BOREAS is a randomized, open label Phase 3 clinical trial that will evaluate the efficacy and safety of navtemadlin (KRT-232) versus best available therapy (BAT) for the treatment of primary or secondary myelofibrosis (MF) in patients who are relapsed or refractory to Janus kinase (JAK) inhibitor treatment. This trial will enroll 282 patients globally.
Navtemadlin (KRT-232) is a potent, selective, orally available inhibitor of murine double minute 2 (MDM2).1,2 MDM2 is a key negative regulator of the tumor suppressor protein p53, also known as “The Guardian of the Genome”. MDM2 is overexpressed in CD34+ myeloid cells of MF patients and elevated MDM2 levels can reduce p53 activity causing the proliferation of CD34+ cancer cells. Inhibiting the MDM2 protein restores p53 function resulting in apoptosis of malignant CD34+ cancer cells.3-5
In a proof-of-concept Phase 2 study, navtemadlin (KRT-232) showed promising activity in patients with MF who are relapsed or refractory to JAK inhibitor treatment. Sixteen percent of patients achieved a best-reduction in spleen volume of ≥35% and 30% of patients achieved a best-reduction in Total Symptom Score ≥50%. In addition, MF patients experienced a median reduction of 87% in their peripheral blood CD34+ cells after 24 weeks on navtemadlin (KRT-232) therapy.6
During the Phase 2 study, a JAK inhibitor washout period was not required which may have reduced the reported spleen volume reductions in MF patients. Spleen responses were found to be superior in patients who were off ruxolitinib (JAK inhibitor treatment) prior to their baseline MRI/CT scan versus those who were remained on ruxolitinib therapy at the time of their baseline scan (best-reduction of spleen volume ≥35%: 29% vs 0%).6
Navtemadlin (KRT-232) demonstrated a tolerable safety profile that included prophylaxis for nausea and vomiting.6
For more information about navtemadlin (KRT-232), please visit www.kartosthera.com/science.
BOREAS Trial Overview
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BOREAS is a global, multicenter, Phase 3 randomized, controlled, open-label study that is designed to evaluate the efficacy and safety of navtemadlin (KRT-232) versus best available therapy (BAT) for the treatment of primary and secondary myelofibrosis in patients who are relapsed or refractory to JAK inhibitor treatment.
Patients will be randomized 2:1 to navtemadlin (KRT-232) or BAT. BAT will be determined by the treating physician. All patients will be treated until disease progression, unacceptable toxicity, death, or withdrawal of consent.
The proportion of patients achieving spleen volume response ≥ 35% at Week 24 by MRI/CT scan (central review).
- The proportion of patients with ≥ 50% reduction in Total Symptom Score (MFSAF v4.0) at Week 24
- Overall survival
- Progression-free survival
- Best overall spleen response
- Duration of spleen volume response ≥ 35%
- The proportion of patients who have RBC transfusion independence at week 24
Adverse Event Reporting
If you believe your patient may have experienced an adverse event while participating in a study that includes navtemadlin (KRT-232), please immediately report the incident following the procedure outlined in study protocol.
Selected Eligibility Criteria
- Adults ≥ 18 years of age
- Confirmed diagnosis of primary myelofibrosis or post-polycythemia vera/post-essential thrombocythemia myelofibrosis in accordance with the World Health Organization (WHO) 2016
- High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
- Patients with wild-type p53
- Relapsed or refractory to prior treatment with an approved JAK inhibitor
- ECOG performance status of 0 to 2
- Prior splenectomy
- Participation in an interventional clinical trial within 28 days before randomization
- Splenic irradiation within 3 months prior to randomization
- History of major hemorrhage or intracranial hemorrhage within 6 months prior to randomization
- History of stroke, reversible ischemic neurological defect or transient ischemic attack within 6 months prior to randomization
- Prior MDM2 inhibitor therapy or p53-directed therapy
- Prior allogeneic stem-cell transplant or plans for allogeneic stem cell transplant
- History of major organ transplant
- Grade 2 or higher QTc prolongation (> 480 milliseconds per NCI-CTCAE criteria, version 5.0)
Please check clinicaltrials.gov for more information.
The BOREAS trial will be conducted in approximately 140 cancer centers across at least 20 countries. Please use the interactive map below to locate a cancer center near you where patients are being enrolled to this trial.
The Steering Committee Members
The physicians shown here are members of the BOREAS Trial Steering Committee, who provide guidance and oversight for the trial.
- Sun D, Li Z, Rew Y, et al. Discovery of AMG 232, a potent, selective, and orally bioavailable MDM2-p53 inhibitor in clinical development. J Med Chem. 2014;57:1454-72.
- Canon J, Osgood T, Olson SH, et al. The MDM2 inhibitor AMG 232 demonstrates robust antitumor efficacy and potentiates the activity of p53-inducing cytotoxic agents.Mol Cancer Ther. 2015;14:649-58.
- Wade M, Li Y, Wahl GM. MDM2, MDMX and p53 in oncogenesis and cancer therapy. Nature Reviews Cancer. 2013;13:83-96.
- Oliner JD, Saiki AY, Caenepeel S. The role of MDM2 amplification and overexpression in tumorigenesis.Cold Spring Harb Perspect Med. 2016;6 pii: a026336.
- Tisato V, Voltan R, Gonelli A, et al. MDM2/X inhibitors under clinical evaluation: perspectives for the management of hematological malignancies and pediatric cancer.J Hematol Oncol. 2017;10:133.
- Al-Ali et al. Navtemadlin (KRT-232), a first-in-class, murine double minute 2 inhibitor (MDM2i) for myelofibrosis (MF) relapsed or refractory (R/R) to Janus-associated kinase inhibitor (JAKi) treatment (TX). HemaSphere. 2020;4:S215.