POIESIS Trial Explores Navtemadlin Plus Jakafi for Myelofibrosis

Myelofibrosis, according to the Cleveland Clinic website, is a rare blood cancer in which scar tissue forms in your bone marrow. Moreover, the disease is a chronic leukemia that makes too many abnormal blood cells that eventually replace normal cells, in turn, causing anemia and spleen enlargement in affected patients.

The phase 3 POIESIS trial will evaluate the addition of navtemadlin to Jakafi in JAK inhibitor-naive myelofibrosis.

Anemia is a condition characterized as a deficiency of red blood cells that can deprive your tissues of oxygen and cause symptoms like fatigue, weakness and shortness of breath. An enlarged spleen, or splenomegaly, can cause a sensation of fullness or discomfort in the upper left section of your abdomen. Myelofibrosis affects the body in many ways, causing other signs and symptoms like thrombocytopenia (a deficiency of platelets), extramedullary hematopoiesis (abnormal growth of blood-forming cells outside of your bone marrow, such as the spleen, liver or lungs) and constitutional symptoms, such as night sweats, itching, bone pain and fever. Only 10% to 20% of patients with myelofibrosis experience portal hypertension, compared with the majority who experience constitutional symptoms.These signs and symptoms, in turn, create an unmet medical need across the treatment landscape of myelofibrosis.

To address these unmet needs, investigators have launched clinical trials that aim to combat the disease and its signs and symptoms. One of these trials is the phase 3 POIESIS study which is investigating navtemadlin as an add-on therapy with the JAK inhibitor Jakafi (ruxolitinib), compared with placebo plus Jakafi in patients with JAK inhibitor-naive myelofibrosis, who experience a suboptimal response to Jakafi. The POIESIS study is a randomized, double-blind, placebo-controlled, multicenter, global clinical trial.

The most recent presentation of information on the investigation was shared at the American Society of Hematology Annual Meeting and Exposition in December 2024. In an article published in Blood, which was shared before the meeting, first study author, Dr. Pankit Vachhani, wrote, “POIESIS has an innovative and unique design that aligns with (myelofibrosis) treatment approaches adopted in routine clinical practice – treat, when necessary, with add-on therapy.”

Vachhani serves as an associate professor of hematology and oncology at the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center.

Phase 3 POIESIS Trial

To understand the clinical benefit the POIESIS trial may offer, it's important to first recognize the significant unmet medical needs faced by patients with myelofibrosis, particularly those who have a suboptimal response to Jakafi. According to the official POIESIS trial website, JAK inhibitors are the only approved treatment options for patients with myelofibrosis. JAK inhibitors, like Jakafi, inhibit the a key pathway (JAK-STAT) that drives myelofibrosis cancer cell proliferation. Because JAK inhibitors are the only approved treatment option in the first-line setting, once progression occurs, patients have limited treatment options.

“There are currently no approved therapies for patients who have not optimally responded to treatment with a JAK inhibitor,” the POIESIS trial website explains.

With the POIESIS trial, it is hoped that navtemadlin, the oral therapy under investigation, may provide additional benefit to Jakafi treatment compared with Jakafi alone. Navtemadlin targets the MDM2 protein; MDM2 decreases the activity of p53, a critical tumor suppressor protein that plays an important role in the body’s natural defenses against cancer, making MDM2 an important target. Notably, in myelofibrosis, MDM2 levels abnormally increase, preventing p53 from carrying out its usual cancer-fighting functions.

Based on this background information, investigators rationalize that because navtemadlin treatment inhibits MDM2 to allow p53 to kill cancer cells, it will eventually offer a potential new treatment for patients with myelofibrosis.

The POIESIS trial is comprised of two treatment periods, the first being a run-in period which is set to enroll approximately 600 patients, according to the journal Blood. Patients who consent to participate in the study will receive Jakafi treatment for 18 to 24 weeks, with the dosage determined by the study doctor. If patients show a suboptimal response to Jakafi or if the treatment proves insufficiently effective, they will move on to the second phase of the study: the randomized add-on period, involving approximately 180 participants.

Conversely, if Jakafi treatment is effective in shrinking the spleen and reducing symptoms, patients may continue their current therapy but will no longer be part of the study, as stated on the POIESIS trial website. Notably, if the patient does not respond at all to treatment with Jakafi, the study doctor will work with that individual to determine their optimal treatment approach following study cessation.

During the randomized add-on period, eligible participants will receive either navtemadlin or a placebo, in addition to their current Jakafi dose from the run-in period. The trial's website states that investigators intend to enroll 180 patients who will be randomly assigned in a 2:1 fashion to receive either navtemadlin (120 patients) or placebo (60 patients) treatment. This means patients have a 2 in 3 chance of receiving the navtemadlin treatment.

Moreover, this portion of the study is blinded to everyone involved, meaning that patients and doctors will not know which add-on treatment is being used: either navtemadlin or placebo.

Prior to treatment initiation, patients must undergo complete clinical evaluations, including providing blood samples, spleen volume measurement via imaging scans (such as MRI or CT), as well as fill out questionnaires that assess the severity of each patient’s related symptoms. Upon enrollment and consent of study participation, these procedures and measurements will be ongoing until either the end of the 28th week of the randomization period or end of treatment, whichever comes second.

Importantly, the POIESIS trial website states that, “For both periods of the study [run-in period and add-on period], patients remain on study unless they cannot tolerate the treatment or their disease progresses.”

The primary end points of the study will be evaluated 24 weeks after the start of the add-on period. Efficacy will be assessed by comparing navtemadlin to placebo based on spleen volume reduction (measured by MRI or CT) and symptom score reduction, as reported in the daily 7-symptom questionnaire. To ensure accurate results, it is crucial for patients to attend all imaging appointments and record their daily symptom scores accurately through week 28 or until treatment ends.

Discussing Clinical Trial Participation

Participation in clinical trials such as the POIESIS study is necessary because these trials help researchers identify new standard-of-care medications that are more effective and safer than currently available options, thus improving the survival and quality of life of countless future patients, according to the POIESIS trial website; in some trials, it may even lead to the discovery of a curative treatment option.

According to the Fred Hutch Cancer Center website, patients should inquire about clinical trials which are applicable to their type and stage of cancer with their care team. Moreover, the clinicaltrials.gov website houses information on thousands of trials which are active and currently enrolling, as well as those which have been completed. Patients can find information for clinical studies on the website by filtering through condition, treatment, location or investigator name on the website's home page. Patients can also access the study status, eligibility criteria and specific institutions which are conducting the clinical trial.

Although clinical trials are vital in the treatment landscape, participation is never required and is a big decision for those participating. Therefore, Fred Hutch Cancer Center website encourages patients who have a caregiver, partner or adult family member, to share their thoughts with them and include them in discussions with the care team about clinical trials. Of note, the National Institute of Mental Health encourages patients to bring questions to their care team which cover topics such as: the study’s purpose and duration, possible risks and benefits, participation and care, and personal and cost concerns.

Notably, the POIESIS trial website also encourages patients to find more information about clinical trials through other resources such as the American Cancer Society, National Cancer Institute, and European Federation of Pharmaceutical Industries and Associations.

Of note, the POIESIS trial is currently enrolling patients with JAK inhibitor-naive myelofibrosis. Patients with prior exposure to a JAK inhibitor will be exluded from enrollment on the trial.

POIESIS is expected to be conducted in approximately 220 cancer centers across multiple countries, including 70 community and academic centers in the United States. In the United States, study sites are located in cities including Los Angeles, California; Salt Lake City, Utah; Tacoma, Washington; San Antonio, Texas, and New York, New York.

Editor’s note: For more information on trial participation, you can contact your nearest participating center for more information or send an email to POIESIS-trial@kartosthera.com, as well as find more information on the clinicaltrials.gov website.

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