What is the mechanism of action of this treatment?

The most common treatments for Myelodysplastic Syndrome (MDS) include hypomethylating agents (HMAs) such as decitabine and azacitidine. These drugs inhibit DNA methyltransferase, leading to the hypomethylation of DNA, which can reactivate tumor suppressor genes and promote the differentiation or apoptosis of abnormal hematopoietic cells. Cedazuridine, often combined with decitabine, inhibits cytidine deaminase, an enzyme that degrades decitabine, thereby increasing its bioavailability and effectiveness. These mechanisms are important for MDS patients as they address the epigenetic abnormalities driving the disease, potentially improving blood counts and reducing the risk of progression to acute myeloid leukemia (AML).

What side effects are associated with this type of intervention?

Common side effects of treatments for Myelodysplastic Syndrome (MDS) that are similar to Inqovi (decitabine and cedazuridine) include hematologic adverse events such as neutropenia, anemia, and thrombocytopenia. Non-hematologic side effects can include febrile neutropenia, infections, fatigue, nausea, and diarrhea. These side effects are typical for hypomethylating agents like decitabine and azacitidine.

What prior FDA approvals exist?

The FDA has approved several hypomethylating agents for the treatment of Myelodysplastic Syndrome (MDS). Azacitidine and decitabine are two primary agents that inhibit DNA methyltransferase, thereby altering gene expression and promoting normal cell differentiation. These agents have shown efficacy in improving survival and response rates in MDS patients. Additionally, lenalidomide has been approved for MDS with deletion 5q cytogenetic abnormality. The combination of decitabine and cedazuridine (Inqovi) is being studied to enhance the bioavailability of decitabine by inhibiting its degradation, potentially offering a more effective oral treatment option for MDS.

What other types of research exist?

Promising novel alternatives to Inqovi for MDS patients include venetoclax combined with hypomethylating agents (HMAs) like azacitidine or decitabine, and gilteritinib combined with azacitidine. Venetoclax has shown superior survival and response rates when combined with HMAs, while gilteritinib has demonstrated higher overall response rates in combination with azacitidine.

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Inqovi Maintenance Therapy for Myelodysplastic Syndrome and Chronic Myelomonocytic Leukemia

Phase 1

Recruiting

Led By Zachariah DeFilipp, MD

Research Sponsored by Massachusetts General Hospital

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Participants must have normal organ and function as defined below: AST (SGOT), ALT (SGPT) and Alkaline phosphatase < 3x institutional upper limit of normal (ULN), Total bilirubin < 1.5 x ULN (with the exception of subjects with a history of Gilbert's syndrome), Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula), LVEF must be equal to or greater than 50%, as measured by MUGA scan or echocardiogram, Female patients of childbearing potential must have a negative pregnancy test, as measured by serum or urine testing, The effects of decitabine/cedazuridine on the developing human fetus are unknown. For this reason women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) during the entire study treatment period and through 6 months after the last dose of treatment, Ability to understand and the willingness to sign a written informed consent document

Eligibility Criteria Prior to Treatment (Post HCT): Maintenance therapy may begin at any time between day 30 and day 120 following hematopoietic cell transplantation. Participants must meet the following criteria to be eligible to treatment on this study: Chimerism studies reveal that ≥ 70% of blood or bone marrow cells, or of the CD33 expressing fraction, are of donor origin, There is no acute graft versus host disease (GVHD), requiring an escalation of corticosteroid dose or addition of other agent in the 4 weeks prior to Cycle 1 Day 1, There is no morphological evidence of relapsed/recurrent/residual disease (as assessed by post HCT bone marrow biopsy and aspirate), There is no systemic infection requiring IV antibiotic or antifungal or antiviral therapy within 7 days of starting decitabine/cedazuridine, ANC ≥ 1000/µL, Platelets ≥ 50,000/µL, AST (SGOT), ALT (SGPT) and Alkaline phosphatase < 3x institutional upper limit of normal (ULN), Total bilirubin < 1.5 x ULN (with the exception of subjects with a history of Gilbert's syndrome), Calculated creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula)

Must not have

Systemic uncontrolled infection

Known diagnosis of active hepatitis B or hepatitis C

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years

Awards & highlights

All Individual Drugs Already Approved

No Placebo-Only Group

Summary

This trial is testing Inqovi, a drug that combines decitabine and cedazuridine, to see if it can prevent relapse in patients with MDS or CMML after a stem cell transplant. Decitabine stops cancer cells from growing, and cedazuridine helps decitabine stay effective longer. The study aims to find the safest dose for these patients. Decitabine has shown effectiveness in various blood-related cancers.

Who is the study for?

This trial is for adults with myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML) who are undergoing their first stem cell transplant. They must have a matched donor, good organ function, and no severe heart issues or infections. Women of childbearing age need a negative pregnancy test and agree to use birth control.

What is being tested?

The trial tests Inqovi as maintenance therapy post-stem cell transplant to prevent MDS/CMML relapse. Inqovi combines decitabine and cedazuridine, aiming to reduce the chance of disease returning after standard treatment.

What are the potential side effects?

Inqovi may cause side effects like nausea, vomiting, diarrhea, constipation, fatigue, joint pain, low blood counts leading to increased infection risk or bleeding problems. It can also affect liver enzymes.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am scheduled for my first stem cell transplant from a donor.

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My bone marrow transplant donor matches me closely.

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I am able to care for myself and perform daily activities.

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My latest bone marrow test shows less than 5% myeloblasts.

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I have been diagnosed with MDS or CMML.

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I am 18 years old or older.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I do not have any untreated infections.

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I have an active hepatitis B or C infection.

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I do not have severe heart failure or a history of poor heart function.

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I have had a stem cell transplant from a donor.

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I have a condition that affects my ability to swallow or absorb pills.

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I have or had serious heart rhythm problems or long-QT syndrome.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Recommended Phase 2 Schedule Dose

Secondary study objectives

Cumulative incidence of acute GVHD

Cumulative incidence of significant chronic GVHD

Median number of days of Inqovi tolerated

+3 more

Side effects data

From 2022 Phase 2 trial • 14 Patients • NCT04055844

57%

Febrile neutropenia

57%

Neutrophil count decreased

21%

Sepsis

21%

Infections and infestations - Other, specify

21%

Lung infection

21%

Bacteremia

14%

Alanine aminotransferase increased

14%

Aspartate aminotransferase increased

14%

Infections and infestations - Other,

Pericardial effusion

INR increased

Intracranial hemorrhage

Sinusitis

Blood and lymphatic system

Upper gastrointestinal

Tooth infection

Hepatic infection

Blood and lymphatic system disorders - Other, specify

Typhlitis

Alanine aminotransferase

Fatigue

General disorders and administration

Disease progression

General disorders and administration site conditions - Other, specify

Syncope

Hepatobiliary disorders

Skin and subcutaneous tissue disorders - Other, specify

Gastrointestinal disorders - Other,

Injury, poisoning and procedural

Neoplasms benign, malignant and

Hypertension

White blood cell decreased

Mucositis oral

Upper gastrointestinal hemorrhage

Fever

Encephalopathy

Hepatic failure

Hyperglycemia

Gastrointestinal disorders - Other, specify

100%

80%

60%

40%

20%

Study treatment Arm

Decitabine + Ruxolitinib + DLI

Awards & Highlights

All Individual Drugs Already Approved

Therapies where all constituent drugs have already been approved are likely to have better-understood side effect profiles.

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

2Treatment groups

Experimental Treatment

Group I: Recommended Phase 2 Dose Expansion (RP2S) InqoviExperimental Treatment1 Intervention

Once the Recommended Phase 2 Dose Expansion (RP2S) is established, 10 additional participants will be enrolled and receive Inqovi (decitabine/cedazuridine) on days 1-3 of a 28 day study cycle.

Group II: Dose Escalation InqoviExperimental Treatment1 Intervention

Study will follow a standard '3+3' dose escalation design: * Initial group of 3 participants will receive Inqovi (decitabine/cedazuridine) on days 1-3 of a 42 day cycle/dose-limiting toxicity (DLT) period. * Additional enrollment, dosage and study cyles will be determined by number of dose-limiting toxicity (DLT) that occur in initial group

0 / 14Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Myelodysplastic Syndrome (MDS) include hypomethylating agents (HMAs) such as decitabine and azacitidine. These drugs inhibit DNA methyltransferase, leading to the hypomethylation of DNA, which can reactivate tumor suppressor genes and promote the differentiation or apoptosis of abnormal hematopoietic cells. Cedazuridine, often combined with decitabine, inhibits cytidine deaminase, an enzyme that degrades decitabine, thereby increasing its bioavailability and effectiveness. These mechanisms are important for MDS patients as they address the epigenetic abnormalities driving the disease, potentially improving blood counts and reducing the risk of progression to acute myeloid leukemia (AML).