What side effects are associated with this type of intervention?

Common treatments for Myelofibrosis include JAK inhibitors like Ruxolitinib and investigational agents such as MDM2 inhibitors like KRT-232. Ruxolitinib is associated with side effects including anemia, thrombocytopenia, and increased risk of infections. Other adverse events may include fatigue, dizziness, and elevated liver enzymes. MDM2 inhibitors, while still under investigation, may cause gastrointestinal disturbances, hematologic toxicities, and fatigue. Combining these treatments could potentially amplify these side effects, necessitating careful monitoring and dose adjustments.

What prior FDA approvals exist?

Ruxolitinib, a JAK1/2 inhibitor, was the first FDA-approved drug for the treatment of Myelofibrosis, demonstrating efficacy in reducing splenomegaly and symptom burden. Another JAK inhibitor, Fedratinib, was later approved for similar indications, showing effectiveness in reducing spleen volume and improving symptoms. Both drugs have been pivotal in managing Myelofibrosis, particularly in patients with higher risk or those who have not responded adequately to other treatments. The combination of KRT-232 (MDM2 Inhibitor) with Ruxolitinib is currently under investigation to potentially enhance therapeutic outcomes by targeting different pathways involved in the disease.

What other types of research exist?

Promising alternatives to KRT-232 combined with Ruxolitinib for Myelofibrosis patients include: 1) Fedratinib, another JAK2 inhibitor, which has shown efficacy in patients with MF, including those resistant to Ruxolitinib. 2) Navitoclax, a BCL2 inhibitor, which is being studied in combination with Ruxolitinib and has shown potential in improving outcomes for MF patients. 3) Luspatercept, an erythroid maturation agent, which may be beneficial for managing anemia associated with MF. These alternatives are based on their mechanisms of action and clinical trial results.

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MDM2 Inhibitor

KRT-232 + Ruxolitinib for Myelofibrosis

Phase 1 & 2

Waitlist Available

Research Sponsored by Kartos Therapeutics, Inc.

Eligibility Criteria Checklist

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

Must have

Spleen ≥5 cm palpable below the LLCM or ≥450 cm3 by MRI or CT

Patients must have at least 2 symptoms with a score of at least 1 on the MFSAF v4.0

Must not have

Prior splenectomy

Patients who are positive for TP53 mutations

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 43 months

Awards & highlights

No Placebo-Only Group

Summary

This trial is testing a new drug, KRT-232, combined with an existing drug, ruxolitinib, for patients with Myelofibrosis who haven't responded well to ruxolitinib alone. Ruxolitinib is known for reducing spleen size and alleviating symptoms. The goal is to find the best dose for this combination. Researchers hope that KRT-232 will help ruxolitinib work better.

Who is the study for?

This trial is for patients with Primary Myelofibrosis, Post-Polycythemia Vera MF, or Post-Essential Thrombocythemia MF who haven't had the best results from Ruxolitinib. They should have been on Ruxolitinib for at least 18 weeks and be stable on it for the last 8 weeks. Their spleen must be enlarged and they need to have certain symptoms related to their condition.

What is being tested?

The study tests KRT-232 combined with Ruxolitinib in patients whose Myelofibrosis hasn't responded well enough to just Ruxolitinib. The goal is to find a safe and effective dose of KRT-232 that works alongside Ruxolitinib.

What are the potential side effects?

Possible side effects include issues like nausea, vomiting, diarrhea, fatigue, changes in blood counts leading to increased risk of infections or bleeding problems, liver function abnormalities, and potential skin reactions.

Eligibility Criteria

Inclusion Criteria

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

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My spleen is enlarged, measuring over 5 cm below the ribcage or over 450 cm3 on imaging.

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I have at least 2 symptoms that affect my daily life.

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I can care for myself and am up and about more than half of my waking hours.

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I have been diagnosed with a form of myelofibrosis according to WHO standards.

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I have been on ruxolitinib for at least 18 weeks and my dose has not changed in the last 8 weeks.

Exclusion Criteria

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

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I have had my spleen removed.

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My cancer has a TP53 mutation.

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My condition worsened while on ruxolitinib treatment.

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I have previously received MDM2 or p53-targeted therapy.

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My spleen size reduced after taking ruxolitinib.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 43 months

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~43 months

This trial's timeline: 3 weeks for screening, Varies for treatment, and 43 months for reporting.

Treatment Details

Study Objectives

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

Primary study objectives

For Phase 1: To determine the KRT-232 RP2D in combination with ruxolitinib

For Phase 2:To determine the spleen volume reduction (SVR) at Week 24

Secondary study objectives

To determine spleen response

To determine the change in Total Symptom Score (TSS) based Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0)

Awards & Highlights

No Placebo-Only Group

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

Trial Design

1Treatment groups

Experimental Treatment

Group I: Part A, Arm 1, Cohort 1Experimental Treatment2 Interventions

KRT-232 by mouth once daily for Days 1-7, off treatment for Days 8-28 (28 day cycle)

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Ruxolitinib

2018

Completed Phase 3

~1170

0 / 10Eligibility 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 Myelofibrosis include JAK inhibitors like Ruxolitinib and MDM2 inhibitors like KRT-232. Ruxolitinib works by inhibiting the JAK1 and JAK2 enzymes, which are part of the signaling pathway that regulates blood cell production and immune function. This helps reduce spleen size and alleviate symptoms such as fatigue and night sweats. KRT-232, an MDM2 inhibitor, works by reactivating the p53 tumor suppressor pathway, leading to the death of malignant cells. Combining these treatments can potentially enhance their efficacy, offering better disease control and symptom relief for MF patients who have a suboptimal response to Ruxolitinib alone.