Ixazomib + Chemotherapy for Leukemia

Recruiting at 17 trial locations

Overseen By Benjamin Brookhart

Age: < 65

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Therapeutic Advances in Childhood Leukemia Consortium

Must not be taking: Investigational drugs, Anti-GVHD agents, CYP3A4 inducers, TKI therapy

Disqualifiers: CNS/testicular disease, Neuropathy, Infections, DNA fragility, others

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 5 weeks

24 Participants Needed

Trial Summary

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

The trial protocol does not specify if you need to stop all current medications, but some medications can be continued up to 24 hours before starting the trial. These include hydroxyurea and certain 'maintenance-style' therapies like vincristine, oral 6-mercaptopurine, oral methotrexate, dexamethasone, and prednisone. However, you cannot be on investigational drugs, anti-GVHD agents, or strong CYP3A4 inducers.

Is ixazomib safe for use in humans?

Ixazomib, also known as Ninlaro, has been shown to have a generally tolerable safety profile in humans, particularly in patients with multiple myeloma. Common side effects include low blood platelet counts, diarrhea, and nausea, with some serious side effects like severe gastrointestinal issues and infections. Close monitoring for these side effects is recommended. ^{1 2 3 4 5}

What makes the drug Ixazomib unique for treating leukemia?

Ixazomib is unique because it is an oral proteasome inhibitor, which means it blocks the action of proteasomes (cellular complexes that break down proteins) to help kill cancer cells. This oral administration can be more convenient compared to traditional intravenous chemotherapy treatments. ^{6 7 8 9 10}

What is the purpose of this trial?

This is a phase 1/2 study of a drug called Ixazomib in combination with cytotoxic chemotherapy consisting of Vincristine, Dexamethasone, Asparaginase, and Doxorubicin (VXLD).

Research Team

Terzah Horton, MD

Principal Investigator

Baylor College of Medicine

Eligibility Criteria

This trial is for children and young adults up to 21 years old with relapsed or refractory Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LLy). Participants must have tried previous therapies, have a certain level of physical ability, and not be breastfeeding. They can't join if they've had too much exposure to anthracyclines, specific CNS diseases, ongoing infections without improvement, significant concurrent illnesses that could affect safety or compliance, DNA fragility syndromes, certain levels of neuropathy, or are on disallowed medications.

Inclusion Criteria

I have not had craniospinal radiation therapy during this treatment.

It's been over 3 weeks since my last monoclonal antibody treatment.

I am mostly able to care for myself, regardless of my age.

Exclusion Criteria

My cancer is only in my brain/CNS or testicles.

I plan to receive other cancer treatments not part of the study.

Significant concurrent disease, illness, psychiatric disorder or social issue compromising patient safety or compliance

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive Ixazomib in combination with chemotherapy drugs including Vincristine, Dexamethasone, Asparaginase, and Doxorubicin to determine the maximum tolerated dose and efficacy

5 weeks

Multiple visits for drug administration and monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Ixazomib

Trial Overview The study tests Ixazomib combined with chemotherapy drugs Vincristine, Dexamethasone, Asparaginase and Doxorubicin in patients who haven't responded well to other treatments. It's designed in two phases: Phase 1 focuses on the drug's safety and tolerability while Phase 2 evaluates its effectiveness against ALL/LLy.

Participant Groups

Group I: Ixazomib Dose Level 2 (Stratum A) Experimental Treatment 7 Interventions

Patients will be treated on ixazomib at 2.0 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. Patients will be treated at this arm Dose Level once patient accrual at Dose Level 1 has been completed and dose escalation is allowed as defined by the 3+3 design.

Group II: Ixazomib Dose Level 1 (Stratum B) Experimental Treatment 8 Interventions

Patients will be treated on ixazomib at 1.6 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. Leucovorin PO/IV at 5 mg/m\^2/dose X 2 doses given 24 and 30 hours after IT Methotrexate or Triple IT will also be given on this arm. This arm is only for patients with Down syndrome (Stratum B).

Group III: Ixazomib Dose Level 1 (Stratum A) Experimental Treatment 7 Interventions

Patients will be treated on ixazomib at 1.6 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. This arm is the starting Dose Level for patients being enrolled.

Group IV: Ixazomib Dose Level -1 (Stratum A) Experimental Treatment 7 Interventions

Patients will be treated on ixazomib at 1.2 mg/m\^2/day on Days 1, 4, 8, and 11. Vincristine IV at 1.5 mg/m\^2 on Days 1, 8, 15 and 22. Pegaspargase IV/IM at 2500 IU/m\^2 on Days 2 and 15, Doxorubicin at 60 mg/m\^2 on Days 1, Dexamethasone IV/PO at 10 mg/m\^2 continuous starting on Day 1 thru Day 14, and IT chemotherapy dependent on patient's CNS status at time of enrollment. This arm Dose Level -1 is needed only if de-escalation from Dose Level 1 is required.

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

Approved in United States as Ninlaro for:

• Multiple myeloma in combination with lenalidomide and dexamethasone

Approved in European Union as Ninlaro for:

• Multiple myeloma in combination with lenalidomide and dexamethasone

Approved in Canada as Ninlaro for:

• Multiple myeloma in combination with lenalidomide and dexamethasone

Approved in Japan as Ninlaro for:

• Multiple myeloma in combination with lenalidomide and dexamethasone

Who Is Running the Clinical Trial?

Therapeutic Advances in Childhood Leukemia Consortium

Lead Sponsor

Trials

21

Recruited

680+

Takeda

Industry Sponsor

Trials

1,255

Recruited

4,219,000+

Dr. Naoyoshi Hirota

Takeda

Chief Medical Officer since 2020

MD from University of Tokyo

Christophe Weber

Takeda

Chief Executive Officer since 2015

PhD in Molecular Biology from Université de Montpellier

Children's Hospital Los Angeles

Collaborator

Trials

257

Recruited

5,075,000+

Findings from Research

Ixazomib is an orally taken proteasome inhibitor that works by blocking the β5 subunit of the proteasome, and it was approved by the FDA in 2015 for treating multiple myeloma in combination with lenalidomide and dexamethasone after at least one prior therapy.

Currently, ixazomib is being studied in Phase III trials for newly diagnosed multiple myeloma and other conditions, indicating its potential for broader applications in treating various cancers and autoimmune diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ixazomib: First Global Approval. Shirley, M.[2018]

Ixazomib, an oral proteasome inhibitor, has been shown to significantly improve progression-free survival in patients with relapsed and/or refractory multiple myeloma when combined with lenalidomide and dexamethasone, with a median survival of 20.6 months compared to 14.7 months for the placebo group.

The drug works by selectively inhibiting the 20S proteasome, leading to the accumulation of proteins that induce stress and apoptosis in myeloma cells, making it a promising treatment option for patients who have undergone prior therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Pharmacological characteristics and clinical study results of the oral proteasome inhibitor ixazomib (NINLARO&#174; capsules; 2.3&#8197;mg, 3&#8197;mg, and 4&#8197;mg)]. Machida, M., Fukunaga, S., Hara, T.[2019]

The study evaluates the safety and efficacy of venetoclax combined with oral azacitidine as maintenance therapy for patients with acute myeloid leukemia (AML) who are in complete remission but have incomplete blood count recovery after intensive treatment.

The primary goal of the trial is to assess relapse-free survival, with secondary outcomes including overall survival and quality of life, highlighting the potential of this combination therapy to prevent relapse in AML patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia. Ivanov, V., Yeh, SP., Mayer, J., et al.[2022]

The combination of venetoclax (Ven) and azacitidine (AZA) shows a high efficacy in treating acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), with an overall complete response rate of 57.9% across 19 studies involving 1615 patients.

This treatment is particularly effective for newly diagnosed AML patients, achieving a complete response rate of 67.5%, although it is less effective for those with relapsed or refractory AML, which had a response rate of only 30%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. Du, Y., Li, C., Yan, J.[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]

The combination of 225 Ac-lintuzumab and venetoclax showed a synergistic effect in killing tumor cells in venetoclax-resistant acute myeloid leukemia (AML) models, indicating a potential new treatment strategy.

This combination therapy not only induced DNA damage but also reduced MCL-1 protein levels, which is linked to resistance against venetoclax, leading to better tumor control and prolonged survival in preclinical studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. Garg, R., Allen, KJH., Dawicki, W., et al.[2021]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Ixazomib: First Global Approval. [2018]

2. Japan pubmed.ncbi.nlm.nih.gov

[Pharmacological characteristics and clinical study results of the oral proteasome inhibitor ixazomib (NINLARO&#174; capsules; 2.3&#8197;mg, 3&#8197;mg, and 4&#8197;mg)]. [2019]

3. Japan pubmed.ncbi.nlm.nih.gov

Safety Profile of Ixazomib in Patients with Relapsed/Refractory Multiple Myeloma in Japan: An All-case Post-marketing Surveillance. [2022]

4. England pubmed.ncbi.nlm.nih.gov

European Medicines Agency review of ixazomib (Ninlaro) for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Safety of ixazomib for the treatment of multiple myeloma. [2017]

6. England pubmed.ncbi.nlm.nih.gov

Design of the VIALE-M phase III trial of venetoclax and oral azacitidine maintenance therapy in acute myeloid leukemia. [2022]

7. England pubmed.ncbi.nlm.nih.gov

The efficacy and safety of venetoclax and azacytidine combination treatment in patients with acute myeloid leukemia and myelodysplastic syndrome: systematic review and meta-analysis. [2023]

8. 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]

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

225Ac-labeled CD33-targeting antibody reverses resistance to Bcl-2 inhibitor venetoclax in acute myeloid leukemia models. [2021]

10. England pubmed.ncbi.nlm.nih.gov

Indirect treatment comparison of oral versus injectable azacitidine as maintenance therapy for acute myeloid leukemia. [2022]