TAS1440 + ATRA for Leukemia

Recruiting at 16 trial locations

Overseen By General Inquiries

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Taiho Oncology, Inc.

Must not be taking: Calcineurin inhibitors, Retinoids

Disqualifiers: CNS leukemia, BCR-ABL leukemia, others

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

Compensation: Varies

Number of Visits: Unknown

52 Participants Needed

Trial Summary

What is the purpose of this trial?

This trial is testing a new drug called TAS1440, alone and with ATRA, in patients with AML who didn't respond to previous treatments or whose cancer returned. It aims to see how the drug works in the body and if it can help treat the leukemia. Bisantrene, a new drug, has shown positive effects in earlier studies with manageable side effects.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, if you are on investigational therapy, you must stop it at least 2 weeks before starting the study treatment.

What data supports the effectiveness of the drug TAS1440 + ATRA for leukemia?

Research shows that all-trans retinoic acid (ATRA) has been effective in treating a specific type of leukemia called acute promyelocytic leukemia. However, its effectiveness in other types of leukemia, like nonacute promyelocytic acute myeloid leukemia, is less clear, with some studies suggesting limited benefit when used alone or in combination with other treatments. ^{1 2 3 4 5}

Is the combination of TAS1440 and ATRA safe for humans?

The combination of all-trans retinoic acid (ATRA) with other drugs has been studied, and in one study, it was found to be safe with acceptable side effects like headache and heart rhythm changes. No serious toxicity was observed in another study when ATRA was combined with a different drug for leukemia treatment. ^{2 6 7 8 9}

What makes the drug TAS1440 unique for treating leukemia?

TAS1440 is unique because it targets the ATR kinase, which is involved in DNA repair, making it effective against leukemia cells that are resistant to traditional therapies. This approach is particularly promising for leukemias with MLL rearrangements, which have a poor prognosis with standard treatments. ^{3 9 10 11 12}

Research Team

James Lowder, MD

Principal Investigator

Astex Pharmaceuticals, Inc.

Eligibility Criteria

This trial is for adults with acute myeloid leukemia (AML) who have not responded to standard treatments or whose disease has returned. They should be in a condition stable enough to complete at least one treatment cycle, have an acceptable level of organ function, and women must not be pregnant or breastfeeding. People with certain heart conditions, active infections, other cancers needing treatment, or those unable to take oral medication cannot join.

Inclusion Criteria

- AST and ALT <5 × ULN (if considered due to leukemic organ involvement).

I have a diagnosed condition.

My kidney function is within the normal range.

Exclusion Criteria

My bilirubin levels are high, or I have severe liver disease.

I am not undergoing active treatment for a second cancer, except if it's breast or prostate cancer being managed with hormone therapy.

I have been diagnosed with a specific type of leukemia called acute promyelocytic leukemia.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part 1

TAS1440 administered as a single agent once daily on specific days during each 28-day cycle

28-day cycles

Treatment Part 2

TAS1440 administered once daily on specific days in combination with ATRA twice daily during each 28-day cycle

28-day cycles

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• ATRA
• TAS1440

Trial Overview The study is testing TAS1440 alone and combined with ATRA in people with relapsed/refractory AML. It aims to evaluate the safety and effectiveness of these treatments over approximately 30 months. Participants will receive TAS1440 as a single agent first then in combination with ATRA.

Participant Groups

Group I: TAS1440 + ATRA Experimental Treatment 1 Intervention

TAS1440 administered QD on specific days during each 28-day cycle in combination with ATRA twice daily (BID) in Part 2.

Group II: TAS1440 Experimental Treatment 1 Intervention

TAS1440 as a single agent administered once daily (QD) on specific days during each 28-day cycle in Part 1.

Who Is Running the Clinical Trial?

Taiho Oncology, Inc.

Lead Sponsor

Trials

79

Recruited

12,700+

Tim Whitten

Taiho Oncology, Inc.

Chief Executive Officer since 2018

MBA and Pharmacy degree

Harold Keer

Taiho Oncology, Inc.

Chief Medical Officer

MD, PhD

Astex Pharmaceuticals, Inc.

Lead Sponsor

Trials

97

Recruited

7,400+

Dr. Harren Jhoti

Astex Pharmaceuticals, Inc.

Chief Executive Officer since 2007

PhD in Biochemistry from Birkbeck College, London

Dr. Harold N. Keer

Astex Pharmaceuticals, Inc.

Chief Medical Officer since 2020

MD

Findings from Research

Tandutinib, a FLT3 inhibitor, shows promising antileukemic activity in about half of AML patients, especially those with FLT3 ITD mutations, and does not cause common chemotherapy side effects like myelosuppression or cardiac toxicity.

Combining tandutinib with standard chemotherapy (the '3 + 7' regimen) enhances its effectiveness and may allow for lower doses of chemotherapy, reducing side effects, making it a potentially safer option for elderly or medically compromised patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin. Schittenhelm, MM., Kampa, KM., Yee, KW., et al.[2020]

In a phase I trial involving 37 pediatric patients with relapsed/refractory acute myeloid leukemia (R/R AML), the combination of decitabine, vorinostat, and FLAG chemotherapy showed a promising overall response rate of 54%, with 16 patients achieving complete response (CR).

The treatment was well-tolerated with no dose-limiting toxicities, and among those who responded, 90% achieved minimal residual disease (MRD) negativity, leading to a significantly higher two-year overall survival rate of 75.6% for MRD-negative patients compared to 17.9% for those with residual disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. Pommert, L., Schafer, ES., Malvar, J., et al.[2023]

In a study involving 7 patient-derived pediatric acute lymphoblastic leukemia (ALL) xenografts, PR-104 demonstrated significantly greater efficacy against T-lineage ALL (T-ALL) compared to B-cell-precursor ALL (BCP-ALL), suggesting it may be a promising treatment for T-ALL.

The expression of the enzyme AKR1C3 was found to be a predictive biomarker for PR-104 sensitivity, as higher levels of AKR1C3 in T-ALL xenografts correlated with increased sensitivity to the drug, indicating that testing for AKR1C3 could help identify patients who would benefit most from PR-104 therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. Moradi Manesh, D., El-Hoss, J., Evans, K., et al.[2021]

References

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

The impact on outcome of the addition of all-trans retinoic acid to intensive chemotherapy in younger patients with nonacute promyelocytic acute myeloid leukemia: overall results and results in genotypic subgroups defined by mutations in NPM1, FLT3, and CEBPA. [2021]

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

[All-trans retinoic acid combined with low-dose cytosine arabinoside treatment for acute myelogenous leukemia with trilineage myelodysplasia--a case report]. [2013]

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

The FLT3 inhibitor tandutinib (formerly MLN518) has sequence-independent synergistic effects with cytarabine and daunorubicin. [2020]

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

Outcome of patients treated for relapsed or refractory acute lymphoblastic leukemia: a Therapeutic Advances in Childhood Leukemia Consortium study. [2022]

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

Potential role for all-trans retinoic acid in nonpromyelocytic acute myeloid leukemia. [2020]

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

A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia. [2020]

7. Australia pubmed.ncbi.nlm.nih.gov

Therapy-related acute myeloid leukaemia and myelodysplastic syndrome in Victoria, Australia 2003-2014. [2018]

8. England pubmed.ncbi.nlm.nih.gov

Therapy-related leukemia and myelodysplastic syndrome in breast cancer patients treated with cyclophosphamide or anthracyclines. [2019]

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

Real-world experience in treating pediatric relapsed/refractory or therapy-related myeloid malignancies with decitabine, vorinostat, and FLAG therapy based on a phase 1 study run by the TACL consortium. [2022]

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

Targeting the kinase activities of ATR and ATM exhibits antitumoral activity in mouse models of MLL-rearranged AML. [2022]

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

Decitabine and vorinostat with FLAG chemotherapy in pediatric relapsed/refractory AML: Report from the therapeutic advances in childhood leukemia and lymphoma (TACL) consortium. [2023]

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

AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. [2021]