CART123 + Ruxolitinib for Acute Myelogenous Leukemia

(AML Trial)

Overseen By Abramson Cancer Center Clinical Trials Service

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: University of Pennsylvania

Must be taking: Ruxolitinib

Must not be taking: Systemic steroids, Immunosuppressants, Fluconazole

Disqualifiers: JAK2 mutation, CNS involvement, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment for individuals with acute myeloid leukemia (AML) that hasn't responded to other treatments. The researchers combine two therapies: CART123 cells, which target and destroy cancer cells, and ruxolitinib, a drug that may enhance this effect. Participants will receive these treatments to assess their safety and any early signs of effectiveness. This study suits individuals whose AML hasn't improved with standard treatments or has returned after a bone marrow transplant. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

Will I have to stop taking my current medications?

The trial does not specify if you must stop taking your current medications, but it does mention restrictions on certain medications like systemic steroids, immunosuppressants, and fluconazole. It's best to discuss your current medications with the trial team to see if any adjustments are needed.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that using CART123 cells with ruxolitinib might be safe and well-tolerated for people with relapsed or hard-to-treat acute myeloid leukemia (AML). Studies also suggest this combination could be effective. As this is an early-stage trial, the primary goal is to assess the treatment's safety. This stage is crucial for identifying potential side effects and determining the correct dosage. Although data is limited, early results are promising and indicate that this treatment could be a safe option for patients. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about CART123 for acute myelogenous leukemia (AML) because it represents a new wave of targeted cancer therapy. Unlike traditional treatments like chemotherapy, which broadly attack fast-growing cells, CART123 is a type of CAR T-cell therapy. This means it involves genetically engineering a patient's own immune cells to specifically target and destroy leukemia cells. Additionally, the combination with Ruxolitinib, and in some study arms, Venetoclax, aims to enhance the effectiveness and reduce the resistance often seen in traditional therapies. This targeted approach not only has the potential for more precise treatment but also could lead to better outcomes with fewer side effects.

What evidence suggests that this trial's treatments could be effective for acute myeloid leukemia?

Research has shown that a combination of CART123 cells and ruxolitinib may help treat relapsed or hard-to-treat acute myeloid leukemia (AML). In this trial, participants in Arm A will receive CART123 cells and ruxolitinib, while Arm B will include CART123 cells, ruxolitinib, and venetoclax. Earlier studies found that some patients showed improvement by Day 28 of treatment. Specifically, one study found that 89.5% of patients were still alive after one year, suggesting possible long-term benefits. This treatment uses specially engineered cells and a drug that blocks certain proteins, potentially targeting cancer cells more effectively. Although it's still early, these results suggest the treatment could benefit some patients with this challenging condition. ^{1 2 3 4 5}

Who Is on the Research Team?

Saar Gill, MD, PhD

Principal Investigator

University of Pennsylvania

Are You a Good Fit for This Trial?

This trial is for adults with relapsed or refractory acute myeloid leukemia (AML) after stem cell transplant. They must have a suitable donor ready for another transplant if needed, be at least 3 months post-transplant without needing immunosuppression, and have certain organ functions within specific ranges.

Inclusion Criteria

My AML returned after a stem cell transplant.

My liver enzymes are within 5 times the normal limit.

I had a stem cell transplant over 3 months ago and don't need medication for graft-versus-host disease.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Lymphodepletion and Ruxolitinib Administration

Participants receive lymphodepleting chemotherapy and begin ruxolitinib dosing

6 days

1 visit (in-person)

CART123 Cell Infusion

Participants receive a single infusion of CART123 cells following ruxolitinib administration

1 day

1 visit (in-person)

Post-Infusion Ruxolitinib Administration

Ruxolitinib dosing continues for up to 14 days post CART123 administration

14 days

Follow-up

Participants are monitored for safety and effectiveness after treatment

3 months

Long-term Follow-up

Participants are monitored for long-term outcomes, including alloHCT

15 years

What Are the Treatments Tested in This Trial?

Interventions

• CART123
• Ruxolitinib

Trial Overview

The study tests CART123 cells combined with Ruxolitinib in AML patients. It's an early-phase trial to check safety and how well it works. Patients get one dose of CART123 after Ruxolitinib and lymphodepletion therapy, with Ruxolitinib starting before chemo and continuing up to two weeks after.

How Is the Trial Designed?

Group I: Arm B: DL-1 Experimental Treatment 2 Interventions

* LD Chemo: Day -6 (-1d) to Day -2 (-1d) * Venetoclax: Day -6 (-1d) through Day +7 - Day +14 post-CART123 infusion * Ruxolitinib: Daily beginning on Day -1 through Day +7 post CART123 infusion. * CART123 Cells: Single infusion on Day 0

Group II: Arm A: DL1 Experimental Treatment 2 Interventions

* LD Chemo: Day -6 to Day -4 (±1d) * Ruxolitinib: Daily beginning on Day -6 (±1d) through D14 post CART123 infusion. * CART123 Cells: Single infusion on Day 0

Group III: Arm A: DL-1 Experimental Treatment 2 Interventions

* LD Chemo: Day -6 to Day -4 (±1d) * Ruxolitinib: Daily beginning on Day -6 (±1d) through D14 post CART123 infusion. * CART123 Cells: Single infusion on Day 0

Who Is Running the Clinical Trial?

University of Pennsylvania

Lead Sponsor

Trials

2,118

Recruited

45,270,000+

Novartis

Industry Sponsor

Trials

1,646

Recruited

2,778,000+

Vasant Narasimhan

Novartis

Chief Executive Officer since 2018

MD from Harvard Medical School, Bachelor's in Biological Sciences from University of Chicago, Master's in Public Policy from John F. Kennedy School of Government

Shreeram Aradhye

Novartis

Chief Medical Officer since 2022

MD from Yale University, MSc in Clinical Epidemiology from University of Pennsylvania

Published Research Related to This Trial

Recent advancements in understanding acute myeloid leukemia (AML) have led to the FDA approval of seven new targeted therapies, which have shown significant clinical benefits both as single agents and in combination with traditional treatments.

These new therapies, including midostaurin and venetoclax, represent a shift in AML treatment, addressing the disease's molecular complexity and improving patient outcomes after decades of stagnation in effective therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New Targeted Agents in Acute Myeloid Leukemia: New Hope on the Rise. Bohl, SR., Bullinger, L., Rücker, FG.[2023]

Midostaurin is the first drug approved by the FDA for treating FLT3-mutant acute myeloid leukemia (AML) since 2000, highlighting its significance in advancing AML treatment options.

As a small-molecule kinase inhibitor targeting the FLT3 receptor, midostaurin represents a new era of targeted therapies for specific genetic subtypes of AML, potentially improving treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midostaurin approved for FLT3-mutated AML. Levis, M.[2022]

Ruxolitinib is shown to be safe and effective for treating myelofibrosis in a study of 176 patients, with a significant reduction in spleen size after treatment (from 219.67 mm to 199.49 mm).

The study reported a high overall survival rate of 89.5% at one year, indicating that ruxolitinib is well tolerated and can be beneficial in real-life clinical settings, although no direct correlation was found between spleen size reduction and overall survival.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of ruxolitinib in patients with myelofibrosis: a retrospective and multicenter experience in Turkey Soyer, N., Ali, R., Turgut, M., et al.[2021]

In a phase I clinical trial involving 20 patients with chronic myelomonocytic leukemia (CMML), ruxolitinib was found to be safe, with no dose-limiting toxicities and only one case of grade 3 thrombocytopenia, indicating a favorable safety profile for this treatment.

Ruxolitinib demonstrated promising efficacy, with a total response rate of 35% and significant improvements in symptoms and spleen size, particularly benefiting patients with disease-related symptoms, suggesting it warrants further investigation in larger studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multi-Institution Phase I Trial of Ruxolitinib in Patients with Chronic Myelomonocytic Leukemia (CMML). Padron, E., Dezern, A., Andrade-Campos, M., et al.[2021]

Recent genome sequencing has identified specific genetic mutations in acute myeloid leukemia (AML) cells, which are crucial for developing targeted therapies.

Current clinical studies are exploring various molecular targeting therapies for AML, including FLT3 inhibitors, PLK1 inhibitors, IDH2 inhibitors, and XPO1 inhibitors, aimed at directly addressing these genetic abnormalities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Progress in molecularly targeted therapies for acute myeloid leukemia]. Tomita, A.[2015]

Ruxolitinib effectively reduces splenomegaly in patients with myeloproliferative neoplasms, showing a significant improvement with a relative risk of 49.12 based on a meta-analysis of randomized clinical trials.

While ruxolitinib is effective, it is associated with an increased incidence of anemia, indicating potential safety concerns that need to be addressed in future studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and Effectiveness of Ruxolitinib for Treatment of Myeloproliferative Neoplasm: A Meta-Analysis]. Yang, ZR., Zhu, HY.[2021]

Ruxolitinib, an oral JAK1/JAK2 inhibitor, has been the standard treatment for intermediate or high-risk myelofibrosis (MF) since its FDA approval in 2011, demonstrating significant efficacy in improving patient outcomes based on data from the phase 3 COMFORT trials.

The review highlights the importance of dose optimization and management of common side effects, such as anemia and thrombocytopenia, to maximize the safety and clinical benefits of ruxolitinib, supported by findings from subsequent trials like JUMP, ROBUST, EXPAND, and REALISE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ten years of treatment with ruxolitinib for myelofibrosis: a review of safety. Verstovsek, S., Mesa, RA., Livingston, RA., et al.[2023]

In a phase I/II study involving 27 patients with relapsed or refractory acute leukemias, ruxolitinib was found to be reasonably well tolerated, with the most common severe side effect being infections, particularly pneumonia.

One patient achieved a complete response with incomplete recovery of peripheral blood (CRp) at the highest dose of 200 mg b.i.d., indicating potential efficacy in this heavily pretreated population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase I/II study of the Janus kinase (JAK)1 and 2 inhibitor ruxolitinib in patients with relapsed or refractory acute myeloid leukemia. Pemmaraju, N., Kantarjian, H., Kadia, T., et al.[2021]

Ruxolitinib is an effective oral treatment for intermediate- or high-risk myelofibrosis, targeting JAK1 and JAK2 to reduce spleen size and improve symptoms, as demonstrated in Phase III trials with significant improvements in quality of life and overall survival.

The treatment has a manageable safety profile, with common side effects including anemia and thrombocytopenia, and requires dosage adjustments based on platelet counts, allowing for personalized patient care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ruxolitinib for the treatment of primary myelofibrosis. Swaim, SJ.[2021]

FLT3 mutations are common in acute myeloid leukemia (AML) patients, making FLT3 a promising target for therapy, with several inhibitors like sorafenib and sunitinib showing clinical activity.

Combining FLT3 inhibitors with other treatments, such as chemotherapy or mTOR inhibitors like everolimus, may enhance their effectiveness in treating AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FLT3 inhibitors for the treatment of acute myeloid leukemia. Wiernik, PH.[2010]

FLT3 mutations, particularly FLT3-ITD, are found in about one-third of acute myeloid leukemia (AML) patients and are linked to worse outcomes with standard treatments, but new FLT3 inhibitors like midostaurin and gilteritinib have significantly improved patient survival rates.

Midostaurin was the first FLT3 inhibitor approved by the FDA in 2017 for newly diagnosed FLT3-mutated AML, while gilteritinib was approved in 2018 for relapsed cases, highlighting a major advancement in targeted therapy for this aggressive cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emerging treatment paradigms with FLT3 inhibitors in acute myeloid leukemia. Short, NJ., Kantarjian, H., Ravandi, F., et al.[2020]

In a phase II study, ruxolitinib, starting at a low dose of 5 mg twice daily, showed significant efficacy in myelofibrosis patients with low platelet counts (50-100 × 10^9/L), with 62% of patients achieving stable doses of 10 mg twice daily by week 24, and median reductions in spleen volume and symptoms of 24.2% and 43.8%, respectively.

While some patients experienced thrombocytopenia requiring dose adjustments, the treatment was generally manageable, with mean hemoglobin levels remaining stable, indicating that ruxolitinib can be safely administered to this subset of patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interim analysis of safety and efficacy of ruxolitinib in patients with myelofibrosis and low platelet counts. Talpaz, M., Paquette, R., Afrin, L., et al.[2021]

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Giving CART123 cells in combination with ruxolitinib may be safe, tolerable, and/or effective in treating patients with relapsed or refractory AML. Eligibility ...

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Phase I, open-label study to assess the safety, feasibility, pharmacokinetics, and preliminary efficacy of CART123 cells given in combination with ...

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CART123 + Ruxolitinib for Acute Myelogenous Leukemia

The study reported a high overall survival rate of 89.5% at one year, indicating that ruxolitinib is well tolerated and can be beneficial in real-life clinical ...