NAVTEMADLIN for Primary myelofibrosis | Post-polycythemia vera myelofibrosis | Post-essential thrombocythemia myelofibrosis

Inclusion criteria

• {"criterion_text":"- Adults >18 years of age."}
• {"criterion_text":"- For full list please refer to the Protocol"}
• {"criterion_text":"- Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF, as assessed by treating physician according to the World Health Organization (WHO) criteria."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Spleen ≥ 5 cm palpable below the LLCM or ≥450 cm3 by MRI or CT"}
• {"criterion_text":"- Patients must have at least 2 symptoms with a score of at least 1 on the MFSAF v4.0"}
• {"criterion_text":"- An MRI or CT scan for spleen volume must be performed no more than 14 days prior to the first dose of navtemadlin."}
• {"criterion_text":"- ECOG performance status of 0 to 2."}
• {"criterion_text":"- Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 28 days prior to the first dose of navtemadlin)."}
• {"criterion_text":"- 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."}

Exclusion criteria

• {"criterion_text":"- Patients who are positive for TP53 mutations."}
• {"criterion_text":"- Documented disease progression or clinical deterioration any time while on ruxolitinib treatment."}
• {"criterion_text":"- Patients who have had a documented spleen response to ruxolitinib."}
• {"criterion_text":"- Participation in another interventional clinical trial within the past 4 weeks of the first dose of navtemadlin (participation in observational studies is permitted)."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Prior splenectomy."}
• {"criterion_text":"- Splenic irradiation within 3 months prior to the first dose of navtemadlin."}
• {"criterion_text":"- Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation"}
• {"criterion_text":"- Prior MDM2 inhibitor therapy or p53-directed therapy"}
• {"criterion_text":"- Women who are pregnant or breastfeeding"}
• {"criterion_text":"- History of major organ transplant"}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- 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."}
• {"criterion_text":"- Grade 2 or higher QTc prolongation (>480 milliseconds per NCICTCAE criteria, version 5.0)."}
• {"criterion_text":"- Active or chronic bleeding within 4 weeks prior to the first dose of navtemadlin."}
• {"criterion_text":"- For full list please refer to the Protocol."}

Primary endpoints

• {"endpoint_text":"- 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)","definition_or_measurement_approach":"DLTs will be used to establish the MTD; the SRC will determine RP2D based on safety and efficacy. Spleen volume reduction (SVR) of ≥35% at Week 24 assessed by MRI/CT scan (central review)."}

Secondary endpoints

• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Proportion achieving ≥35% spleen volume reduction (SVR) at any timepoint compared to Baseline assessed by MRI or CT."}
• {"endpoint_text":"- The percentage change in TSS as measured by the MFSAF v4.0 at any time point from Baseline while on study.","definition_or_measurement_approach":"Percentage change in Total Symptom Score (TSS) measured by the Myelofibrosis Symptom Assessment Form v4.0 versus Baseline."}
• {"endpoint_text":"- Duration of a ≥ 35% reduction in SVR from Baseline as measured by MRI (or by CT scan for applicable subjects).","definition_or_measurement_approach":"Duration from first achievement of ≥35% SVR until loss of response, measured by MRI or CT."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Palpation-measured spleen size reduction from Baseline at each visit; includes proportion achieving ≥50% decrease in palpated spleen size."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Rate of RBC transfusion usage (average units per patient-month) and rate of change from transfusion dependence to independence."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Proportion achieving complete response (CR) and partial response (PR) per IWG-MRT and modified ELN criteria at any timepoint vs Baseline."}
• {"endpoint_text":"- OS is defined as the interval from randomization to death from any cause","definition_or_measurement_approach":"Overall survival (OS): time from randomization to death from any cause."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Progression-free survival (PFS): time from Cycle 1 Day 1 to disease progression (≥25% spleen volume increase), leukemic transformation (specified blasts criteria lasting ≥2 weeks), or death."}
• {"endpoint_text":"- 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).","definition_or_measurement_approach":"Leukemia-free survival: time from Cycle 1 Day 1 to first documented leukemic transformation using specified blast criteria."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"Safety assessed by physical exams, labs, AEs, SAEs, ECGs, and vital signs."}
• {"endpoint_text":"- 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","definition_or_measurement_approach":"PK parameters to be determined for navtemadlin, its acyl glucuronide (M1), and ruxolitinib: Cmax, Cmin, AUC, Tmax, etc."}

Italy

Earliest CTIS Part Ii Submission Date

10-07-2024

Latest Decision Or Authorization Date

12-02-2026

Processing Time Days

582

Number Of Sites

5

Number Of Participants

20

France

Earliest CTIS Part Ii Submission Date

10-07-2024

Latest Decision Or Authorization Date

05-02-2026

Processing Time Days

575

Number Of Sites

4

Number Of Participants

6

Primary sponsor

Full Name

Kartos Therapeutics Inc.

Organisation Type

Pharmaceutical company

Country Of Registered Address

United States

Contract research organisations

Name

Fisher Clinical Services Inc.

Responsibilities

Code 14 (as listed in sponsorDuties)

Name

Ppd Inc.

Responsibilities

Code 4 (as listed in sponsorDuties)

Name

Syneos Health Netherlands B.V.

Responsibilities

Multiple codes including operational roles and investigator payments (codes 1,12,15,5,6,8)

Name

Endpoint Clinical Inc.

Responsibilities

Code 3 (as listed in sponsorDuties)

Name

PrimeVigilance GmbH

Responsibilities

Pharmacovigilance / safety (code 8)

Name

Eurofins Central Laboratory LLC

Responsibilities

Laboratory services (code 4)

Third parties

• {"country":"United States","full_name":"Fisher Clinical Services Inc.","duties_or_roles":"sponsorDuties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"Fisher Clinical Services GmbH","duties_or_roles":"sponsorDuties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Celerion Inc.","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Ppd Inc.","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Perceptive Informatics Inc.","duties_or_roles":"sponsorDuties codes: 15 (Central imaging)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Eurofins Central Laboratory LLC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"Netherlands","full_name":"Syneos Health Netherlands B.V.","duties_or_roles":"sponsorDuties codes: 1, 12, 15 (Investigator Payments), 5, 6, 8","organisation_type":"Pharmaceutical company"}
• {"country":"Germany","full_name":"PrimeVigilance GmbH","duties_or_roles":"sponsorDuties codes: 8","organisation_type":"Pharmaceutical company"}
• {"country":"Switzerland","full_name":"Fisher Clinical Services GmbH (Allschwil)","duties_or_roles":"sponsorDuties codes: 14","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Endpoint Clinical Inc.","duties_or_roles":"sponsorDuties codes: 3","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Labconnect LLC","duties_or_roles":"sponsorDuties codes: 15 (central lab /sample management/storage)","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Eresearchtechnology Inc.","duties_or_roles":"sponsorDuties codes: 15 (ePRO)","organisation_type":"Pharmaceutical company"}
• {"country":"United States","full_name":"Q Squared Solutions LLC","duties_or_roles":"sponsorDuties codes: 4","organisation_type":"Laboratory/Research/Testing facility"}
• {"country":"United States","full_name":"Flagship Biosciences Inc.","duties_or_roles":"sponsorDuties codes: 15 (Genetic testing), 4","organisation_type":"Pharmaceutical company"}