Ixazomib + Chemotherapy for Leukemia

Not currently recruiting at 18 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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether adding Ixazomib, a new drug, to a mix of chemotherapy drugs can improve treatment for certain types of leukemia. The study aims to determine the best dose of Ixazomib when combined with other chemotherapy medicines to see if it better controls the disease. This trial suits patients diagnosed with relapsed or hard-to-treat acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LLy) who have not succeeded with other treatments. As a Phase 1 trial, this research focuses on understanding how the treatment works in people, offering participants a chance to be among the first to receive this new drug.

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

Research shows that Ixazomib, a pill medication, has been tested for safety in various clinical settings. Studies have found it to be generally well-tolerated, with most patients not experiencing serious long-term side effects. Common side effects include nausea, diarrhea, and fatigue, but these are usually mild.

Ixazomib is already FDA-approved for treating multiple myeloma, a type of blood cancer, indicating that its safety is well understood. However, its use with chemotherapy drugs like Vincristine, Dexamethasone, Asparaginase, and Doxorubicin remains under study. This trial is in the early stages, focusing on safety to determine if the combined treatment is safe enough for further research.

Prospective trial participants should discuss potential side effects and benefits with their doctor for more personalized information. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about ixazomib for leukemia because it represents a novel approach by specifically targeting and inhibiting a protein complex involved in cell degradation, known as the proteasome. Unlike traditional chemotherapy, which broadly attacks all rapidly dividing cells, ixazomib offers a more targeted mechanism, potentially leading to fewer side effects. Moreover, ixazomib is administered orally, which can be more convenient compared to the intravenous delivery required by many standard treatments. This unique combination of precise action and ease of administration is what sets ixazomib apart from existing therapies and fuels optimism about its potential benefits for patients.

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

Research has shown that ixazomib may help treat blood cancers like multiple myeloma. In earlier studies, when combined with other drugs, 67% of patients experienced a reduction or halt in cancer growth. Patients tolerated the treatment well, which is important for long-term use. While ixazomib has been primarily studied for multiple myeloma, this trial will explore its potential when combined with chemotherapy for leukemia. Participants in this trial will receive ixazomib at different dose levels alongside chemotherapy, as it has proven effective in similar conditions. This suggests it might be a valuable addition to leukemia treatment plans. ^{6 7 8 9 10}

Who Is on the Research Team?

Terzah Horton, MD

Principal Investigator

Baylor College of Medicine

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. ninlarohcp.com ninlarohcp.com/real-world-evidence

Real-World Evidence for the NINLARO® (ixazomib) Regimen The NINLARO® regimen has been investigated in patients with relapsed multiple myeloma in both randomized controlled trials and real-world studies.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10344838/

Real-world effectiveness of ixazomib combined with ... mPFS was 21.5, 21.9 and 5.8 months in patients receiving IXA-Rd as L2, L3, L4 + respectively. Among patients receiving IXA-Rd in L2 and L3, mPFS ...

3. clinical-lymphoma-myeloma-leukemia.com clinical-lymphoma-myeloma-leukemia.com/article/S2152-2650(23)02148-1/fulltext

Use Via Early Access to Ixazomib (UVEA-IXA) Study The overall response rate was 67% in all evaluable patients, and 72% and 63%, respectively, in patients who received 1 and ≥ 2 prior lines of ...

4. nature.com nature.com/articles/s41375-019-0384-1

Ixazomib, lenalidomide, and dexamethasone in patients ... The trial showed that ixazomib was an efficacious, well-tolerated, once-weekly oral drug. After a median follow-up of 31 months, there was a 39% ...

5. ajmc.com ajmc.com/view/ixazomib-shows-efficacy-tolerability-in-real-world-r-r-multiple-myeloma-treatment

Ixazomib Shows Efficacy, Tolerability in Real-World R/R ... Among all evaluable patients, the ORR was 60%. In those who had undergone 1 and 2 or more lines of prior therapy, the ORRs were 64% and 57%, ...

6. ninlarohcp.com ninlarohcp.com/adverse-reactions

Safety Profile for the NINLARO ® (ixazomib) Regimen Read the safety profile for NINLARO®, including important warnings and precautions, adverse reactions, and discontinuation rates. See Important Safety ...

7. oncologymedinfo.com oncologymedinfo.com/productsandpipeline/downloaddocument/SRD-USA-NIN-0004

SAFETY DATA SHEET - Medical Information Information on toxicological effects. Acute toxicity. Fatal if swallowed. Ixazomib citrate (CAS 1239908-20-3). Result: LD50 – not performed; ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5574012/

Management of adverse events associated with ixazomib ... No cumulative toxicities were observed, indicating the potential feasibility of long‐term IRd treatment. Safety data from TOURMALINE‐MM1 are reviewed and ...

9. content.takeda.com content.takeda.com/?contenttype=PI&product=NIN&language=ENG&country=SGP&documentnumber=1

1. Name of the Medicinal Product NINLARO® ixazomib (as ... The safety profile of ixazomib is based on all available clinical trial data and post-marketing experience to date. Adverse Drug Reaction Overview. Safety data ...

10. myeloma.org myeloma.org/ninlaro-ixazomib

Ninlaro (ixazomib) Ninlaro is the third proteasome inhibitor approved by the FDA since 2003, and it is the first proteasome inhibitor that is taken orally (by mouth).