Talazoparib for Leukemia

Recruiting at 1 trial location

Overseen By Jacqueline S. Garcia, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Dana-Farber Cancer Institute

Must not be taking: PARP inhibitors, Investigational agents

Disqualifiers: CNS leukemia, Active HIV, HCV, HBV, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

12 Participants Needed

Trial Summary

What is the purpose of this trial?

This research study is testing if Talazoparib is an effective treatment for patients with AML and MDS that have a mutation in the cohesin complex.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot have received any leukemia-directed chemotherapy within 2 weeks before joining the study. You also cannot be on any investigational agents or immunosuppression therapy, except for topical steroids.

What safety data exists for Talazoparib in humans?

Talazoparib has been studied for safety in patients with advanced breast cancer and other conditions, showing promising safety results. A Phase I trial also explored its safety in patients with advanced blood cancers, aiming to determine the maximum tolerated dose. ^{1 2 3 4 5}

How does the drug Talazoparib differ from other treatments for leukemia?

Talazoparib is unique because it is a PARP inhibitor, which means it works by blocking a protein that helps repair DNA damage in cancer cells, potentially making it effective for certain types of leukemia where DNA repair is a factor. This mechanism is different from traditional chemotherapy, which typically targets rapidly dividing cells. ^{6 7 8 9 10}

Research Team

Jacqueline S. Garcia, MD

Principal Investigator

Dana-Farber Cancer Institute

Eligibility Criteria

Adults with AML or MDS and a cohesin complex mutation who can't have intensive chemotherapy. They should have at least 5% blasts in blood/marrow, be ineligible for approved AML therapies, and not received leukemia treatment within 2 weeks before the trial. Participants need normal organ function, agree to contraception, and not be pregnant.

Inclusion Criteria

My MDS/AML has not improved after 2 treatments with specific medications.

I have secondary AML not recommended for any approved AML therapy.

Participants must have normal organ function as defined below: total bilirubin ≤ 2.5 × institutional upper limit of normal (unless considered to be secondary to leukemia) AST(SGOT)/ALT(SGPT) ≤ 2.5 × institutional upper limit of normal (unless considered to be secondary to leukemia) creatinine clearance ≥ 60 mL/min/1.73 m2 Documented pathogenic mutation in cohesin complex including a mutation in STAG2, SMC1A, RAD21, PDS5B, or SMC3 gene from a CLIA-approved test (local testing allowed; will be centrally confirmed). Patient must have a minimum VAF of 5%. Historical testing (up to 3 months) allowed for treatment start on study as long as no disease-modifying agent was received since testing.

Exclusion Criteria

Participants who are receiving any other investigational agents.

I have had treatments for MDS/AML with no restrictions and am over 2 months post-stem cell transplant, not on immunosuppressants for 14 days.

I have leukemia that has spread to my brain.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Part I

Talazoparib is administered orally on a daily basis. Hydroxyurea is allowed for up to two cycles per institutional guidelines.

8 weeks

Weekly visits for monitoring

Treatment Part II

Talazoparib is administered orally on a daily basis. Decitabine is administered on days 1-5. Hydroxyurea is allowed for up to two cycles per institutional guidelines.

8 weeks

Weekly visits for monitoring

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Bi-weekly visits

Treatment Details

Interventions

• Talazoparib

Trial Overview The study is examining Talazoparib's effectiveness on patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) that carry specific genetic mutations. It will see if this drug can help where standard treatments aren't suitable.

Participant Groups

Group I: Talazoparib Part I Experimental Treatment 1 Intervention

* Talazoparib is administered orally on a daily basis * Hydroxyurea is allowed for up to two cycles per institutional guidelines

Group II: Talazoparib + Decitabine Part II Experimental Treatment 2 Interventions

* Talazoparib is administered orally on a daily basis * Hydroxyurea is allowed for up to two cycles per institutional guidelines * Decitabine on days 1-5

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

Approved in United States as Talzenna for:

• Deleterious or suspected deleterious germline BRCA-mutated HER2-negative locally advanced or metastatic breast cancer

Approved in European Union as Talzenna for:

• Monotherapy for the treatment of adult patients with germline BRCA1/2 mutations, who have HER2-negative locally advanced or metastatic breast cancer

Who Is Running the Clinical Trial?

Dana-Farber Cancer Institute

Lead Sponsor

Trials

1,128

Recruited

382,000+

Pfizer

Industry Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

Talazoparib showed promising antitumor activity in patients with advanced breast cancer who have germline BRCA1/2 mutations, achieving a confirmed objective response rate of 21% in those with a recent response to platinum therapy and 37% in those with multiple prior treatments.

The most common side effects were manageable, with anemia occurring in 52% of patients, and only 4% of patients discontinued the drug due to adverse events, indicating a relatively safe profile for talazoparib in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). Turner, NC., Telli, ML., Rugo, HS., et al.[2021]

In the ABRAZO study, talazoparib (1 mg/day) maintained global health status and quality of life (GHS/QoL) in patients with advanced breast cancer, with median time to deterioration of GHS/QoL being 2.8 months for those with prior platinum therapy and 5.5 months for those with multiple cytotoxic regimens.

Patients reported significant improvements in breast and arm symptoms, as well as their future perspective, despite some deterioration in role functioning and dyspnoea symptoms, indicating that talazoparib can provide meaningful benefits in symptom management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial. Hurvitz, SA., Quek, RGW., Turner, NC., et al.[2021]

Talazoparib is an oral PARP inhibitor recently approved in the USA for treating adults with specific types of breast cancer, particularly those with BRCA mutations, highlighting its targeted efficacy in a defined patient population.

The drug is also being explored for use in other cancers, including metastatic castration-resistant prostate cancer and early triple negative breast cancer, indicating its potential versatility in cancer treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib: First Global Approval. Hoy, SM.[2020]

In a Phase I trial involving 33 patients with advanced hematologic malignancies, talazoparib was found to be relatively well tolerated, with the maximum tolerated dose (MTD) being 2.0 mg/day for acute myeloid leukemia and 0.9 mg/day for chronic lymphocytic leukemia.

The treatment demonstrated preliminary anti-leukemic activity, with 54.5% of patients achieving stable disease, indicating potential effectiveness in managing these types of cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase I trial of talazoparib in patients with advanced hematologic malignancies. Gopal, AK., Popat, R., Mattison, RJ., et al.[2022]

Talazoparib tosylate is an FDA and EMA-approved oral PARP inhibitor specifically effective for treating breast cancer in patients with germline BRCA mutations, showing superior efficacy compared to other PARP inhibitors and standard chemotherapy.

The drug works through a mechanism called synthetic lethality, which means it targets cancer cells' weaknesses, providing significant clinical benefits for patients with advanced or metastatic breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Talazoparib to treat BRCA-positive breast cancer. Guney Eskiler, G.[2019]

The study identified that the dual MERTK and FLT3 kinase inhibitor MRX-2843 synergizes effectively with vincristine to inhibit the growth of both B-ALL and T-ALL leukemia cells, suggesting a promising combination therapy for patients who do not respond to standard treatments.

Using lipid nanoparticle formulations to deliver MRX-2843 and vincristine in specific ratios improved anti-leukemia activity and prolonged survival in a mouse model of T-ALL, highlighting the importance of drug ratios and dosing in enhancing therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia. Kelvin, JM., Chimenti, ML., Zhang, DY., et al.[2023]

High-risk acute lymphoblastic leukemia (ALL) is challenging to treat, especially in relapsed cases, and new therapeutic strategies are needed due to the limitations of current treatments and their associated toxicity.

Recent advancements, particularly the use of tyrosine kinase inhibitors (TKIs) for BCR-ABL1-positive ALL, have significantly improved treatment outcomes, highlighting the importance of targeted therapies based on genetic profiling of the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Improving outcomes for high-risk ALL: translating new discoveries into clinical care. Hunger, SP., Raetz, EA., Loh, ML., et al.[2011]

Two novel kinase fusions, OFD1-JAK2 and NCOR1-LYN, were identified in pediatric patients with high-risk acute lymphoblastic leukaemia (ALL) who also had IKZF1 deletions, indicating potential new therapeutic targets.

Patients with these fusions exhibited high-risk features, such as elevated white blood cell counts and poor initial response to treatment, highlighting the need for targeted therapies to improve outcomes in this vulnerable population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia with IKZF1 deletion. Yano, M., Imamura, T., Asai, D., et al.[2016]

In a study of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), IKZF1 deletion was found in 60% of patients and was significantly linked to poorer overall survival and higher relapse rates, particularly in those treated with ponatinib-based regimens.

The analysis revealed that patients receiving dasatinib-based treatments had unfavorable outcomes regardless of their genetic abnormalities, highlighting the need for tailored treatment strategies based on genetic profiles.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib. Sasaki, Y., Kantarjian, HM., Short, NJ., et al.[2022]

In a study of 105 pediatric patients with high-risk B-lineage acute lymphoblastic leukemia (B-ALL), 15% were found to have kinase-activating fusions, which are linked to poor outcomes with standard chemotherapy but may respond well to targeted tyrosine kinase inhibitors.

The presence of an IKZF1 deletion was significantly associated with worse event-free survival, suggesting that patients with this genetic alteration may benefit from intensified therapy, regardless of whether they have a kinase-activating fusion.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia. Tran, TH., Harris, MH., Nguyen, JV., et al.[2019]

References

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

A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline BRCA1/2 Mutations (ABRAZO). [2021]

2. England pubmed.ncbi.nlm.nih.gov

Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial. [2021]

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

Talazoparib: First Global Approval. [2020]

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

A Phase I trial of talazoparib in patients with advanced hematologic malignancies. [2022]

5. Spain pubmed.ncbi.nlm.nih.gov

Talazoparib to treat BRCA-positive breast cancer. [2019]

6. Netherlands pubmed.ncbi.nlm.nih.gov

Development of constitutively synergistic nanoformulations to enhance chemosensitivity in T-cell leukemia. [2023]

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

Improving outcomes for high-risk ALL: translating new discoveries into clinical care. [2011]

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

Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia with IKZF1 deletion. [2016]

9. England pubmed.ncbi.nlm.nih.gov

Genetic correlates in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with Hyper-CVAD plus dasatinib or ponatinib. [2022]

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

Prognostic impact of kinase-activating fusions and IKZF1 deletions in pediatric high-risk B-lineage acute lymphoblastic leukemia. [2019]