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

20 Participants Needed

Trial Summary

What is the purpose of this trial?

This phase Ib trial tests the safety, side effects, best dose and effectiveness of regorafenib in combination with venetoclax and azacitidine in treating patients with acute myeloid leukemia (AML) that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Regorafenib is in a class of medications called kinase inhibitors. It works by blocking the action of an abnormal protein that signals cancer cells to multiply. This helps to slow or stop the spread of cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (BCL-2) inhibitors. It may stop the growth of cancer cells by blocking BCL-2, a protein needed for cancer cell survival. Azacitidine is in a class of medications called demethylation agents. It works by helping the bone marrow to produce normal blood cells and by killing abnormal cells. Giving regorafenib in combination with venetoclax and azacitidine may be safe, tolerable and/or effective in treating patients with relapsed or refractory AML.

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.

What data supports the effectiveness of the drug combination Regorafenib, Venetoclax, and Azacitidine for treating Acute Myeloid Leukemia?

Research shows that the combination of Venetoclax and Azacitidine improves survival and remission rates in older or unfit patients with newly diagnosed acute myeloid leukemia compared to Azacitidine alone. ^{1 2 3 4 5}

What safety data exists for Regorafenib in humans?

Regorafenib has been studied in humans for conditions like metastatic colorectal cancer, and common side effects include hand-foot skin reaction, high blood pressure, fatigue, diarrhea, and liver issues. These side effects often occur early in treatment and can be managed with dose adjustments and close monitoring. ^{6 7 8 9 10}

What makes the drug combination of Regorafenib, Venetoclax, and Azacitidine unique for treating Acute Myeloid Leukemia?

This drug combination is unique because it combines Regorafenib, a multi-kinase inhibitor that targets various cancer-related pathways, with Venetoclax, which promotes cancer cell death by inhibiting a protein called BCL-2, and Azacitidine, which affects DNA methylation to stop cancer cell growth. This multi-faceted approach targets different mechanisms in cancer cells, potentially offering a novel treatment option for Acute Myeloid Leukemia. ^{6 11 12 13 14}

Research Team

Paul Koller

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

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 a history of bleeding or clotting disorders.

I have an active brain or spinal cord disease.

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

Timeline

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)

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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 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 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 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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Venetoclax in combination with azacitidine in Japanese patients with acute myeloid leukaemia: phase 1 trial findings. [2021]

2. England pubmed.ncbi.nlm.nih.gov

Venetoclax plus azacitidine in Japanese patients with untreated acute myeloid leukemia ineligible for intensive chemotherapy. [2023]

3. United States 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. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

TP53 or Not TP53: That Is the Question. [2023]

5. Switzerland 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. [2023]

6. England 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. [2020]

7. Japan pubmed.ncbi.nlm.nih.gov

[New molecular targeting drugs for metastatic colorectal cancer]. [2023]

8. Japan pubmed.ncbi.nlm.nih.gov

Fatigue associated with newly approved vascular endothelial growth factor receptor tyrosine kinase inhibitors in cancer patients: an up-to-date meta-analysis. [2018]

9. Switzerland 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. [2015]

10. United States pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of the oral multikinase inhibitor regorafenib and its association with real-world treatment outcomes. [2022]

11. Germany pubmed.ncbi.nlm.nih.gov

Regorafenib. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

Neratinib augments the lethality of [regorafenib + sildenafil]. [2020]

13. England pubmed.ncbi.nlm.nih.gov

Safety and efficacy of regorafenib in patients with treatment-refractory metastatic colorectal cancer in Turkey: the single-arm, open-label REGARD study. [2021]

14. United States 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. [2022]