What side effects are associated with this type of intervention?

Common treatments for solid tumors, such as BET inhibitors (e.g., ZEN003694) and PARP inhibitors (e.g., Talazoparib), often have a range of side effects. BET inhibitors can cause fatigue, gastrointestinal issues (nausea, diarrhea), and hematologic toxicities (anemia, thrombocytopenia). PARP inhibitors are known to cause nausea, fatigue, anemia, thrombocytopenia, and neutropenia. Both classes of drugs may also lead to more severe adverse events such as myelodysplastic syndrome or acute myeloid leukemia, although these are less common.

What prior FDA approvals exist?

The FDA has approved several PARP inhibitors for the treatment of solid tumors, particularly in cancers with DNA damage repair deficiencies. For example, Talazoparib has been approved for advanced breast cancer with BRCA mutations. Other PARP inhibitors like Olaparib and Rucaparib have been approved for ovarian and prostate cancers with similar genetic profiles. While BET inhibitors like ZEN003694 are still under investigation, the combination of these inhibitors with PARP inhibitors is being explored to enhance anti-tumor efficacy by preventing cancer cells from repairing their DNA, thereby causing cell death.

What other types of research exist?

Promising novel alternatives for solid tumor patients in 2024 include: 1) Niraparib, another PARP inhibitor, which has shown efficacy in various solid tumors. 2) Olaparib, a well-established PARP inhibitor, continues to be a strong alternative with ongoing research in combination therapies. 3) Nivolumab and Pembrolizumab, immune checkpoint inhibitors, have shown significant promise in treating various solid tumors, either alone or in combination with other therapies. 4) Enfortumab Vedotin, an antibody-drug conjugate, has shown efficacy in urothelial carcinoma and may be explored for other solid tumors. 5) Combination therapies involving novel agents like BET inhibitors and other targeted therapies are also under investigation and may provide new options.

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PARP Inhibitor

ZEN-3694 + Talazoparib for Cancer

Phase 2

Recruiting

Led By Timothy A Yap

Research Sponsored by National Cancer Institute (NCI)

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Patients must have a tumor lesion that can be biopsied with 'low' or 'minimal' risk and at least one measurable disease site, as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1

Age >= 18 years

Must not have

Patients with cerebrovascular accident (CVA), myocardial infarction, or unstable angina within 6 months prior to the first dose of ZEN003694 (ZEN-3694) or talazoparib

Patients who have previously received ZEN003694 (ZEN-3694) or who have been treated with an investigational BET inhibitor

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 2 years

Awards & highlights

Summary

This trial tests if combining ZEN-3694 and talazoparib can shrink advanced tumors that don't respond to standard treatments. ZEN-3694 blocks proteins that help tumors grow, and talazoparib stops cancer cells from fixing their damaged DNA, causing them to die. The study also looks at how patients' genes affect their response to this treatment. Talazoparib is a potent PARP inhibitor that has shown significant efficacy in treating advanced BRCA1 and BRCA2 mutated breast cancer.

Who is the study for?

Adults with advanced solid tumors that are metastatic or unresectable, where standard treatments have failed. Participants must meet specific health criteria like adequate blood cell counts and organ function, agree to use contraception, and not be pregnant or breastfeeding. Some cohorts require genetic mutations in cancer-related genes (e.g., BRCA1/2 or KRAS). Prior therapies are allowed but with certain time frames for recovery.

What is being tested?

The trial is testing the combination of ZEN-3694, a BET protein inhibitor which may stop tumor growth by targeting overproduced proteins in cancer cells, and Talazoparib, a PARP enzyme inhibitor that prevents cancer cells from repairing their DNA. The study also examines how patients' genetics affect their response to this treatment.

What are the potential side effects?

Potential side effects include issues related to the body's ability to repair DNA damage which could lead to increased risk of developing new cancers or worsening existing ones. Other common drug-related side effects such as fatigue, nausea, allergic reactions might occur.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have a tumor that can be safely biopsied and at least one tumor that can be measured.

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I am 18 years old or older.

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I have chronic hepatitis B but my viral load is undetectable with treatment.

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I had hepatitis C but am cured, or I'm being treated with no detectable virus.

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I am 18 years old or older.

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I can take care of myself but might not be able to do heavy physical work.

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My cancer is advanced, cannot be surgically removed, and standard treatments are not effective.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I haven't had a stroke, heart attack, or severe chest pain in the last 6 months.

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I have not been treated with ZEN-3694 or any experimental BET inhibitors.

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I am not taking any blood thinners except for low molecular weight heparin.

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I have a digestive issue that affects how my body absorbs medication.

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I cannot or will not take pills.

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I am not taking any strong CYP3A4 inhibitors or inducers, or can stop them 7 days before starting ZEN-3694.

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I do not have any unmanaged ongoing illnesses.

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More than a quarter of my bone marrow has been exposed to radiation.

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I do not have an active infection needing IV antibiotics or any severe illness requiring hospitalization.

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I am not pregnant or breastfeeding.

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I am allergic to medications similar to ZEN-3694 or talazoparib.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Objective response rate (ORR)

Secondary study objectives

Clinical benefit rate (CBR)

Duration of response

Incidence of adverse events

+2 more

Other study objectives

Analysis of formalin-fixed paraffin-embedded and blood and blood samples

Assess emergent resistant mutations

Correlate baseline mutations with treatment response

+5 more

Side effects data

From 2021 Phase 3 trial • 431 Patients • NCT01945775

48%

Nausea

43%

Fatigue

29%

Neutropenia

28%

Alopecia

25%

Diarrhoea

23%

Headache

22%

Constipation

22%

Decreased appetite

22%

Vomiting

22%

Palmar-plantar erythrodysaesthesia syndrome

19%

Anaemia

17%

Pyrexia

16%

Cough

15%

Back pain

15%

Dyspnoea

14%

Abdominal pain

14%

Neutrophil count decreased

12%

Aspartate aminotransferase increased

12%

Alanine aminotransferase increased

12%

Weight decreased

12%

Arthralgia

12%

Paraesthesia

11%

Pain in extremity

11%

Myalgia

10%

Upper respiratory tract infection

10%

Leukopenia

10%

Dizziness

10%

Asthenia

10%

Rash

Dysgeusia

Oropharyngeal pain

Dyspepsia

Insomnia

Musculoskeletal pain

Mucosal inflammation

Musculoskeletal chest pain

Lacrimation increased

Dry skin

Hot flush

Neuropathy peripheral

Anxiety

Bone pain

Viral upper respiratory tract infection

Pleural effusion

Thrombocytopenia

Dry mouth

Oedema peripheral

Stomatitis

Peripheral sensory neuropathy

Neck pain

Non-cardiac chest pain

White blood cell count decreased

Abdominal pain upper

Sinusitis

Platelet count decreased

Depression

Urinary tract infection

Influenza like illness

Muscle spasms

General physical health deterioration

Pneumonia

Dehydration

Nervous system disorder

Deep vein thrombosis

Pathological fracture

Muscular weakness

Encephalopathy

Bronchopneumopathy

Febrile neutropenia

Colitis

Localised oedema

Sepsis

Staphylococcal bacteraemia

International normalised ratio increased

Malignant pleural effusion

Acute promyelocytic leukaemia

Malignant melanoma

Pericarditis malignant

Second primary malignancy

Salpingo-oophorectomy

Cerebrovascular accident

Uterine haemorrhage

Lymphadenectomy

Cellulitis

Device related infection

Discomfort

100%

80%

60%

40%

20%

Study treatment Arm

Physician's Choice Treatment

Talazoparib

Trial Design

1Treatment groups

Experimental Treatment

Group I: Treatment (ZEN-3694, talazoparib)Experimental Treatment5 Interventions

Patients receive ZEN-3694 PO QD and talazoparib PO QD on days 1-28 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients undergo diagnostic imaging throughout the study and undergo blood sample collection and tumor biopsy while on study.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Biopsy

2014

Completed Phase 4

~1090

Biospecimen Collection

2004

Completed Phase 3

~2020

Talazoparib

2021

Completed Phase 2

~2820

0 / 18Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

BET inhibitors, such as ZEN003694, work by targeting the bromodomain and extra-terminal (BET) family of proteins, which play a crucial role in regulating gene expression that promotes tumor growth. By inhibiting these proteins, BET inhibitors can prevent the proliferation of cancer cells. PARP inhibitors, like Talazoparib, block the PARP enzyme involved in DNA repair. This inhibition prevents cancer cells from repairing their damaged DNA, leading to cell death. These mechanisms are particularly important for solid tumor patients because they target the fundamental processes that allow cancer cells to grow and survive, offering a targeted approach that can potentially improve treatment outcomes and reduce side effects compared to traditional chemotherapy.

Development of the PARP inhibitor talazoparib for the treatment of advanced BRCA1 and BRCA2 mutated breast cancer.