Trial: Study of Navtemadlin as Maintenance The…

Trial Details

Sponsor: Kartos Therapeutics, Inc. (industry)

Phase: 2/3

Start date: July 17, 2023

Planned enrollment: 268

Trial ID: NCT05797831

More trial details at ClinicalTrials.gov

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Navtemadlin (KRT-232, AMG-232)

Overview

Navtemadlin (KRT‑232; formerly AMG‑232) is an investigational, oral MDM2 inhibitor being developed for TP53 wild‑type (WT) malignancies. The most advanced program is in myelofibrosis (MF) after JAK inhibitor (JAKi) therapy; additional studies include Merkel cell carcinoma (MCC) after anti‑PD‑1/L1 therapy, acute myeloid leukemia (AML), and solid tumors. It is not FDA‑approved as of October 7, 2025. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

Target: MDM2–p53 protein–protein interaction. Navtemadlin binds MDM2 with high affinity, stabilizes/reactivates p53 in TP53 WT cells, and induces p21‑mediated cell‑cycle arrest and apoptosis via pro‑apoptotic BCL‑2 family proteins. (pubs.acs.org)
Drug class/background: Next‑generation, selective, orally bioavailable MDM2 inhibitor derived from Amgen’s AMG‑232 program. (pubs.acs.org)

Efficacy

Myelofibrosis (post‑JAK inhibitor; monotherapy) - Phase 3 BOREAS (NCT03662126; randomized 2:1 vs best available therapy [BAT]): At week 24 (intention‑to‑treat; data cutoff March 11, 2024), navtemadlin 240 mg once daily on days 1–7 of 28‑day cycles achieved SVR35 (≥35% spleen volume reduction) in 15% (18/123) vs 5% (3/60) with BAT (p=0.08) and TSS50 (≥50% total symptom score reduction) in 24% (30/123) vs 12% (7/60) (p=0.05). Biomarker improvements (reductions in bone‑marrow fibrosis, driver‑mutation allele burden, and circulating CD34+ cells) were greater with navtemadlin. (ash.confex.com)

Myelofibrosis (add‑on to ruxolitinib; suboptimal responders) - Phase 1/2 KRT‑232‑109 (EHA 2023): Among efficacy‑evaluable patients at week 24 (n=19), navtemadlin + ruxolitinib yielded SVR ≥35% in 32% and TSS50 in 32%. These data supported the ongoing phase 3 POIESIS add‑on trial. (onclive.com)

Merkel cell carcinoma (post–anti‑PD‑1/L1; monotherapy) - Phase 1b/2 dose‑finding (KRT‑232‑103; NOTOS precursor; NCT03787602): At the selected regimen (180 mg once daily, days 1–5 of 28‑day cycles), confirmed ORR was 25% (2/8 evaluable), unconfirmed+confirmed ORR 38%, and disease control rate 63%; responses tended to be higher in chemo‑naïve patients. A pivotal NOTOS study is ongoing. (ascopubs.org)

Solid tumors and other settings - First‑in‑human phase 1 (TP53 WT advanced solid tumors or multiple myeloma): Acceptable safety up to 240 mg on a 7‑day‑on/21‑day‑off schedule; no objective responses by local review, with some stable disease observed. (pubmed.ncbi.nlm.nih.gov)

Preclinical/ translational highlights - Potent MDM2 binding and xenograft regression; enhanced activity in combination with DNA‑damaging chemotherapy or MEK inhibition in models. (aacrjournals.org)

Safety

Across studies, the main toxicities are myelosuppression and gastrointestinal (GI) events.

Phase 3 BOREAS (MF): Grade 3/4 TEAEs were thrombocytopenia 37% (navtemadlin) vs 21% (BAT), anemia 29% vs 25%, neutropenia 24% vs 12%; grade 3/4 GI events included diarrhea 5% vs 2%, nausea 3% vs 0%, vomiting 2% vs 0%. Antidiarrheal prophylaxis (first two cycles) and antiemetics (each dosing day) were used per protocol. Dose reductions for hematologic TEAEs occurred in 26%. (ash.confex.com)
Phase 1b/2 MCC: Grade 3/4 hematologic AEs were anemia 32%, lymphopenia 32%, thrombocytopenia 19%; lower doses (≤180 mg) had fewer reductions and longer treatment duration. (ascopubs.org)
Phase 1 solid tumors: Common AEs were diarrhea, nausea, vomiting, fatigue, decreased appetite, and anemia; dose‑limiting thrombocytopenia/neutropenia occurred at higher doses. (pubmed.ncbi.nlm.nih.gov)

TrialFetch AI Analysis

Goal: Evaluate whether maintenance navtemadlin improves outcomes versus observation/placebo in patients with TP53 wild-type advanced or recurrent endometrial cancer who achieved a radiographic response to first-line taxane–platinum chemotherapy, and to select the optimal Phase 3 dose.

Patients: Adults with histologically or cytologically confirmed TP53 wild-type endometrial cancer, ECOG 0–1, who have advanced or recurrent disease and completed one line (up to 6 cycles) of taxane–platinum chemotherapy with a complete or partial response. Adequate hematologic, hepatic, and renal function required. Key exclusions include sarcomas or small-cell/neuroendocrine histology, recent investigational or immune/cytokine therapy, indwelling surgical drains, clinically significant QTc prolongation (≥ grade 2), major organ transplant, and recent major or intracranial hemorrhage.

Design: Two-part, randomized study. Part 1 assesses safety and preliminary efficacy of two navtemadlin dose regimens versus an observational control to select the Phase 3 dose. Part 2 is a randomized, placebo-controlled evaluation of the selected navtemadlin dose versus matched placebo. Independent review committee will assess radiographic endpoints. Planned enrollment is 268.

Treatments: Navtemadlin oral intermittent dosing on Days 1–7 of 28-day cycles. Part 1 includes 180 mg and 240 mg cohorts plus an observation arm. Part 2 randomizes patients to navtemadlin (selected Phase 3 dose; protocol lists 180 mg and 240 mg schedules) or matched placebo. Navtemadlin (KRT-232) is an oral, selective MDM2 inhibitor that reactivates p53 signaling in TP53 wild-type tumors to promote apoptosis. Across early trials in TP53 wild-type malignancies (myelofibrosis, Merkel cell carcinoma, AML, solid tumors), navtemadlin has shown on-target pharmacodynamics, signals of clinical activity, and a safety profile dominated by class-typical cytopenias and gastrointestinal adverse events.

Outcomes: Primary: Part 1—selection of Phase 3 dose by a safety review committee based on safety data; Part 2—progression-free survival by independent review committee. Secondary: PFS by IRC and investigator in Part 1; time to first subsequent treatment in Part 2; pharmacokinetics (Cmax, AUC, Tmax) in both parts; disease control rate among participants whose best response to prior chemotherapy was PR.

Burden on patient: Moderate. The regimen is oral and intermittent, reducing infusion visits, and imaging schedules are expected to be similar to standard maintenance surveillance. However, participation entails regular clinic visits for safety monitoring, hematology and chemistry labs due to risk of cytopenias and GI toxicities, and pharmacokinetic blood draws around early dosing days. Part 1 includes closer safety follow-up to inform dose selection. No mandated additional biopsies are indicated, and placebo/observation groups reduce procedural burden, but the need for periodic assessments and potential dose holds or supportive care for myelosuppression adds to visit frequency and monitoring demands.

Last updated: Oct 2025

Eligibility

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Sites (83)

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Medizinische Universität Innsbruck

Innsbruck, 6020, Austria

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Status: Recruiting

Medizinische Universität Wien

Vienna, 1090, Austria

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University Hospital Graz, Department of Gynecology and Obstetrics

Graz, 8036, Austria

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CHUM - University of Montreal Hospital Centre

Montreal, H2X 3E4, Canada

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Cross Cancer Institute

Edmonton, T6G 1Z2, Canada

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Odense University Hospital

Odense, DK-5000, Denmark

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Tartu University Hospital

Tartu, 50406, Estonia

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Kuopio University Hospital

Kuopio, 70200, Finland

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Turku University Hospital

Turku, 20520, Finland

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American Hospital Network LLC

Tbilisi, 0102, Georgia

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Caucasus Medical Centre

Tbilisi, 0186, Georgia

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LTD High Technology hospital Medcenter

Batumi, 6000, Georgia

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National Institute of Oncology

Budapest, H-1122, Hungary

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University of Debrecen Clinical Center

Debrecen, 4032, Hungary

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Rambam Medical Center

Haifa, Rambam Medical Center, Israel

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Shaare Zedek Medical Center

Jerusalem, 9103102, Israel

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Sourasky Medical Center

Tel Aviv, 6423906, Israel

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"Azienda Unità Sanitaria Locale della Romagna - Hospital ""Infermi"" of Rimini Oncology Department"

Rimini, 47923, Italy

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Status: Recruiting

A.O. Cannizzaro

Catania, 95126, Italy

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ASST di Lecco-Ospedale Alessandro Manzoni

Lecco, 23900, Italy

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Status: Recruiting

IRCCS Istituto Romangolo per lo Studio dei Tumori "Dino Amadori"

Forlì, 47014, Italy

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Status: Recruiting

Osp. Niguarda

Milan, 20162, Italy

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Ospedale Filippo Del Ponte

Varese, 21110, Italy

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Ospedale Guglielmo da Saliceto

Piacenza, 29121, Italy

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Ospedale Policlinico San Martino

Genoa, 16132, Italy

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Ospedale San Luca

Lucca, 55100, Italy

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Ospedale Santa Maria delle Croci

Ravenna, 48121, Italy

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Ospedale di Prato S. Stefano

Prato, 59100, Italy

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Policlinico Umberto

Rome, 00161, Italy

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University Hospital of Parma

Parma, 43126, Italy

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Status: Recruiting

Health Sciences Kaunas Clinics

Kaunas, LT-45434, Lithuania

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Status: Recruiting

Nation Cancer Institute of Lithuania, Vilnius

Vilnius, LT-08660, Lithuania

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Status: Recruiting

Oslo University Hospital HF

Oslo, 0379, Norway

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Southern Hospital Sorlandet

Kristiansand, 4604, Norway

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Sykehusapotek Nord Tromsø

Tromsø, 9038, Norway

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Białostockie Centrum Onkologii

Bialystok, 15-027, Poland

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Centrum Badań klinicznych Jagiellońskie Centrum Innowacji

Krakow, 31-115, Poland

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Status: Recruiting

Lower Silesian Oncology, Pulmonology and Hematology Center, Department of Oncological Gynecology

Wroclaw, 53-413, Poland

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Status: Recruiting

NIO-PIB Klinika Gine-Onk

Warsaw, 02-781, Poland

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Status: Recruiting

NIO-PIB Oddzial w Gliwicach

Gliwice, 44-102, Poland

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Siedleckie Centrum Onkologii

Olsztyn, 10-228, Poland

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Szpitale Pomorskie

Gdansk, 80-210, Poland

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Uniwersytecki Szpital

Poznan, 60-569, Poland

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Uniwersyteckie Centrum Kliniczne

Gdansk, 80-214, Poland

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Bucharest CF2 Hospital

Bucharest, 012244, Romania

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Gral Medical S.R.L. - Oncofort Hospital

Piteşti, 110283, Romania

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Onco Clinic Consult S.A.

Craiova, 200094, Romania

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Oncocenter, Oncology Clinic SRL

Timișoara, 300166, Romania

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Oncology Center "Sf. Nectarie"

Craiova, 200542, Romania

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Ovidius Clinical Hospital SRL

Constanța, 905900, Romania

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SC Oncomed SRL

Timișoara, 300239, Romania

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Institute of Oncology Ljubljana

Ljubljana, 1000, Slovenia

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University Clinical Center Maribor

Maribor, 2000, Slovenia

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CHUAC (Hospital de Coruña)

A Coruña, 15006, Spain

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H.G.U. Jerez de la Frontera

Jerez de la Frontera, 11407, Spain

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HCU Santiago de Compostela

Santiago de Compostela, 15706, Spain

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Hospital Galdakao-Usansolo

Galdakao, 48960, Spain

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Hospital U Insular de GC

Las Palmas, 35016, Spain

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Hospital Universitario de Jaen

Jaén, 23007, Spain

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Hospital Universitario de Valme

Seville, 41014, Spain

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Hospital de Leon

León, 24008, Spain

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Hospital del Mar

Barcelona, 08003, Spain

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Karolinska University Hospital

Stockholm, SE-171 76, Sweden

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Linkoping University Hospital

Linköping, 581 85, Sweden

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Kaiser Permanente Center

Vallejo, California, 94589, United States

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Northside Hospital

Atlanta, Georgia, 30342, United States

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St. Joseph

Savannah, Georgia, 31405, United States

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Dr. Sudarshan K. Sharma, Ltd.

Hinsdale, Illinois, 60521, United States

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Indiana University

Indianapolis, Indiana, 46202, United States

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Parkview Research Center

Fort Wayne, Indiana, 46845, United States

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Maryland Oncology Hematology, P.A.

Silver Spring, Maryland, 20904, United States

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Minnesota Oncology Hematology, P.A.

Minneapolis, Minnesota, 55404, United States

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Washington University School of Medicine

St Louis, Missouri, 63108, United States

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Women's Cancer Center of Nevada

Las Vegas, Nevada, 89106, United States

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Good Samaritan Hospital Medical Center

West Islip, New York, 11795, United States

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FirstHealth Carolinas

Pinehurst, North Carolina, 28374, United States

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OhioHealth Institute

Columbus, Ohio, 43214, United States

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Oklahoma Cancer Specialists and Research Institute

Tulsa, Oklahoma, 74146, United States

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Northwest Cancer Specialists

Portland, Oregon, 97227, United States

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Oncology Associates of Oregon

Eugene, Oregon, 97401, United States

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Texas Oncology-Austin Central

Austin, Texas, 78745, United States

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Texas Oncology-Fort Worth Cancer Center

Fort Worth, Texas, 76104, United States

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Texas Oncology-San Antonio Medical Center

San Antonio, Texas, 78130, United States

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Status: Recruiting

A Phase 2/3 Study of Navtemadlin as Maintenance Therapy in Subjects With TP53WT Advanced or Recurrent Endometrial Cancer Who Responded to Chemotherapy

Trial Details

Show Summary from Sponsor

Investigational Drug AI Analysis

Show for: Navtemadlin (KRT-232, AMG-232)

Overview

Mechanism of action

Efficacy

Safety

Further reading

TrialFetch AI Analysis

Eligibility

Show Criteria

Sites (83)

Medizinische Universität Innsbruck

Medizinische Universität Wien

University Hospital Graz, Department of Gynecology and Obstetrics

CHUM - University of Montreal Hospital Centre

Cross Cancer Institute

Odense University Hospital

Tartu University Hospital

Kuopio University Hospital

Turku University Hospital

American Hospital Network LLC

Caucasus Medical Centre

LTD High Technology hospital Medcenter

National Institute of Oncology

University of Debrecen Clinical Center

Rambam Medical Center

Shaare Zedek Medical Center

Sourasky Medical Center

"Azienda Unità Sanitaria Locale della Romagna - Hospital ""Infermi"" of Rimini Oncology Department"

A.O. Cannizzaro

ASST di Lecco-Ospedale Alessandro Manzoni

IRCCS Istituto Romangolo per lo Studio dei Tumori "Dino Amadori"

Osp. Niguarda

Ospedale Filippo Del Ponte

Ospedale Guglielmo da Saliceto

Ospedale Policlinico San Martino

Ospedale San Luca

Ospedale Santa Maria delle Croci

Ospedale di Prato S. Stefano

Policlinico Umberto

University Hospital of Parma

Health Sciences Kaunas Clinics

Nation Cancer Institute of Lithuania, Vilnius

Oslo University Hospital HF

Southern Hospital Sorlandet

Sykehusapotek Nord Tromsø

Białostockie Centrum Onkologii

Centrum Badań klinicznych Jagiellońskie Centrum Innowacji

Lower Silesian Oncology, Pulmonology and Hematology Center, Department of Oncological Gynecology

NIO-PIB Klinika Gine-Onk

NIO-PIB Oddzial w Gliwicach

Siedleckie Centrum Onkologii

Szpitale Pomorskie

Uniwersytecki Szpital

Uniwersyteckie Centrum Kliniczne

Bucharest CF2 Hospital

Gral Medical S.R.L. - Oncofort Hospital

Onco Clinic Consult S.A.

Oncocenter, Oncology Clinic SRL

Oncology Center "Sf. Nectarie"

Ovidius Clinical Hospital SRL

SC Oncomed SRL

Institute of Oncology Ljubljana

University Clinical Center Maribor

CHUAC (Hospital de Coruña)

H.G.U. Jerez de la Frontera

HCU Santiago de Compostela

Hospital Galdakao-Usansolo

Hospital U Insular de GC

Hospital Universitario de Jaen

Hospital Universitario de Valme

Hospital de Leon

Hospital del Mar

Karolinska University Hospital

Linkoping University Hospital

Kaiser Permanente Center

Northside Hospital