Cobimetinib for Chronic Myelomonocytic Leukemia

(CONCERTO Trial)

Recruiting at 3 trial locations

Overseen By Braxton Smith

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Utah

Must not be taking: CYP3A inhibitors, St. John's Wort

Disqualifiers: CNS leukemia, Cardiovascular disease, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: up to 12 months

29 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests cobimetinib (Cotellic) to evaluate its effectiveness for individuals with chronic myelomonocytic leukemia (CMML) that exhibits RAS pathway activation. Participants will take cobimetinib daily in a 21-day cycle, followed by a 7-day break. The trial targets individuals diagnosed with CMML who have specific gene mutations linked to their leukemia. As a Phase 2 trial, the research focuses on assessing the treatment's effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial does not specify if you must stop all current medications, but you cannot take certain medications like strong CYP3A inhibitors or inducers. If you're on these, a washout period (time without taking these medications) of at least 5 half-lives is required before starting the trial.

Is there any evidence suggesting that cobimetinib is likely to be safe for humans?

Research has shown that cobimetinib has safety information from earlier studies. The FDA has approved it for use with certain other conditions, suggesting general safety. However, warnings exist about possible risks, especially for unborn babies, when cobimetinib is combined with other treatments. This indicates potential safety concerns, particularly for pregnant women. As this trial is in an early stage, the researchers are still learning about its safety. Participants should consider these factors and consult their healthcare providers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Cobimetinib is unique because it targets the MEK pathway, which is a key part of the signaling cascade involved in cell growth and survival. Most treatments for chronic myelomonocytic leukemia (CMML) focus on controlling symptoms and slowing disease progression, often through chemotherapy or hypomethylating agents. Unlike these standard treatments, cobimetinib specifically inhibits MEK1 and MEK2, potentially offering a more targeted approach to disrupt cancer cell growth. Researchers are excited about cobimetinib because it could provide a new, more precise way to manage CMML, potentially leading to improved outcomes for patients.

What evidence suggests that cobimetinib might be an effective treatment for chronic myelomonocytic leukemia?

Research has shown that cobimetinib might help treat chronic myelomonocytic leukemia (CMML) in patients with RAS pathway mutations. Cobimetinib targets specific proteins in the RAS pathway, which play a role in cell growth and survival. Early results suggest it could slow or halt cancer cell growth in CMML patients. Although detailed human data is still being collected, targeting the RAS pathway offers a promising treatment approach. This trial will evaluate cobimetinib as an option for individuals with this specific type of leukemia. ^{2 6 7 8 9}

Who Is on the Research Team?

Ami Patel

Principal Investigator

Huntsman Cancer Institute

Are You a Good Fit for This Trial?

Adults aged 18+ with Chronic Myelomonocytic Leukemia (CMML) and specific RAS pathway mutations, who have either not been treated or did not respond to hypomethylating agents. They must be able to perform daily activities (ECOG ≤3), have good kidney and liver function, heart function ≥50%, and no central nervous system leukemia. Women of childbearing potential must test negative for pregnancy and use effective contraception.

Inclusion Criteria

I have CMML with specific gene mutations and haven't responded to HMA treatment.

Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines

My FLT3-ITD ratio is 0.05 or higher from a recent test.

Exclusion Criteria

I have a history of lung scarring or fibrosis.

I have had serious eye conditions or am at high risk for them.

I have not had major surgery in the last 4 weeks.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive cobimetinib daily in 28-day cycles, with 21 days of treatment followed by a 7-day break

up to 12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 36 months

Long-term follow-up

Assessment of overall survival and long-term efficacy

up to 60 months

What Are the Treatments Tested in This Trial?

Interventions

• Cobimetinib

Trial Overview The trial is testing the drug Cobimetinib in patients with CMML that has certain genetic changes. Participants will take Cobimetinib daily for three weeks followed by a one-week break, repeating this cycle until they meet criteria for stopping treatment. The study aims to see how well the drug works in these patients.

How Is the Trial Designed?

Group I: Treatment: all patients Experimental Treatment 1 Intervention

Cobimetinib is taken on a 28-day cycle. Each dose consists of three 20 mg tablets (60 mg) and should be taken once daily for 21 consecutive days (Days 1 to 21-treatment period); followed by a 7-day break (Days 22 to 28-treatment break). Each subsequent cobimetinib treatment cycle should start after a 7-day treatment break has elapsed.

Cobimetinib is already approved in European Union, United States, Canada, Switzerland, Japan for the following indications:

Approved in European Union as Cotellic for:

• Melanoma

Approved in United States as Cotellic for:

• Melanoma

Approved in Canada as Cotellic for:

• Melanoma

Approved in Switzerland as Cotellic for:

• Melanoma

Approved in Japan as Cotellic for:

• Melanoma

Who Is Running the Clinical Trial?

University of Utah

Lead Sponsor

Trials

1,169

Recruited

1,623,000+

Genentech, Inc.

Industry Sponsor

Trials

1,578

Recruited

569,000+

Ashley Magargee

Genentech, Inc.

Chief Executive Officer since 2024

MBA from Harvard University, BA from Princeton University

Levi Garraway

Genentech, Inc.

Chief Medical Officer since 2021

MD, PhD

Published Research Related to This Trial

Bosutinib is an effective second-line treatment for chronic myelogenous leukemia (CML) in patients who are resistant or intolerant to first-line therapies like imatinib, dasatinib, and nilotinib, but it is not effective for those with the T315I mutation.

In a Phase 3 trial involving 502 patients, bosutinib showed similar efficacy to imatinib for newly diagnosed chronic phase CML, but due to this similarity, it is not recommended as a first-line treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib: a second-generation tyrosine kinase inhibitor for chronic myelogenous leukemia. Stansfield, L., Hughes, TE., Walsh-Chocolaad, TL.[2014]

Bosutinib is a newly approved tyrosine kinase inhibitor for chronic myeloid leukemia that is effective even in the presence of most kinase domain mutations, making it a valuable treatment option.

The primary side effects of bosutinib are gastrointestinal issues, which should be considered when selecting it as a treatment in the appropriate clinical setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical advances in the management of chronic myelogenous leukemia: focus on bosutinib and patient considerations. Sweet, K., Pinilla-Ibarz, J., Zhang, L.[2021]

Bosutinib is a dual inhibitor of Src and Abl kinases, showing strong efficacy against the Bcr-Abl fusion protein, which is critical in chronic myeloid leukaemia (CML), with lower concentrations needed to inhibit Bcr-Abl phosphorylation compared to imatinib.

In ongoing clinical trials, bosutinib has demonstrated effectiveness in CML patients who are resistant or intolerant to imatinib, and it is currently being compared to imatinib in a phase III study for first-line therapy in CML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib. Keller, G., Schafhausen, P., Brümmendorf, TH.[2017]

In a study of 87 patients with chronic myeloid leukemia (CML) treated with bosutinib, the drug demonstrated effectiveness with complete cytogenetic and major molecular response rates of 67% and 55%, respectively, after a median treatment duration of 15.6 months.

Bosutinib was generally well-tolerated, although 94% of patients experienced at least one adverse event, with diarrhea being the most common side effect; overall survival rates at 1 and 2 years were high at 95% and 91%, respectively.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective observational research study to describe the real-world use of bosutinib in patients with chronic myeloid leukemia in the United Kingdom and the Netherlands. Claudiani, S., Janssen, JJWM., Byrne, J., et al.[2022]

Bosutinib is an effective second-line treatment for patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) who are resistant or intolerant to other tyrosine kinase inhibitors (TKIs), showing durable hematologic and cytogenetic responses in clinical trials.

While bosutinib is not superior to imatinib for newly diagnosed CML, it is safe for use, with common side effects like diarrhea and nausea being generally mild and self-limiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bosutinib for the treatment of chronic myeloid leukemia. Doan, V., Wang, A., Prescott, H.[2019]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04409639

Cobimetinib in Newly Diagnosed or HMA-treated CMML Patients ... This is an open-label, nonrandomized phase 2 trial to assess the efficacy of cobimetinib in RAS pathway activated CMML.

2. mycancergenome.org mycancergenome.org/content/clinical_trials/NCT04409639/

Clinical Trial: NCT04409639 - CMML This is an open-label, nonrandomized phase 2 trial to assess the efficacy of cobimetinib in RAS pathway activated CMML.

3. researchgate.net researchgate.net/publication/365836962_Concerto_NCT04409639_A_Phase_2_Trial_of_Cobimetinib_in_Newly_Diagnosed_and_HMA-Treated_CMML_Patients_with_RAS_Pathway_Mutations

Concerto (NCT04409639): A Phase 2 Trial of Cobimetinib ... CMML presentation and outcome are variable, reflecting genetic and clinical heterogeneity.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11096042/

Chronic Myelomonocytic Leukemia: 2024 Update on ... ASCT is the only treatment modality that secures cure or long-term survival and is appropriate for MMM high/intermediate-2 risk disease.

5. cancertrials.ohsu.edu cancertrials.ohsu.edu/s/concerto-cobimetinib-in-chronic-myelomonocytic-leukemia-with-ras-pathway-mutations-706377/

Cobimetinib in Chronic Myelomonocytic Leukemia with ... The primary purpose of this research is to see if the use of cobimetinib (the study drug) may be effective for the treatment of chronic myelomonocytic leukemia ...

6. clinicaltrials.gov clinicaltrials.gov/study/NCT04409639

Cobimetinib in Newly Diagnosed or HMA-treated CMML ... This is an open-label, nonrandomized phase 2 trial to assess the efficacy of cobimetinib in RAS pathway activated CMML.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2015/206192Orig1s000PharmR.pdf

206192Orig1s000 - accessdata.fda.gov Based on the current study and its mechanism of action, a warning for embryofetal risk is recommended for cobimetinib used in combination with ...

8. haematologica.org haematologica.org/article/view/haematol.2021.279500

How I diagnose and treat chronic myelomonocytic leukemia While there are no clear safety or efficacy data on the use of luspatercept in CMML, I do consider off-label use in a select group of SF3B1 ...

9. onlinelibrary.wiley.com onlinelibrary.wiley.com/doi/full/10.1002/ajh.26455

Chronic myelomonocytic leukemia: 2022 update on ... DNMT3A mutations are seen in ~5% of CMML patients and independently and adversely impact both OS and LFS. Of note, a recurrent Arginine882 (R882) ...