Quizartinib + Chemotherapy for Leukemia

(QuANTUM-WILD Trial)

Recruiting at 287 trial locations

Overseen By Daiichi Sankyo Contact for Clinical Trial Information

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Daiichi Sankyo

Must be taking: Chemotherapy

Must not be taking: All-trans retinoic acid

Disqualifiers: APL, Secondary AML, FLT3-ITD, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

700 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that treatment with all-trans retinoic acid (ATRA) must be discontinued before starting induction chemotherapy.

What data supports the effectiveness of the drug Quizartinib combined with chemotherapy for leukemia?

Research shows that Quizartinib, when combined with chemotherapy, improved survival and response rates in patients with certain types of acute myeloid leukemia (AML), particularly those with FLT3-ITD mutations. In one study, patients receiving Quizartinib with low-dose chemotherapy had significantly better survival rates compared to those receiving chemotherapy alone. ^{1 2 3 4 5}

Is the combination of Quizartinib and chemotherapy safe for humans?

Quizartinib combined with chemotherapy has been studied for safety in people with acute myeloid leukemia (AML). Some patients experienced serious side effects like febrile neutropenia (fever with low white blood cells), pericardial effusion (fluid around the heart), and QT prolongation (heart rhythm changes). However, the treatment was generally tolerable, and most side effects were manageable. ^{1 3 6 7 8}

What makes the drug Quizartinib + Chemotherapy unique for treating leukemia?

Quizartinib, when combined with chemotherapy, offers a novel approach for treating leukemia by targeting specific mutations in cancer cells, potentially improving outcomes for patients with certain types of leukemia that are resistant to other treatments. ^{9 10 11 12 13}

What is the purpose of this trial?

This study will compare the effects of Quizartinib versus placebo in combination with chemotherapy in participants with newly diagnosed FMS-like tyrosine kinase 3 (FLT3)-internal tandem duplication (ITD) negative acute myeloid leukemia (AML).

Research Team

Global Clinical Leader

Principal Investigator

Daiichi Sankyo

Eligibility Criteria

This trial is for adults aged 18 to 70 with newly diagnosed acute myeloid leukemia (AML) that lacks the FLT3-ITD mutation. Participants should be able to perform daily activities with minimal assistance (ECOG status of 0-2) and must understand and sign a consent form. They should be starting the standard '7+3' induction chemotherapy.

Inclusion Criteria

I can understand and sign the consent form for this trial.

I am currently on a '7+3' chemotherapy regimen.

I have been newly diagnosed with a type of leukemia called AML.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction and Consolidation Chemotherapy

Participants receive induction and consolidation chemotherapy with quizartinib or placebo for 14 days after chemotherapy completion

Up to 120 days

Maintenance Therapy

Participants receive quizartinib or placebo as maintenance therapy for up to 36 cycles

Up to 36 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 42 months

Treatment Details

Interventions

• Chemotherapy
• Quizartinib

Trial Overview The study is testing whether adding Quizartinib, an experimental drug, to standard chemotherapy is more effective than adding a placebo in patients with AML who do not have the FLT3-ITD mutation.

Participant Groups

Group I: Arm C: Quizartinib + Chemotherapy then Placebo Maintenance Experimental Treatment 3 Interventions

Participants will receive quizartinib at 60 mg/day orally once daily for 14 days starting after the completion of chemotherapy in Induction and Consolidation Phase. In the Maintenance Phase, participants will receive placebo at 60 mg/day orally once daily for up to 36 cycles (28-day cycle)

Group II: Arm A: Quizartinib + Chemotherapy Experimental Treatment 2 Interventions

Participants will receive quizartinib at 60 mg/day orally once daily for 14 days starting after the completion of chemotherapy in Induction and Consolidation Phase. In the Maintenance Phase, participants will receive quizartinib at 60 mg/day orally once daily for up to 36 cycles (28-day cycle)

Group III: Arm B: Placebo + Chemotherapy Placebo Group 2 Interventions

Participants will receive placebo at 60 mg/day orally once daily for 14 days starting after the completion of chemotherapy in Induction and Consolidation Phase. In the Maintenance Phase, participants will receive placebo at 60 mg/day orally once daily for up to 36 cycles (28-day cycle)

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

Approved in European Union as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in United States as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in Canada as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in Japan as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in China as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Approved in Switzerland as Chemotherapy for:

• Breast cancer
• Metastatic breast cancer
• Various other cancers

Who Is Running the Clinical Trial?

Daiichi Sankyo

Lead Sponsor

Trials

443

Recruited

493,000+

Hiroyuki Okuzawa

Daiichi Sankyo

Chief Executive Officer

Degree in Social Sciences from Hitotsubashi University

Yuki Abe

Daiichi Sankyo

Chief Medical Officer since 2023

MD

Findings from Research

Quizartinib, a selective FLT3 inhibitor, was found to be well tolerated at a dose of 60 mg/m²/day in children with relapsed acute leukemia, showing a favorable toxicity profile during intensive chemotherapy.

The treatment resulted in significant biological activity, with complete inhibition of FLT3 phosphorylation in all patients and promising response rates, particularly in those with FLT3-ITD mutations, indicating potential for further testing in this population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. Cooper, TM., Cassar, J., Eckroth, E., et al.[2022]

In a study of 202 older patients with acute myeloid leukemia (AML) who were not suitable for intensive chemotherapy, the addition of quizartinib to low-dose ara-C (LDAC) did not improve overall survival for the entire group, but it significantly enhanced response rates in patients with the FLT3-ITD mutation.

For the 27 FLT3-ITD patients, those receiving quizartinib plus LDAC had a median overall survival of 13.7 months compared to 4.2 months for those on LDAC alone, indicating that quizartinib could be a promising option for improving outcomes in this specific subgroup.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. Dennis, M., Thomas, IF., Ariti, C., et al.[2022]

In a phase 1 trial involving 19 newly diagnosed acute myeloid leukemia (AML) patients, quizartinib, a selective FLT3 inhibitor, was found to be safe and tolerable when combined with standard chemotherapy, with a maximum tolerated dose identified as 40 mg/d for 14 days.

The combination treatment showed promising efficacy, with 84% of patients responding and 74% achieving a composite complete response, indicating that quizartinib may enhance outcomes for patients with FLT3-ITD mutations in AML.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. Altman, JK., Foran, JM., Pratz, KW., et al.[2021]

The combination of paclitaxel and quizartinib significantly reduces the proliferation of the MV4-11 leukemia cell line and increases apoptosis compared to either drug alone, indicating a synergistic effect.

This combination therapy works by inhibiting the FLT3/STAT5 signaling pathway, as evidenced by lower levels of phosphorylated FLT3 and STAT5 proteins in the combination group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Effects of Paclitaxel and Quizartinib Alone and in Combination on AML Cell Line MV4-11 and Its STAT5 Signal Pathway]. Bai, ZW., Wu, MQ., Zhou, BW., et al.[2022]

In a phase III trial, the FLT3 inhibitor quizartinib showed a survival benefit compared to traditional chemotherapy in patients with relapsed or refractory FLT3-mutant acute myeloid leukemia.

The promising results from quizartinib suggest it may become a first-line treatment option for this type of leukemia, pending outcomes from ongoing studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quizartinib Bests Chemo for FLT3-Mutant AML. [2019]

Small molecule inhibitors (SMIs) for acute myeloid leukemia (AML) can be more tolerable than traditional chemotherapy, but they have a high potential for drug-drug interactions (DDIs) that can affect treatment success, especially since AML patients often take multiple medications.

CYP3A4 is the main enzyme that metabolizes these SMIs, and strong inhibitors or inducers of this enzyme can lead to increased toxicity or decreased efficacy, necessitating careful monitoring and possible dose adjustments for drugs like venetoclax and quizartinib.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia. Megías-Vericat, JE., Solana-Altabella, A., Ballesta-López, O., et al.[2020]

In a phase 1 study involving 13 patients with FLT3-ITD-mutated acute myeloid leukemia (AML) after allogeneic hematopoietic-cell transplant, quizartinib showed acceptable tolerability as a maintenance therapy, with 77% of subjects receiving it for over a year.

The study indicated early evidence of reduced relapse rates with quizartinib maintenance therapy, although some patients experienced significant adverse events, including neutropenia and anemia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant. Sandmaier, BM., Khaled, S., Oran, B., et al.[2023]

Quizartinib is an effective treatment for patients with FLT3-ITD acute myeloid leukemia (AML), as it inhibits the FLT3 gene activity, leading to tumor cell death, and has shown promise in clinical trials for relapsed or refractory cases.

The drug has received breakthrough therapy designation from the FDA, highlighting its potential, but further studies are necessary to assess its safety, efficacy in combination with other treatments, and to address its side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quizartinib (AC220): a promising option for acute myeloid leukemia. Zhou, F., Ge, Z., Chen, B.[2020]

Recent advancements in leukemia treatments have led to high cure rates, such as over 90% for hairy cell leukemia with cladribine and rituximab, and 80-90% for acute promyelocytic leukemia using all-trans retinoic acid and arsenic trioxide.

Chronic lymphocytic leukemia, once considered incurable, may now be potentially curable with targeted therapies like Bruton tyrosine kinase inhibitors and venetoclax, showcasing the significant progress in leukemia treatment options.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cure of leukemia through the optimist's prism. Kantarjian, HM., Jain, N., Garcia-Manero, G., et al.[2023]

Amphotericin B can enhance the effectiveness of chemotherapy drugs like actinomycin D, adriamycin, and vincristine against AKR leukemia, even in cells that have developed resistance to these treatments.

While resistance to actinomycin D developed quickly in leukemia cells, resistance to vincristine and adriamycin occurred more slowly; however, amphotericin B still improved the efficacy of these drugs against resistant cells, although the enhancement decreased as resistance increased.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Potentiation of anticancer agent cytotoxicity against sensitive and resistant AKR leukemia by amphotericin B1. Valeriote, F., Medoff, G., Dieckman, J.[2015]

Rodent leukemia models, particularly L1210 and P388, are effective for screening drugs against human leukemias and lymphomas, with L1210 being the most successful for clinically active compounds and P388 better for antibiotics and natural products.

The study highlights the potential of the Ara-C analog 2,2'-anhydro-arabinofuranosyl-5-fluorocytosine (AAFC) as a promising treatment for acute myelogenous leukemia (AML), showing oral activity and effectiveness against brain-invading leukemias, which could improve upon current treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Murine and human leukemias. Burchenal, JH.[2019]

Children with acute myelogenous leukemia (AML) show significantly higher drug resistance to most chemotherapy drugs compared to those with acute lymphoblastic leukemia (ALL), except for a few like cytarabine, mercaptopurine, and thioguanine.

Patients with relapsed AML exhibit similar sensitivity to certain drugs like cytarabine and idarubicin as initial AML patients, but those who died from refractory disease were notably more resistant to key drugs, indicating that drug resistance is a critical factor in treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Ex vivo drug resistance profile in childhood acute myelogenous leukemia: no drug is more effective in comparison to acute lymphoblastic leukemia. Styczynski, J., Wysocki, M., Debski, R., et al.[2019]

Olaparib enhances the effectiveness of conventional chemotherapy and DNMT inhibitors in treating acute myeloid leukemias driven by MLL fusion proteins, which are typically hard to treat.

The combination of olaparib with these treatments leads to significant reductions in cell growth and increased DNA damage, suggesting a mechanism where olaparib helps to induce cell cycle block and apoptosis in leukemia cells.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

PARPi potentiates with current conventional therapy in MLL leukemia. Zhao, L., So, CWE.[2020]

References

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

A Phase I Study of Quizartinib Combined with Chemotherapy in Relapsed Childhood Leukemia: A Therapeutic Advances in Childhood Leukemia & Lymphoma (TACL) Study. [2022]

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

Randomized evaluation of quizartinib and low-dose ara-C vs low-dose ara-C in older acute myeloid leukemia patients. [2022]

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

Phase 1 study of quizartinib in combination with induction and consolidation chemotherapy in patients with newly diagnosed acute myeloid leukemia. [2021]

4. China pubmed.ncbi.nlm.nih.gov

[Effects of Paclitaxel and Quizartinib Alone and in Combination on AML Cell Line MV4-11 and Its STAT5 Signal Pathway]. [2022]

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

Quizartinib Bests Chemo for FLT3-Mutant AML. [2019]

6. Germany pubmed.ncbi.nlm.nih.gov

Drug-drug interactions of newly approved small molecule inhibitors for acute myeloid leukemia. [2020]

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

Results of a phase 1 study of quizartinib as maintenance therapy in subjects with acute myeloid leukemia in remission following allogeneic hematopoietic stem cell transplant. [2023]

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

Quizartinib (AC220): a promising option for acute myeloid leukemia. [2020]

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

The cure of leukemia through the optimist's prism. [2023]

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

Potentiation of anticancer agent cytotoxicity against sensitive and resistant AKR leukemia by amphotericin B1. [2015]

11. Switzerland pubmed.ncbi.nlm.nih.gov

Murine and human leukemias. [2019]

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

Ex vivo drug resistance profile in childhood acute myelogenous leukemia: no drug is more effective in comparison to acute lymphoblastic leukemia. [2019]

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

PARPi potentiates with current conventional therapy in MLL leukemia. [2020]