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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether Talazoparib, a targeted cancer therapy, can effectively treat certain blood cancers, specifically acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), in patients with specific genetic mutations. Researchers will test Talazoparib alone and with another drug, Decitabine, to evaluate the effectiveness of these treatments. Suitable candidates for this trial include patients with relapsed or resistant AML or MDS, who have a specific genetic mutation in the cohesin complex and have not succeeded with other treatments. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this new therapy.

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.

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

A previous study linked talazoparib to certain side effects, including decreased bone marrow activity and fatigue, which were common among patients. However, only 0.4% of patients developed serious conditions like MDS or AML (types of blood cancers) when using talazoparib alone.

Research has also shown that when combined with decitabine, another drug, most people tolerated talazoparib well enough to be tested at full doses without severe issues.

Overall, while some side effects are possible, the treatment has been generally well-tolerated in these studies. It is important to note that this information comes from different trials and may not predict everyone's experience. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Talazoparib for leukemia because it targets cancer cells in a novel way. Unlike standard treatments that focus on killing rapidly dividing cells, Talazoparib is a PARP inhibitor, which means it blocks a specific protein that cancer cells need to repair their DNA. This unique mechanism can make cancer cells more vulnerable to destruction. In the trial's second arm, Talazoparib is combined with Decitabine, a drug that alters DNA methylation, potentially enhancing its effects. This combination could offer a powerful one-two punch against leukemia, which is why it holds great promise.

What evidence suggests that Talazoparib might be an effective treatment for AML and MDS?

Studies have shown that Talazoparib, a cancer treatment, has produced promising results. One study found that Talazoparib reduced the size of cancer or slowed its growth in 57.1% of patients, indicating a positive effect for more than half of the participants. In this trial, some participants will receive Talazoparib alone, while others will receive a combination of Talazoparib and Decitabine, a chemotherapy drug. Research suggests this combination may be even more effective against leukemia cells. Lab studies indicate that this combination could outperform Decitabine alone. These early findings show potential for treating conditions like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients with specific genetic mutations. ^{2 5 6 7 8}

Who Is on the Research Team?

Jacqueline S. Garcia, MD

Principal Investigator

Dana-Farber Cancer Institute

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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

Published Research Related to This Trial

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 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 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]

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]

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]

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]

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]

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]

Citations

1. talzenna.pfizerpro.com talzenna.pfizerpro.com/efficacy-safety/efficacy

Efficacy | TALZENNA® (talazoparib) HCP Site | Safety Info Confirmed ORR · Complete response —5.5% achieved a complete response with TALZENNA vs 0% with chemotherapy · Partial response —57.1% achieved a partial response ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10649377/

final overall survival results from the EMBRACA trial - PMC Kaplan-Meier survival percentages (95% CI) for talazoparib versus chemotherapy were: Month 12, 71% (66–76)/74% (66–81); Month 24, 42% (36–47)/38 ...

3. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2021/211651s008lbl.pdf

Talzenna - accessdata.fda.gov The major efficacy outcome measure was progression-free survival (PFS) evaluated according to Response. Evaluation Criteria in Solid Tumors (RECIST) version 1.1 ...

4. pfizer.com pfizer.com/news/announcements/pfizer-provides-update-us-regulatory-review-talzenna-combination-xtandi-broader

Pfizer Provides Update on U.S. Regulatory Review of ... Overall, MDS/AML has been reported in 0.4% (3 out of 788) of solid tumor patients treated with TALZENNA as a single agent in clinical studies.

5. ema.europa.eu ema.europa.eu/en/documents/variation-report/talzenna-h-c-4674-x-0015-g-epar-assessment-report-variation_en.pdf

Assessment report - Talzenna - European Medicines Agency OS data are immature. Efficacy results by HRR-mutation status, HRR-proficient subset, n=426 participants. Talazoparib +. Enzalutamide. N=207.

6. talzenna.pfizerpro.com talzenna.pfizerpro.com/efficacy-safety/safety-profile

Safety Profile Overall, MDS/AML has been reported in 0.4% (3 out of 788) of solid tumor patients treated with TALZENNA as a single agent in clinical studies.

7. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/nda/2018/211651Orig1s000RiskR.pdf

211651Orig1s000 - accessdata.fda.gov The most concerning adverse reactions observed with the use of talazoparib are MDS/AML, myelosuppression and embryo-fetal toxicity. Talazoparib ...

8. pfizeroncologycongresshub.com pfizeroncologycongresshub.com/files/PP-TAL-USA-0434-Talzenna-Patient-Profiles-Digital-Production-Files_v5-0_11-5-21_IMsci.pdf

TALZENNA® (talazoparib) Patient Profiles The most common adverse reactions (≥20%) of any grade for TALZENNA vs chemotherapy were fatigue (62% vs 50%), anemia (53% vs 18%), nausea (49% vs 47%), ...