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Talazoparib and Belinostat for the Treatment of Metastatic or Unresectable Breast Cancer, Metastatic Castration Resistant Prostate Cancer, or Metastatic Ovarian Cancer

Trial Status: Active

This phase I trial is to find the best dose of belinostat when given together with talazoparib in treating patients with breast cancer that has spread to other places in the body (metastatic) or cannot be removed by surgery (unresectable), metastatic prostate cancer that continues to grow despite the surgical removal of the testes or medical intervention to block androgen production (castration resistant), or metastatic ovarian cancer. Talazoparib is an inhibitor of PARP, an enzyme that helps repair deoxyribonucleic acid (DNA) when it becomes damaged. Blocking PARP may help keep cancer cells from repairing their damaged DNA, causing them to die. PARP inhibitors are a type of targeted therapy. Belinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving talazoparib and belinostat may kill more tumor cells.

Inclusion Criteria

  • Men or women with histologically confirmed metastatic or unresectable breast cancer that is HER2 negative as assessed by 2018 American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guidelines. Trial participants with hormone receptor positive disease must have progression on at least one hormonal therapy and a cyclin-dependent kinase (CDK) inhibitor AND be considered a candidate for chemotherapy. OR
  • Men with metastatic castration resistant prostate cancer with progression on androgen deprivation therapy and at least one additional agent in the metastatic setting. OR
  • Women with metastatic high grade serous ovarian cancer with progression on at least one chemotherapy agent
  • Measurable disease as defined by RECIST 1.1 criteria
  • Trial participants must be at least 21 days from last dose of chemotherapy and recovered from all chemotherapy-related reversible toxicity to grade 0 or 1, with the exception of alopecia and neuropathy
  • The last radiation therapy (including palliative radiation) must have occurred >= 3 weeks prior to study registration
  • Trial participants must have experienced disease progression at the time of study enrollment
  • Age >= 18 years
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • White blood cell count >= 3,000/ul
  • Neutrophil count >= 1,500/ul
  • Hemoglobin >= 8.5 g/dL
  • Platelet count >= 150,000/ul
  • Total bilirubin =< 1.5 x upper limit of normal (ULN) OR direct bilirubin =< ULN for patients with total bilirubin levels > 1.5 x ULN
  • Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) =< 2.5 x UNL but =< 5.0 x UNL in case of liver metastases; . In the presence of liver metastases the liver isoenzyme fraction must be measured and liver isoenzyme fraction (absolute value) must be =< 2 x UNL
  • Alkaline phosphatase (ALP) =< 1.5 x UNL but =< 2.5 x ULN in case of liver metastases or =< 5 x ULN in the case of bone metastasis. In the presence of liver metastases the liver isoenzyme fraction must be measured and liver isoenzyme fraction (absolute value) must be =< 2 x UNL
  • Albumin within normal limits
  • Creatinine clearance >= 60 ml/min measured by Cockcroft-Gault
  • Trial participants with treated brain metastases are eligible provided the metastases are recently treated and/or clinically stable and greater than 4 weeks has elapsed from time of treatment and date of initiation of study drug
  • Trial participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen should be included
  • Males and females of reproductive potential must use two forms of effective contraception during the duration of the trial and for minimum of 7 months after last dose of study drug. A woman of reproductive potential is defined as a premenopausal female with intact uterus and ovaries. For women, non-childbearing potential is defined as: * >= 45 years of age and has not had menses for > 2 years. * Amenorrheic for < 2 years without a hysterectomy and oophorectomy and a follicle-stimulating hormone value in the postmenopausal range upon pre-study (screening) evaluation. * Post hysterectomy, oophorectomy or tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure
  • Ability to understand and the willingness to sign a written informed consent

Exclusion Criteria

  • Previous or current treatment with a histone deacetylase inhibitor (HDACi)
  • Participation in other investigational studies concurrently if these therapies include a therapeutic intervention
  • Treatment with any investigational agent within 30 days (or 5 serum half-lives of the investigational drug, whichever is longer) of enrollment
  • Evidence of current serious uncontrolled concomitant cardiovascular nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (include uncontrolled diabetes mellitus) or gastrointestinal disease
  • History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating Investigator, including, but not limited to: * Myocardial infarction or arterial thromboembolic events within 6 months prior to screening or severe or unstable angina, New York Heart Association (NYHA) class III or IV disease, or a corrected QT (QTc) interval > 450 msec. * Uncontrolled hypertension or diabetes mellitus. * Another known malignancy that is progressing or requires active treatment. * Active infection requiring systemic therapy. * Known active central nervous system (CNS) metastases and/or carcinomatous meningitis
  • Any contraindication to oral agents or significant nausea and vomiting, malabsorption, or significant small bowel resection that, in the opinion of the investigator, would preclude adequate absorption
  • Allergy to talazoparib, belinostat or to the inactive components of talazoparib or belinostat formulations
  • Pregnancy or breastfeeding
  • QTc >= 450 ms or congenital long QT syndrome given potential for prolongation with belinostat
  • Current or anticipated use within 7 days prior to enrollment, or anticipated use during the study of drugs which are moderate or strong inhibitors of UGT1A1 (protease inhibitors, tyrosine kinase inhibitors, and ketoconazole)
  • Current or anticipated use within 7 days prior to enrollment, or anticipated use during the study, of strong P-glycoprotein (P-gp) inhibitors (amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, valspodar, and verapamil)
  • Subjects homozygous for UGT1A1*28 allele; this will be determined via clinical testing by polymerase chain reaction with capillary electrophoresis by the University of Michigan Molecular Diagnostics laboratory
  • Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial

Michigan

Ann Arbor
University of Michigan Comprehensive Cancer Center
Status: ACTIVE
Contact: Monika Leigh Burness
Phone: 734-763-0807

PRIMARY OBJECTIVE:

I. To establish the recommended phase 2 dose (RP2D) of daily oral talazoparib given in combination with belinostat.

SECONDARY OBJECTIVES:

I. To describe the adverse events and dose limiting toxicity (DLT)s associated with talazoparib when administered with belinostat via National Cancer Institute (NCI)’s Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

II. To describe the pharmacokinetics of talazoparib and belinostat with combination therapy of talazoparib and belinostat.

III. To describe efficacy of talazoparib in combination with belinostat as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 objective response criteria.

EXPLORATORY OBJECTIVES:

I. To define the effect of combination therapy on relative and absolute frequency of circulating tumor cells and circulating clusters.

II. To determine the effect of combination therapy on cancer stem cell (CSC) and DNA repair markers in circulating tumor cells using multi-color immunofluorescence.

III. To characterize the effect of combination therapy on pathway activation using single-cell ribonucleic acid (RNA)-sequence analysis of circulating tumor cells.

IV. To determine if homologous recombination deficiency (HRD) correlates with response to therapy.

OUTLINE: This is a dose-escalation study of belinostat.

Patients receive belinostat intravenously (IV) over 30 minutes once daily (QD) on days 1-5 and talazoparib orally (PO) QD on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
University of Michigan Comprehensive Cancer Center

Principal Investigator
Monika Leigh Burness

  • Primary ID UMCC 2020.122
  • Secondary IDs NCI-2021-01400, HUM00187603
  • Clinicaltrials.gov ID NCT04703920