Study of the Safety and Efficacy of KRT-232 Combined with Ruxolitinib in Patients with Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (Post–PV-MF), Or Post–Essential Thrombocythemia MF (Post-ET-MF) Who Have a Suboptimal Response to Ruxolitinib

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Kartos Therapeutics Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

4 Dec 2020 → ongoing

Decision date (initial)

2024-11-14

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

External identifiers

EU CT number

2024-514468-26-00

EudraCT number

2019-004554-29

WHO UTN

U1111-1308-4860

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Dose response, Pharmacodynamic, Therapy, Pharmacokinetic

- To determine the navtemadlin RP2D in combination with ruxolitinib

- To determine the spleen volume reduction (SVR) at Week 24

Secondary objectives 11

1. To determine spleen response
2. To determine the change in Total Symptom Score (TSS) based on Myelofibrosis Symptom Assessment Form version 4.0 (MFSAF v4.0)
3. To determine the duration of spleen response (DoR-spleen)
4. To determine spleen size reduction as measured by palpation
5. To determine red blood cell (RBC) transfusion usage
6. To determine the clinical response rate: complete response (CR) and partial response (PR)
7. To determine the overall survival (OS) rate
8. To determine progression-free survival (PFS)
9. To determine the leukemia-free survival rate
10. To determine the safety and tolerability of navtemadlin
11. To monitor the PK of navtemadlin, navtemadlin glucuronide and ruxolitinib

Conditions and MedDRA coding

Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (Post–PV-MF), Or Post–Essential Thrombocythemia MF (Post-ET-MF)

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 10

1. Adults >18 years of age.
2. Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF, as assessed by treating physician according to the World Health Organization (WHO) criteria.
3. Treatment with ruxolitinib for ≥ 18 weeks prior to study entry, and on a stable dose of ruxolitinib in the 8 weeks prior to Sponsor approval of the enrollment form.
4. Spleen ≥ 5 cm palpable below the LLCM or ≥450 cm3 by MRI or CT
5. Patients must have at least 2 symptoms with a score of at least 1 on the MFSAF v4.0
6. An MRI or CT scan for spleen volume must be performed no more than 14 days prior to the first dose of navtemadlin.
7. ECOG performance status of 0 to 2.
8. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of navtemadlin).
9. Female subjects of childbearing potential and their male partners, or male subjects who have female partners of childbearing potential must both use an effective contraception method during the study. In addition, after the last dose of study drug, female subjects must continue to use contraception for 1 month and 1 week and male subjects must continue to use contraception for 3 months and 1 week.
10. For full list please refer to the Protocol

Exclusion criteria 18

1. Patients who are positive for TP53 mutations.
2. Documented disease progression or clinical deterioration any time while on ruxolitinib treatment.
3. Patients who have had a documented spleen response to ruxolitinib.
4. Participation in another interventional clinical trial within the past 4 weeks of the first dose of navtemadlin (participation in observational studies is permitted).
5. Other JAK inhibitors, except for ruxolitinib treatment; other recent/concurrent treatment such as a major surgery, chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, or investigational therapy within 4 weeks or approximately 5 half-lives before the first dose of navtemadlin, whichever is shorter. Hydroxyurea is permitted up until the day prior to study Day 1 of study treatment with navtemadlin.
6. Prior splenectomy.
7. Splenic irradiation within 3 months prior to the first dose of navtemadlin.
8. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation
9. Prior MDM2 inhibitor therapy or p53-directed therapy
10. Women who are pregnant or breastfeeding
11. History of major organ transplant
12. Subjects must be negative for HIV-1 antibody, negative for HbsAg, negative for Hepatitis B core antibody, and negative for viral RNA if HCV antibody is positive. Subjects must be negative for Hepatitis B DNA, if either HbsAg or Hepatitis B core antibody is positive.
13. Active serious viral, mycobacterial, parasitic, fungal, and bacterial infections, including acute hepatitis A, herpes zoster, and progressive multifocal leukoencephalopathy (PML). Active serious infections must be resolved before screening/enrollment. Subjects with acute infections requiring systemic antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
14. Patients with uncontrolled intercurrent illness including, but not limited to; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular arrhythmia; or patients with psychiatric illness/social situations that would limit compliance with study requirements; or patients who have been committed to an institution by judicial or administrative authority.
15. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma.
16. Grade 2 or higher QTc prolongation (>480 milliseconds per NCICTCAE criteria, version 5.0).
17. Active or chronic bleeding within 4 weeks prior to the first dose of navtemadlin.
18. For full list please refer to the Protocol.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. - DLTs will be used to establish the MTD of navtemadlin in combination with ruxolitinib. The SRC will determine the RP2D based on safety and efficacy data of the combination of navtemadlin and ruxolitinib. - The proportion of subjects achieving SVR of ≥ 35% at Week 24 by MRI/CT scan (central review)

Secondary endpoints 11

1. The proportion of subjects achieving ≥ 35% SVR at any time point from Baseline while on study, as assessed by MRI (or by CT scan for applicable subjects).
2. The percentage change in TSS as measured by the MFSAF v4.0 at any time point from Baseline while on study.
3. Duration of a ≥ 35% reduction in SVR from Baseline as measured by MRI (or by CT scan for applicable subjects).
4. Reduction in spleen size from Baseline to each visit at which spleen is palpated, including the proportion of subjects who have a ≥ 50% decrease in spleen size
5. Red blood cell (RBC) transfusion usage: • Rate of RBC transfusion usage (average number of RBC units per patient-month) • Rate of change from RBC transfusion dependent to transfusion independent
6. The proportion of subjects with CR and PR at any time point, from Baseline while on study, defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment(IWG-MRT) and modified European Leukemia Net (ELN) criteria
7. OS is defined as the interval from randomization to death from any cause
8. PFS is the interval from Cycle 1 Day 1 to: • Disease progression (≥ 25% increase in spleen volume) or • Leukemic transformation (bone marrow blasts ≥20% or peripheral blood blasts ≥ 20% associated with an absolute blast count of at least 1 x 109/L that lasts for at least 2 weeks) or • Death from any cause
9. Leukemia-free survival is defined as the interval from Cycle 1 Day 1 to the date of first documented transformation to leukemia (bone marrow blasts ≥20% or peripheral blood blasts ≥20% associated with an absolute blast count of at least 1 x 109/L that lasts for at least 2 weeks).
10. Analyses of the safety endpoints will include the following measurements or assessments: physical examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), electrocardiograms (ECGs), and vital signs
11. Navtemadlin, acyl glucuronide metabolite (M1) and ruxolitinib PK parameters will be determined, including but not limited to: • Maximum observed concentration (Cmax) • Minimum observed concentration (Cmin) • Area under the plasma concentration-time curve (AUC) • Time of maximum plasma concentration

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 8

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Kartos Therapeutics Inc.

Sponsor organisation

Kartos Therapeutics Inc.

Address

275 Shoreline Drive Suite 300

City

Redwood City

Postcode

94065-1490

Country

United States

Scientific contact point

Organisation

Kartos Therapeutics Inc.

Contact name

Clinical Operations- John Mei

Public contact point

Organisation

Kartos Therapeutics Inc.

Contact name

Clinical Operations- John Mei

Third parties 15

Locations

2 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 17 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

4 submissions — initial application plus substantial / non-substantial modifications