Eltanexor + Inqovi for Myelodysplastic Syndrome
Recruiting in Palo Alto (17 mi)
Overseen bySteven Z Pavletic, M.D.
Age: 18+
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1 & 2
Recruiting
Sponsor: National Cancer Institute (NCI)
Must not be taking: Myeloid growth factors
Disqualifiers: Thrombocytopenia, Neutropenia, Cardiac conditions, others
No Placebo Group
Trial Summary
What is the purpose of this trial?This trial is testing a new drug combination (KPT-8602 and Inqovi) for adults with severe blood disease (high-risk MDS) who haven't improved with standard treatments. Inqovi stops cancer cell growth, while KPT-8602 blocks a protein that helps cancer cells survive.
Will I have to stop taking my current medications?
The trial protocol does not specify if you must stop taking your current medications. However, any prior therapy must be completed more than 4 weeks before starting the trial, except for Inqovi. Please consult with the trial team for specific guidance.
What data supports the effectiveness of the drug Inqovi for treating Myelodysplastic Syndrome?
Inqovi, a combination of decitabine and cedazuridine, has been shown to be effective for treating Myelodysplastic Syndrome (MDS) with clinical studies reporting complete remission rates of 21% and 18% in different trials, and similar effectiveness to intravenous decitabine. The drug was approved by the FDA based on these findings.
12345Is the combination of Eltanexor and Inqovi safe for treating myelodysplastic syndrome?
Inqovi, a combination of decitabine and cedazuridine, has been studied for safety in treating myelodysplastic syndromes. Common serious side effects include low white blood cell counts (neutropenia), low platelet counts (thrombocytopenia), and fever with low white blood cell counts (febrile neutropenia). These side effects are similar to those seen with intravenous decitabine.
13456What makes the drug Eltanexor + Inqovi unique for treating myelodysplastic syndrome?
Eltanexor + Inqovi is unique because it combines an oral fixed-dose of decitabine and cedazuridine, which allows for effective oral administration by preventing the breakdown of decitabine in the body, with Eltanexor, an investigational oral drug that targets nuclear export in cells, offering a novel approach for patients who are resistant to other treatments.
12347Eligibility Criteria
Adults over 18 with high-risk Myelodysplastic Syndromes (MDS) that didn't improve after treatment can join. They need to be fairly active, have good organ function, and not pregnant or breastfeeding. Participants must agree to use birth control and have no recent growth factor treatments or uncontrolled illnesses.Inclusion Criteria
I have high-risk MDS and my previous treatment with HMA didn't work well.
- AST(SGOT)/ALT(SGPT) <= 3 X institutional upper limit of normal OR <= 5 X institutional upper limit of normal if related to MDS-specific cause
My organs and bone marrow work well.
+11 more
Exclusion Criteria
I have not had any other cancer in the last 2 years.
I have active or uncontrolled Hepatitis C.
My low platelet count does not improve with transfusions.
+9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
1 visit (in-person)
Treatment
Participants receive KPT-8602 and Inqovi in 28-day cycles, with Inqovi taken daily on days 1-5 and KPT-8602 on a schedule assigned by the researcher
6 cycles (approximately 6 months)
At least 1 visit per cycle (in-person)
Follow-up
Participants are monitored for safety and effectiveness after treatment
8 years
Follow-up visits at the clinic
Extension
Participants may continue taking the drugs if their disease improves after 6 cycles
Participant Groups
The trial is testing Eltanexor (KPT-8602) combined with Inqovi (Decitabine-Cedazuridine), both oral tablets for MDS. Over at least six 28-day cycles, participants take these drugs at home and visit the clinic regularly for exams and tests like blood work and bone marrow biopsies.
2Treatment groups
Experimental Treatment
Group I: Phase II- Dose expansion for HR-MDSExperimental Treatment2 Interventions
Inqovi for 5 days, followed by RP2D/Phase II dose of KPT-8602
Group II: Phase I- Dose escalation of KPT-8602 for HR-MDSExperimental Treatment2 Interventions
Inqovi for 5 days, followed by escalating doses of KPT-8602
Inqovi is already approved in United States, European Union for the following indications:
🇺🇸 Approved in United States as Inqovi for:
- Myelodysplastic syndromes (MDS)
🇪🇺 Approved in European Union as Inqovi for:
- Myelodysplastic syndromes (MDS)
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
National Institutes of Health Clinical CenterBethesda, MD
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Who Is Running the Clinical Trial?
National Cancer Institute (NCI)Lead Sponsor
References
FDA Approval Summary: Decitabine and Cedazuridine Tablets for Myelodysplastic Syndromes. [2023]On July 7, 2020, the Food and Drug Administration approved Inqovi (Otsuka Pharmaceutical Co.), an oral fixed-dose combination tablet comprising 35 mg decitabine, a hypomethylating agent, and 100 mg cedazuridine, a cytidine deaminase inhibitor (abbreviated DEC-C) for treatment of adult patients with myelodysplastic syndromes (MDS). Evidence of effectiveness of DEC-C was established in phase III ASTX727-02 (N = 133) in adults with MDS. The study involved a two-sequence crossover comparing DEC-C and intravenous (IV) decitabine 20 mg/m2 once daily for the first 5 days of each 28-day cycle in the first 2 cycles. From cycle 3 onward, patients received DEC-C. Five-day cumulative area under the curve (5-d AUC) of decitabine for DEC-C was similar to that of IV decitabine, with geometric mean ratio 0.99 (90% confidence interval: 0.93-1.06). Clinical benefit was supported by study ASTX727-02 and the similarly designed phase II study ASTX727-01-B (n = 80), with complete remission (CR) of 21% and 18% and median duration of CR 7.5 and 8.7 months, respectively. Adverse reactions were consistent with IV decitabine. Postmarketing assessments were issued to address the effect of cedazuridine on QT prolongation, food effect, moderate and severe hepatic impairment, and severe renal impairment on the pharmacokinetics and safety of DEC-C.
Role of cedazuridine/decitabine in the management of myelodysplastic syndrome and chronic myelomonocytic leukemia. [2021]Myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML) are clonal hematopoietic stem cell disorders. Complex disease biology has posed significant challenge to the development of novel therapeutics. Despite myriad clinical trials, none have been superior to azacitidine and decitabine (DEC) therapy. These therapies present a substantial burden for patients with 5 and 7 days of parenteral treatment in an infusion clinic. To overcome this limitation, a fixed drug combination of oral DEC-cedazuridine (C-DEC), a cytidine deaminase inhibitor with documented safety profile was developed. This drug was recently approved by the US FDA, Australian TGA and Health Canada for newly diagnosed or previously treated intermediate or high risk by international prognostic scoring system, MDS and CMML. In this review, we detail the pharmacokinetic and clinical activity of C-DEC in the management of MDS and CMML.
Decitabine/Cedazuridine: First Approval. [2021]A fixed dose oral combination (FDC) of decitabine and cedazuridine (Inqovi®), is being developed by Astex Pharmaceuticals (a subsidiary of Otsuka Pharmaceuticals) for the treatment of various cancers like myelodysplastic syndromes (MDS), chronic myelomonocytic leukaemia (CMML), acute myeloid leukaemia (AML), glioma and solid tumours. Decitabine, a DNA methyltransferase inhibitor approved for the treatment of MDS and CMML, is degraded by cytidine deaminase in the gastrointestinal tract and liver, thereby limiting oral bioavailability. Cedazuridine is a proprietary, patented cytidine deaminase inhibitor that, when added to decitabine, increases oral bioavailability of the drug. In July 2020, decitabine/cedazuridine received its first approval in the USA and Canada for the treatment of MDS and CMML. In the USA, it is indicated for use in adults with MDS and CMML, including previously treated and untreated, de novo and secondary MDS with the following French-American-British subtypes (refractory anaemia, refractory anaemia with ringed sideroblasts, refractory anaemia with excess blasts and CMML) and intermediate-1, intermediate-2 and high-risk International Prognostic Scoring System groups. Clinical studies for AML, glioma and solid tumours are underway in several countries worldwide. This article summarizes the milestones in the development of decitabine/cedazuridine leading to this first approval for the treatment of MDS and CMML.
[New treatment for myelodysplastic syndromes: luspatercept and oral hypomethylating agents]. [2022]Several novel myelodysplastic syndromes (MDS) treatment drugs are being developed, and luspatercept and oral hypomethylating medicines have already been licensed in the United States and other countries. Luspatercept is a ligand trap that inhibits SMAD2/3 signals by combining the extracellular domain of the activin type IIA receptor with the human immunoglobulin G1 Fc domain. In the phase 2 study for low-risk MDS, the hematological improvement-erythroid (HI-E) was found in 63% of patients, and in the phase 3 study for transfusion-dependent low-risk MDS with ring sideroblasts, 38% of patients achieved transfusion independence. A combination of oral decitabine with oral cedazuridine, an inhibitor of cytidine deaminase, which metabolizes decitabine, demonstrated pharmacological equivalence with intravenous decitabine and has overall response rates of 60% and 43% for high-risk MDS in phase 2 and 3 trials, respectively. Furthermore, oral azacitidine and its combination with oral cedazuridine have been under development.
Oral cedazuridine/decitabine for MDS and CMML: a phase 2 pharmacokinetic/pharmacodynamic randomized crossover study. [2021]This phase 2 study was designed to compare systemic decitabine exposure, demethylation activity, and safety in the first 2 cycles with cedazuridine 100 mg/decitabine 35 mg vs standard decitabine 20 mg/m2 IV. Adults with International Prognostic Scoring System intermediate-1/2- or high-risk myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) were randomized 1:1 to receive oral cedazuridine/decitabine or IV decitabine in cycle 1, followed by crossover to the other treatment in cycle 2. All patients received oral cedazuridine/decitabine in subsequent cycles. Cedazuridine and decitabine were given initially as separate capsules in a dose-confirmation stage and then as a single fixed-dose combination (FDC) tablet. Primary end points: mean decitabine systemic exposure (geometric least-squares mean [LSM]) of oral/IV 5-day area under curve from time 0 to last measurable concentration (AUClast), percentage long interspersed nuclear element 1 (LINE-1) DNA demethylation for oral cedazuridine/decitabine vs IV decitabine, and clinical response. Eighty patients were randomized and treated. Oral/IV ratios of geometric LSM 5-day AUClast (80% confidence interval) were 93.5% (82.1-106.5) and 97.6% (80.5-118.3) for the dose-confirmation and FDC stages, respectively. Differences in mean %LINE-1 demethylation between oral and IV were ≤1%. Clinical responses were observed in 48 patients (60%), including 17 (21%) with complete response. The most common grade ≥3 adverse events regardless of causality were neutropenia (46%), thrombocytopenia (38%), and febrile neutropenia (29%). Oral cedazuridine/decitabine (100/35 mg) produced similar systemic decitabine exposure, DNA demethylation, and safety vs decitabine 20 mg/m2 IV in the first 2 cycles, with similar efficacy. This study is registered at www.clinicaltrials.gov as #NCT02103478.
Multicenter study of decitabine administered daily for 5 days every 4 weeks to adults with myelodysplastic syndromes: the alternative dosing for outpatient treatment (ADOPT) trial. [2023]Decitabine, a DNA-targeted hypomethylating agent, is approved by the United States Food and Drug Administration for treatment of patients with myelodysplastic syndromes (MDS) on a schedule of 15 mg/m(2) administered via intravenous (IV) infusion every 8 hours for 3 days. This study assessed the efficacy and safety of an alternative dosing regimen administered on an outpatient basis in academic and community-based practices.
Oral eltanexor treatment of patients with higher-risk myelodysplastic syndrome refractory to hypomethylating agents. [2022]Patients with higher-risk myelodysplastic syndromes (MDS) refractory to hypomethylating agents (HMAs) have limited therapeutic options and an expected overall survival (OS) of 3-5 months. Eltanexor is an investigational oral selective inhibitor of nuclear export with low central nervous system penetrance and an acceptable tolerability profile. Preclinical studies suggest that myeloid malignancies are sensitive to nuclear export inhibition. Eltanexor exhibited efficacy in hematologic models, supporting exploration in a clinical trial. This phase 1/2 study (NCT02649790) assessed single-agent activity of eltanexor in patients with higher-risk MDS and 5-19% myeloblasts. Two starting doses of eltanexor were evaluated: 20 mg (n = 15), 10 mg (n = 5), both administered on days 1-5 each week of a 28-day cycle. Twenty patients with primary HMA-refractory MDS, with a median age of 77 years (range 62-89), and a median of two prior treatment regimens (range 1-4) were enrolled. Of these, 15 were evaluated for efficacy and 20 for safety. The overall response rate (ORR) was 53.3%, with seven patients (46.7%) achieving marrow complete remission (mCR) and one additional patient achieving hematologic improvement (HI). In the 10 mg group, three patients (60%) reached mCR and two (40%) stable disease (SD), while for 20 mg, four patients (40%) had mCR and two (20%) SD. A total of three patients (20%) had HI and became transfusion independent ≥ 8 weeks. Median OS for the efficacy-evaluable patients (n = 15) was 9.86 months (7.98, NE). Overall, the most frequently reported treatment-related adverse events were nausea (45%), diarrhea (35%), decreased appetite (35%), fatigue and neutropenia (both 30%). Single-agent oral eltanexor was active, safe, and well tolerated in patients with higher-risk, primary HMA-refractory MDS.