemia
- Chronic myeloid leukemia
- Meningeal leukemia
🇪🇺 Approved in European Union as Depocyt for:
- Lymphomatous meningitis
🇨🇦 Approved in Canada as Cytosar-U for:
- Acute myeloid leukemia
- Acute lymphocytic leukemia
- Chronic myeloid leukemia
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Virginia Commonwealth University Massey Cancer CenterRichmond, VA
Comprehensive Cancer Center of Wake Forest UniversityWinston-Salem, NC
Loading ...
Who Is Running the Clinical Trial?
Wake Forest University Health SciencesLead Sponsor
National Cancer Institute (NCI)Collaborator
References
A 2:1 randomized, open-label, phase II study of selinexor vs. physician's choice in older patients with relapsed or refractory acute myeloid leukemia. [2022]Selinexor, a selective inhibitor of nuclear export, has demonstrated promising activity in patients with acute myeloid leukemia (AML). This randomized, phase II study evaluated selinexor 60 mg twice weekly (n = 118) vs. physician's choice (PC) treatment (n = 57) in patients aged ≥60 years with relapsed/refractory (R/R) AML. The primary outcome was overall survival (OS). Median OS did not differ significantly for selinexor vs. PC (3.2 vs. 5.6 months; HR = 1.18 [95% CI: 0.79-1.75]; p = 0.422). Complete remission (CR) plus CR with incomplete hematologic recovery trending in favor of selinexor occurred in a minority of patients. Selinexor treated patients had an increased incidence of adverse events. The most common grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anemia, hyponatremia. Despite well-balanced baseline characteristics, there were numerically higher rates of TP53 mutations, prior myelodysplastic syndrome, and lower absolute neutrophil counts in the selinexor group; warranting further investigation of selinexor in more carefully stratified R/R AML patients.Registered trial: NCT02088541.
A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia. [2022]Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents.
Phase 1 study of selinexor in combination with salvage chemotherapy in Adults with relapsed or refractory Acute myeloid leukemia. [2023]Selinexor, an oral inhibitor of the nuclear transport protein Exportin-1, shows promising single-agent activity in clinical trials of relapsed/refractory (R/R) acute myeloid leukemia (AML) and preclinical synergy with topoisomerase (topo) IIα inhibitors. We conducted a phase 1, dose-escalation study of selinexor with mitoxantrone, etoposide, and cytarabine (MEC) in 23 patients aged < 60 years with R/R AML. Due to dose-limiting hyponatremia in 2 patients on dose level 2 (selinexor 40 mg/m2), the maximum tolerated dose was 30 mg/m2. The most common grade ≥ 3 treatment-related non-hematologic toxicities were febrile neutropenia, catheter-related infections, diarrhea, hyponatremia, and sepsis. The overall response rate was 43% with 6 patients (26%) achieving complete remission (CR), 2 (9%) with CR with incomplete count recovery, and 2 (9%) with a morphologic leukemia-free state. Seven of 10 responders proceeded to allogeneic stem cell transplantation. The combination of selinexor with MEC is a feasibile treatment option for patients with R/R AML.
A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia. [2021]Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.
Combinatorial targeting of XPO1 and FLT3 exerts synergistic anti-leukemia effects through induction of differentiation and apoptosis in FLT3-mutated acute myeloid leukemias: from concept to clinical trial. [2023]Targeted therapies against FLT3-mutated acute myeloid leukemias have shown limited clinical efficacy primarily because of the acquisition of secondary mutations in FLT3 and persistent activation of downstream pro-survival pathways such as MEK/ERK, PI3K/AKT, and STAT5. Activation of these additional kinases may also result in phosphorylation of tumor suppressor proteins promoting their nuclear export. Thus, co-targeting nuclear export proteins (e.g., XPO1) and FLT3 concomitantly may be therapeutically effective. Here we report on the combinatorial inhibition of XPO1 using selinexor and FLT3 using sorafenib. Selinexor exerted marked cell killing of human and murine FLT3-mutant acute myeloid leukemia cells, including those harboring internal tandem duplication and/or tyrosine kinase domain point mutations. Interestingly, selinexor treatment of murine FLT3-mutant acute myeloid leukemia cells activated FLT3 and its downstream MAPK or AKT signaling pathways. When combined with sorafenib, selinexor triggered marked synergistic pro-apoptotic effects. This was preceded by elevated nuclear levels of ERK, AKT, NFκB, and FOXO3a. Five days of in vitro combination treatment using low doses (i.e., 5 to 10 nM) of each agent promoted early myeloid differentiation of MOLM13 and MOLM14 cells without noticeable cell killing. The combinatorial therapy demonstrated profound in vivo anti-leukemia efficacy in a human FLT3-mutated xenograft model. In an ongoing phase IB clinical trial the selinexor/sorafenib combination induced complete/partial remissions in six of 14 patients with refractory acute myeloid leukemia, who had received a median of three prior therapies (ClinicalTrials.gov: NCT02530476). These results provide pre-clinical and clinical evidence for an effective combinatorial treatment strategy targeting XPO1 and FLT3 in FLT3- mutated acute myeloid leukemias.
Selinexor in combination with decitabine in patients with acute myeloid leukemia: results from a phase 1 study. [2021]Current treatment options for older and relapsed or refractory (R/R) acute myeloid leukemia (AML) patients are limited and represent an unmet need. Based on preclinical studies showing strong anti-leukemic effects in vivo, this phase I dose-escalation study assessed the safety and preliminary clinical activity of the oral exportin-1 inhibitor, selinexor, in combination with the hypomethylating agent, decitabine 20 mg/m2, in adults with R/R AML and in older (age ≥ 60) untreated AML patients. There were no protocol-defined dose limiting toxicities. The recommended phase 2 dose of selinexor was 60 mg (∼35 mg/m2) given twice-weekly. Notable grade ≥3 toxicities included asymptomatic hyponatremia (68%), febrile neutropenia (44%), sepsis (44%), hypophosphatemia (36%), and pneumonia (28%). In 25 patients, the overall response rate was 40%. Modification of selinexor to a flat dose of 60 mg, twice-weekly for two weeks after decitabine, improved tolerability of the regimen and demonstrated preliminary clinical activity in poor-risk patients with AML.