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 Food and Drug Administration (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,
messenger ribonucleic acid (mRNAs) encoding oncogenes (including cellular
myelocytomatosis oncogene (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 World Health Organization (WHO) criteria, and for both Phase I and II:
- have HR-MDS (Revised International Prognostic Scoring System (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
- Eastern Cooperative Oncology Group (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 National Institutes of Health (NIH) Center with an
enrollment of up to 80 planned participants.
