Ivosidenib + Venetoclax +/- Azacitidine for Leukemia

Recruiting at 4 trial locations

Overseen By Courtney DiNardo, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: CYP3A inducers

Disqualifiers: Active infection, Active malignancy, HIV, others

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

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: Unknown

Duration: 28 days per cycle, up to 3 years

96 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine the optimal dose and understand the side effects of combining two drugs, ivosidenib (Tibsovo) and venetoclax, with or without azacitidine, to treat certain blood cancers. These drugs stop cancer cells from growing and spreading. The trial seeks participants with specific blood cancers, such as acute myeloid leukemia (AML) with an IDH1 mutation, who have not responded to standard treatments or are newly diagnosed but cannot undergo standard chemotherapy. Individuals with this type of leukemia that affects daily life may be suitable for this trial.

As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the chance to be among the first to receive this new treatment combination.

Do I have to stop taking my current medications for the trial?

The trial protocol does not specify if you must stop taking your current medications, but you cannot use other chemotherapeutic or anti-leukemic agents during the study, except for certain exceptions like intrathecal chemotherapy or hydroxyurea. Also, you should not take strong CYP3A inducers within 3 days of starting the study therapy.

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

Research has shown that the combination of ivosidenib, venetoclax, and azacitidine is generally safe for people with certain blood cancers. Studies indicate that this treatment is well-tolerated and effective against cancer cells with specific mutations.

Evidence confirms that this combination can overcome some resistance seen with other treatments. Most side effects are manageable, though serious reactions can occur. However, these are uncommon, and doctors closely monitor patients to address any issues quickly.

Overall, the treatment shows promise in fighting cancer while prioritizing patient safety. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the combination of Ivosidenib and Venetoclax for treating leukemia because these drugs work in unique ways compared to existing options. Ivosidenib targets and inhibits a mutant form of the IDH1 enzyme, which is often present in certain types of leukemia, thereby disrupting the cancer's energy production and growth. Venetoclax, on the other hand, targets and blocks the BCL-2 protein, which helps cancer cells survive, leading to their death. This combination could potentially offer a more effective approach with a higher chance of overcoming resistance seen in standard treatments like chemotherapy.

What evidence suggests that this trial's treatments could be effective for hematologic malignancies?

Research has shown that combining the drugs ivosidenib, venetoclax, and azacitidine may help patients with certain blood cancers remain in remission longer. In this trial, participants will receive a combination of these three drugs. One study found that using ivosidenib with azacitidine was more effective than standard treatments. Another study demonstrated that ivosidenib, when used with a drug affecting DNA, worked better than venetoclax with the same type of drug. These findings suggest that the combination of ivosidenib, venetoclax, and azacitidine could be more effective for treating blood cancers with an IDH1 mutation. ^{5 6 7 8 9}

Who Is on the Research Team?

Courtney DiNardo, MD

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients with IDH1-mutated blood cancers like AML, MDS, or MPN who are either treatment-naive and ineligible for standard chemotherapy or have relapsed/refractory disease. Participants must be in stable condition with acceptable organ function and agree to contraception. Those previously treated with ivosidenib/venetoclax, active infections (HBV/HCV/HIV), uncontrolled medical conditions, severe allergies to study drugs, or on certain medications are excluded.

Inclusion Criteria

I have AML or a related condition and cannot have standard chemotherapy.

My liver is functioning well, according to my recent tests.

I haven't had cancer treatment in the last 7 days.

Exclusion Criteria

I am not pregnant, using effective birth control, or not of childbearing potential.

My white blood cell count is above 25 x 10⁹/L.

Patients with any concurrent uncontrolled clinically significant medical condition including infection, laboratory abnormality, or psychiatric illness, which could place the patient at unacceptable risk of study treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive venetoclax orally daily on days 1-14, ivosidenib orally daily on days 15-28 of cycle 1 and days 1-28 of subsequent cycles, and may receive azacitidine intravenously or subcutaneously on days 1-7. Cycles repeat every 28 days.

28 days per cycle, up to 3 years

Follow-up

Participants are monitored for safety and effectiveness after treatment completion, with follow-up at 30 days and then monthly for 3 years.

3 years

What Are the Treatments Tested in This Trial?

Interventions

• Azacitidine
• Ivosidenib
• Venetoclax

Trial Overview The trial examines the effectiveness of combining venetoclax and ivosidenib with or without azacitidine in treating hematologic malignancies. It aims to determine the best dose while assessing side effects when these drugs work together compared to using just venetoclax and ivosidenib.

How Is the Trial Designed?

Group I: Treatment (venetoclax, ivosidenib, azacitidine) Experimental Treatment 3 Interventions

Patients receive venetoclax PO daily on days 1-14. Patients also receive ivosidenib PO daily on days 15-28 of cycle 1 and days 1-28 of subsequent cycles. Patients may also receive azacitidine IV over 30-60 minutes or SC on days 1-7. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Ivosidenib is already approved in United States, European Union for the following indications:

Approved in United States as Tibsovo for:

• Acute myeloid leukemia (AML) with IDH1 mutation

Approved in European Union as Tibsovo for:

• Acute myeloid leukemia (AML) with IDH1 mutation

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

Published Research Related to This Trial

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]

Venetoclax, when combined with azacitidine, has shown effectiveness in treating a 73-year-old patient with acute myeloid leukemia (AML) who was undergoing dialysis and ineligible for standard therapies.

The combination of venetoclax and azacitidine appears to be a safe and feasible treatment option for AML patients with comorbidities, such as those requiring dialysis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Administration of combined venetoclax and azacitidine in a patient with acute myeloid leukemia and multiple comorbidities undergoing dialysis: A case report. Akagi, Y., Yamashita, Y., Kosako, H., et al.[2023]

Outpatient induction therapy using low-dose venetoclax combined with itraconazole and azacitidine is feasible and safe for newly diagnosed acute myeloid leukemia (ND-AML) patients, with 77.7% of participants completing the first treatment cycle as outpatients.

The treatment showed promising efficacy, with a composite complete response rate of 53.9% after the first cycle and 85.7% after the second cycle, indicating that this regimen could be a viable option for patients eligible for intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Low dose venetoclax plus itraconazole outpatient induction in newly diagnosed acute myeloid leukemia: A phase 2 study. De la Garza-Salazar, F., Colunga-Pedraza, PR., Gómez-Almaguer, D., et al.[2023]

In a study of nine AML patients with acquired resistance to venetoclax, the typical BCL2 mutation associated with resistance was not found, suggesting that this mutation is not necessary for developing resistance in AML.

The study identified that existing mutations, particularly the expansion of FLT3-ITD, were primarily responsible for venetoclax resistance, indicating that monitoring these mutations could help in developing strategies to prevent or overcome resistance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Not BCL2 mutation but dominant mutation conversation contributed to acquired venetoclax resistance in acute myeloid leukemia. Zhang, X., Qian, J., Wang, H., et al.[2022]

Venetoclax is a highly effective treatment for relapsed or refractory chronic lymphocytic leukemia (CLL), achieving response rates of about 80% in clinical trials involving 240 patients from 2011 to 2016.

While venetoclax has an acceptable safety profile, common side effects include neutropenia and diarrhea, and there is a risk of tumor lysis syndrome (TLS), which can be managed through careful dose ramp-up and patient education, leading to no reported TLS events in ongoing trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: Management and Care for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia . Brumbaugh Paradis, H., Alter, D., Llerandi, D.[2018]

In the phase III CLL14 trial, a 12-month treatment with venetoclax combined with obinutuzumab significantly improved progression-free survival and rates of undetectable minimal residual disease compared to traditional chemoimmunotherapy with chlorambucil and obinutuzumab in patients with untreated chronic lymphocytic leukaemia.

Venetoclax + obinutuzumab is a well-tolerated, chemotherapy-free treatment option for CLL, with manageable side effects like neutropenia, making it suitable for patients who cannot undergo intensive chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Venetoclax: A Review in Previously Untreated Chronic Lymphocytic Leukaemia. Blair, HA.[2021]

In a study of 6 children with refractory or relapsed acute myeloid leukemia (AML), the combination of venetoclax, azacitidine, and cladribine (VAC regimen) resulted in significant treatment responses, with 4 achieving complete remission and 1 showing partial remission.

Despite severe side effects like grade IV neutropenia and thrombocytopenia, there were no treatment-related deaths or infections, indicating that the VAC regimen is both effective and safe for this vulnerable patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Safety and the Short-Term Efficacy of Venetoclax Combined with Azacitidine Followed by Cladribine in Children with Refractory/Relapsed Acute Myeloid Leukemia]. DU, WW., Liu, SX., Wang, Y., 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]

Citations

1. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/40491347/

Indirect treatment comparison of ivosidenib and other ... Results of the NMA showed that ivosidenib + azacitidine was the treatment with the greatest effect, while the MAIC showed that ivosidenib + ...

2. ashpublications.org ashpublications.org/blood/article/144/Supplement%201/219/530721/A-Phase-Ib-II-Study-of-Ivosidenib-with-Venetoclax

A Phase Ib/II Study of Ivosidenib with Venetoclax ± Azacitidine ... Combining IVO, VEN, and AZA into one regimen may improve durability of long-term remission. Herein, we report updated results from the multisite ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S2950328025000871

Ivosidenib or venetoclax combined with hypomethylating ... In this real-world study of patients with mIDH1 ND-AML, IVO+HMA vs VEN+HMA improved CR, time to response, and event-free survival. •. With enhanced efficacy ...

4. nejm.org nejm.org/doi/full/10.1056/NEJMoa2117344

Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid ... Ivosidenib and azacitidine showed significant clinical benefit as compared with placebo and azacitidine in this difficult-to-treat population.

5. ascopost.com ascopost.com/issues/digital-supplement-ash-meeting-highlights-2023/study-examines-real-world-outcomes-with-ivosidenib-vs-venetoclax-in-acute-myeloid-leukemia/

Study Examines Real-World Outcomes With Ivosidenib vs ... Treatment with the IDH1-targeted agent ivosidenib plus a hypomethylating agent was associated with better outcomes than venetoclax plus a hypomethylating agent.

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10320628/

A Phase Ib/II Study of Ivosidenib with Venetoclax ± ... IVO + VEN + AZA is safe and active in patients with IDH1-mutated myeloid malignancies. Combination therapy appears to overcome resistance mechanisms observed ...

7. ashpublications.org ashpublications.org/bloodneoplasia/article/2/4/100152/546463/Ivosidenib-or-venetoclax-combined-with

Ivosidenib or venetoclax combined with hypomethylating ... In this real-world study of patients with mIDH1 ND-AML, IVO+HMA vs VEN+HMA improved CR, time to response, and event-free survival.

8. clinicaltrials.gov clinicaltrials.gov/study/NCT03471260

NCT03471260 | Ivosidenib and Venetoclax With or Without ... Giving ivosidenib and venetoclax with azacitidine may work better in treating patients with hematologic malignancies compared to ivosidenib and venetoclax alone ...

9. ascopubs.org ascopubs.org/doi/10.1200/JCO.2023.41.16_suppl.7012

Updated efficacy and safety data from the AGILE study in ... IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival (OS), complete remission (CR), and CR or CR with partial ...