Regorafenib + Venetoclax + Azacitidine for Acute Myeloid Leukemia

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: City of Hope Medical Center

Must be taking: Venetoclax, Azacitidine

Must not be taking: CYP3A4 inducers, CYP3A inhibitors

Disqualifiers: Stem cell transplant, Active CNS disease, Uncontrolled infection, Unstable cardiac disease, others

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

Compensation: Varies

Number of Visits: 4

Duration: 12 months

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new combination of three medications—regorafenib, venetoclax, and azacitidine—to determine their safety and effectiveness in treating acute myeloid leukemia (AML) that has returned or not responded to treatment. Regorafenib blocks a protein that aids cancer cell growth, venetoclax prevents cancer cell survival, and azacitidine promotes the production of normal blood cells while eliminating abnormal ones. The trial seeks participants with AML that hasn't improved with other treatments or has relapsed, particularly those with symptoms affecting daily life. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new combination therapy.

Do I need to stop my current medications to join the trial?

The trial does not specify if you need to stop all current medications, but you cannot take certain drugs like strong CYP3A4 inducers or inhibitors. You can continue venetoclax and/or azacitidine if you are already on them.

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

Previous studies have tested regorafenib, venetoclax, and azacitidine for safety in humans. Regorafenib can inhibit proteins that promote cancer cell growth and is already approved for some cancers, providing some safety information. Venetoclax blocks a protein essential for cancer cell survival. Azacitidine aids the body in producing normal blood cells and eliminating abnormal ones.

Reports from these studies have noted health changes, such as unusual lab results. However, such occurrences are common with many treatments and do not always indicate that the treatment is unsafe. The trial is in an early phase, so researchers are primarily focused on ensuring safety and determining the optimal dose. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of regorafenib, venetoclax, and azacitidine for treating Acute Myeloid Leukemia (AML) because it brings a fresh approach to tackling this aggressive cancer. Unlike standard treatments that often focus on chemotherapy alone, this combo targets cancer cells in multiple ways. Regorafenib inhibits various enzymes that promote cancer growth, venetoclax disrupts proteins that help cancer cells survive, and azacitidine incorporates into the DNA to stop cancer cell division. This multi-pronged attack has the potential to be more effective than existing options, potentially leading to better outcomes for patients with AML.

What evidence suggests that this combination treatment could be effective for acute myeloid leukemia?

Research suggests that combining regorafenib, venetoclax, and azacitidine could be promising for treating relapsed or refractory acute myeloid leukemia (AML). In this trial, participants will receive these three drugs together. Regorafenib blocks proteins that aid cancer cell growth, potentially slowing or stopping the spread of cancer. Venetoclax targets the BCL-2 protein, essential for cancer cell survival. Azacitidine aids the bone marrow in producing normal blood cells and eliminating abnormal ones. Together, these drugs might effectively target cancer cells in AML patients who did not respond to previous treatments or whose cancer has returned. ^{1 2 3 4 6}

Who Is on the Research Team?

Paul Koller

Principal Investigator

City of Hope Medical Center

Are You a Good Fit for This Trial?

This trial is for patients with acute myeloid leukemia (AML) that has either returned after treatment or hasn't responded to previous treatments. Participants should have a form of AML suitable for the drugs being tested.

Inclusion Criteria

International normalized ratio (INR) OR Prothrombin (PT) ≤ 1.5 x ULN

I am capable of having children and have not been sterilized.

I have cancer outside the bone marrow but it also affects my bone marrow.

Exclusion Criteria

I have an active brain or spinal cord disease.

I have a history of bleeding or clotting disorders.

I haven't had cancer treatments like chemo or immunotherapy in the last 14 days.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive regorafenib, venetoclax, and azacitidine in 28-day cycles for up to 12 cycles

12 months

Monthly visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

12 months

Every 3 months (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Regorafenib
• Venetoclax

Trial Overview

The trial tests regorafenib, venetoclax, and azacitidine's safety and effectiveness in treating relapsed/refractory AML. It aims to find the best dose while assessing how well these drugs work together against AML.

How Is the Trial Designed?

Group I: Treatment (regorafenib, venetoclax, azacitidine) Experimental Treatment 5 Interventions

Patients receive regorafenib PO QD on days 1-21 of each cycle, venetoclax PO QD on days 1-21 of each cycle, and azacitidine IV over 10-40 minutes on days 1-7 of each cycle. Cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration during screening and on study as well as blood sample collection on study.

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

Approved in European Union as Vidaza for:

• Acute myeloid leukemia
• Chronic myelomonocytic leukemia
• Myelodysplastic syndromes

Approved in United States as Vidaza for:

• Myelodysplastic syndromes
• Chronic myelomonocytic leukemia

Approved in Canada as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Approved in Japan as Vidaza for:

• Myelodysplastic syndromes
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Regorafenib is an oral multi-kinase inhibitor that has shown significant survival benefits in metastatic colorectal cancer and has been FDA approved for this use since 2012.

The drug also improves progression-free survival in patients with metastatic gastrointestinal stromal tumors and advanced hepatocellular carcinoma, leading to its FDA approval for these conditions as well.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib. Ettrich, TJ., Seufferlein, T.[2018]

In a phase I trial involving 9 patients with advanced nonsquamous non-small-cell lung cancers, regorafenib combined with cisplatin and pemetrexed showed promising efficacy, with 56% of patients achieving a partial response and a median progression-free survival of 7 months.

Regorafenib was found to have acceptable tolerability and only minor pharmacokinetic interactions with the chemotherapy agents, indicating it can be safely combined with standard treatments for this type of lung cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Preliminary Safety, Pharmacokinetics, and Efficacy of Regorafenib, Cisplatin, and Pemetrexed in Patients With Advanced Nonsquamous Non-Small-Cell Lung Cancers. Hellmann, MD., Sturm, I., Trnkova, ZJ., et al.[2022]

In a phase II study involving 60 older or unfit patients with newly diagnosed acute myeloid leukemia (AML), the combination of venetoclax with cladribine and low-dose cytarabine alternating with venetoclax and 5-azacitidine resulted in a high composite complete response rate of 93%.

The treatment showed promising overall survival and disease-free survival rates, with only one death occurring within 4 weeks, indicating that this regimen is effective and has a favorable safety profile for this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II Study of Venetoclax Added to Cladribine Plus Low-Dose Cytarabine Alternating With 5-Azacitidine in Older Patients With Newly Diagnosed Acute Myeloid Leukemia. Kadia, TM., Reville, PK., Wang, X., et al.[2023]

In a study of 13 patients with acute leukemia treated with venetoclax and azacitidine, 46% developed COVID-19, highlighting a significant risk associated with this treatment during the pandemic.

The study found that 33% of those who contracted COVID-19 died from the virus, indicating that COVID-19 can lead to severe outcomes in patients receiving AZA-VEN therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

SARS-CoV-2 Infection in Patients Treated with Azacitidine and Venetoclax for Acute Leukemia: A Report of a Case Series Treated in a Single Institution. Drozd-Sokołowska, J., Mądry, K., Barankiewicz, J., et al.[2023]

Regorafenib is the first approved tyrosine kinase inhibitor for metastatic colorectal cancer, showing significant improvements in progression-free and overall survival in patients who had previously undergone multiple lines of chemotherapy and targeted therapies, based on results from two phase III trials.

While regorafenib has a safety profile similar to other tyrosine kinase inhibitors, it is associated with specific adverse events like hand-foot skin reaction and hypertension, which can be managed effectively through patient education and timely dose adjustments, allowing patients to continue benefiting from the treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving patient outcomes with regorafenib for metastatic colorectal cancer - patient selection, dosing, patient education, prophylaxis, and management of adverse events. Hofheinz, RD., Arnold, D., Kubicka, S., et al.[2015]

In patients with newly diagnosed unfit acute myeloid leukemia (AML), the combination of azacitidine and venetoclax is a standard first-line treatment.

However, patients with TP53-mutated AML and poor-risk cytogenetics do not benefit from adding venetoclax to azacitidine, suggesting that alternative treatment regimens should be considered for these individuals.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. Green, SD., Zeidner, JF.[2023]

In a Japanese subgroup of the phase 3 VIALE-A trial, venetoclax-azacitidine significantly improved overall survival rates compared to placebo-azacitidine, with 67% of patients alive at 12 months versus 46% in the placebo group.

The treatment also resulted in a high complete response (CR) and CR with incomplete hematologic recovery (CRi) rate of 67%, while maintaining a safety profile similar to the global study, indicating it is a viable first-line treatment for Japanese patients with acute myeloid leukemia ineligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. Yamamoto, K., Shinagawa, A., DiNardo, CD., et al.[2023]

In a phase 1/2 study involving six Japanese patients aged 60 and older with acute myeloid leukaemia, the combination of venetoclax and azacitidine demonstrated a high response rate, with 83% of patients achieving a response, including three complete remissions.

The treatment was generally well tolerated, with a median overall survival of 15.7 months, although some patients experienced serious adverse events, including grade 3 fungal pneumonia, which required treatment adjustments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. Taniguchi, S., Yamauchi, T., Choi, I., et al.[2021]

This study aims to evaluate the efficacy and safety of a combination treatment of dose-adjusted regorafenib and FOLFIRI in patients with metastatic colorectal cancer (mCRC), focusing on progression-free survival as the primary endpoint.

By adjusting the doses of regorafenib and irinotecan based on individual genetic factors, the study seeks to reduce treatment-related adverse events, making the combination therapy more tolerable for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Regorafenib plus FOLFIRI with irinotecan dose escalated according to uridine diphosphate glucuronosyltransferase 1A1genotyping in previous treated metastatic colorectal cancer patients:study protocol for a randomized controlled trial. Ma, CJ., Chang, TK., Tsai, HL., et al.[2020]

Regorafenib is an effective oral multikinase inhibitor used in treating colorectal cancer, targeting multiple pathways involved in tumor growth.

Aflibercept and ramucirumab are both angiogenesis inhibitors that help treat metastatic colorectal cancer by blocking blood vessel formation, with aflibercept being the second FDA-approved anti-angiogenic agent for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[New molecular targeting drugs for metastatic colorectal cancer]. Komatsu, Y., Harada, K., Fukushima, H., et al.[2023]

Citations

1.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06454409

Study Details | NCT06454409 | Regorafenib in ...

Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

2.

clinicaltrials.gov

clinicaltrials.gov/study/NCT06454409?term=AREA%5BConditionSearch%5D(Cancer)%20AND%20AREA%5BBasicSearch%5D(BCL2%20inhibitors)&rank=7

Study Details | Regorafenib in Combination With ...

An unfavorable change in the health of a participant, including abnormal laboratory findings, that happens during a clinical study or within a certain amount of ...

3.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC9636149/

Molecular targeted therapy for anticancer treatment - PMC

Molecular targeted therapies have transformed cancer treatment, enabling personalized treatment of tumors in which growth is being powered by specific ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC11442590/

Targeted therapy of cancer stem cells: inhibition of mTOR in ...

In this review, we demonstrate the association between the mTOR pathway and cancer, including CSCs. Additionally, we discuss a new concept for anti-cancer drug ...

5.

smartpatients.com

smartpatients.com/trials/NCT06454409

Regorafenib in Combination With Venetoclax and ...

Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

6.

clin.larvol.com

clin.larvol.com/trial-detail/NCT06454409

Regorafenib in Combination With Venetoclax and ...

AEs will be graded according to the NCI CTCAE v 5.0 and reported by type, frequency, severity, attribution, time course, and duration. Up to 30 days after last ...