Background:
- The myelodysplastic syndromes (MDS) are a group of clonal bone marrow neoplasms
characterized by ineffective hematopoiesis, cytopenia, and high risk of
transformation to acute myeloid leukemia (AML).
- The median survival of patients with newly-diagnosed higher-risk MDS (HR-MDS)
according to the Revised International Prognostic Scoring System (IPSS-R) is 1.5
years.
- Hypomethylating agents (HMAs), such as azacitidine and decitabine, are the standard
of care therapy for HR-MDS. However, less than half of patients respond to HMAs, and
even the best responses are transient and non-curative.
- The only curative treatment for patients with MDS is allogeneic hematopoietic stem
cell transplantation (HSCT); however only a small portion are eligible for
transplant.
- More effective therapies are needed for patients with HR-MDS.
- A promising approach for improving HMA efficacy in the treatment of MDS is by
exploiting therapeutic synergism in combinatorial approaches.
- Inqovi (decitabine-cedazuridine) is an oral formulation of decitabine plus cytidine
deaminase inhibitor that was recently FDA-approved for MDS, based on a similar
safety and efficacy profile to decitabine for injection.
- KPT-8602 (eltanexor) is an orally-available, second-generation selective inhibitor
of nuclear export (SINE) that covalently binds to exportin 1 (XPO1).
- XPO1 is a protein that mediates the nuclear export of molecules from the nucleus to
the cytoplasm of the cell. Among affected molecules are tumor suppressor genes,
mRNAs encoding oncogenes (including c-MYC), and newly assembled ribosomal subunits.
- By interfering with c-MYC translation, KPT-8602 may diminish rebound methylation
after decitabine cessation and improve treatment responses in patients with MDS.
- Preliminary reports from a Phase 1/2 trial of KPT-8602 monotherapy in patients with
higher-risk MDS who have failed HMAs show anti-tumor activity and an acceptable
toxicity profile.
- Sequential addition of KPT-8602 to Inqovi may improve treatment responses in
patients with MDS by acting synergistically to inhibit further DNA methylation.
Objective:
- Phase I: To determine the recommended phase 2 dose (RP2D) of KPT-8602 in combination
with Inqovi in adult participants with higher-risk MDS
- Phase II: To determine overall response rate (ORR) of KPT-8602 in combination with
Inqovi in adult participants with higher- risk MDS
Eligibility:
- Participants must have histologically or cytologically confirmed MDS according to
2016 WHO criteria, and for both Phase I and II:
- have HR-MDS (IPSS-R > 3.5) with inadequate response to hypomethylating agent (HMA)
therapy [(received >= 4 cycles of the standard dose (35 mg decitabine and 100 mg
cedazuridine) without prior dose-reductions, with failure to achieve at least a PR
or experienced disease progression prior to completing 4 cycles)
- Age >= 18 years
- ECOG performance status <= 2 (KPS >= 60)
Design:
- Participants with HR-MDS will be enrolled in both Phase I and II.
- Participants will be treated with Inqovi at a fixed dose of 1 tablet (35 mg
decitabine and 100 mg cedazuridine) daily on Days 1-5 of each 28-day cycle, followed
by KPT-8602 at escalating doses (Phase I) or the RP2D (Phase II).
- In Phase I, KPT-8602 will be dose-escalated following a standard 3+3 design, with a
starting dose level of 10 mg for 10 days (staggered) within a cycle. If tolerated,
the dose will be escalated to 14 days per cycle, or dose de-escalated to 5 mg at 14
or 10 days.
- This study will be done at the NIH Clincal Center with an enrollment of up to 80
planned participants.
