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Talazoparib and Avelumab for the Treatment of Advanced Breast Cancer, the TALAVE study

Trial Status: Active

This phase I / II trial studies the side effects of talazoparib and avelumab for the treatment of breast cancer that has spread to other places in the body (advanced). Avelumab is a type of protein that recognizes and attaches to other proteins in the body. It specifically recognizes and attaches to a protein called PD-L1 which is found on the surface of some cancer cells, where it acts to protect those cells from being attacked by the immune system (the part of the body that fights infection but which is also involved in fighting cancer). When avelumab attaches to PD-L1, it stops PD-L1 from working and so allows the immune system to recognize and kill the cancer cells. Talazoparib is a drug that stops the activity of a protein called PARP. PARP is involved in repairing damage to the deoxyribonucleic acid (DNA) within cells. When PARP is turned off by talazoparib in cancer cells, DNA damage cannot be repaired and leads to the death of the cancer cells. Giving talazoparib and avelumab may have the capacity to increase the response to immunotherapy.

Inclusion Criteria

  • Histologically confirmed advanced breast cancer not amenable to curative treatment by surgery or radiotherapy, that is amenable to biopsy. Patients will be enrolled in one of two cohorts: cohort 1 - BRCA1/2 mutant cohort: pre-identified presence of somatic or germline BRCA1/2 deleterious mutation with HER2-negative breast cancers (HER2 definition by current American Society of Clinical Oncology [ASCO]/College of American Pathologists [CAP] guidelines); cohort 2 - BRCA1/2 wild status cohort: patients with triple negative breast cancer (TNBC) without a known germline or somatic BRCA1/2 mutation. Variants of unknown significance will not be eligible. Patients with germline deleterious mutations may have been identified at any time point prior to inclusion in the protocol and do NOT need to have this genetic testing repeated regardless of time frame and intervening therapy
  • Life expectancy of more than 3 months
  • Measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 (tumor >= 1 cm in longest diameter on axial image on computed tomography [CT] or magnetic resonance imaging [MRI] and/or lymph node[s] >= 1.5 cm in short axis on CT or MRI) on baseline imaging
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1
  • Patients with TNBC and no BRCA mutation who have progressed on a “taxane” based regimen in prior lines of therapy. Patients who refuse standard therapy would also be eligible, as long as their refusal is documented. Note: If a taxane is not an appropriate option for the patient then they will also be eligible to participate as long as it is documented by the treating physician
  • Patients with a standard 12-lead electrocardiogram (ECG) with the following parameters at screening (defined as the mean of the triplicate ECGs): * Corrected QT (QTc) interval at screening < 481 msec * Resting heart rate 50-100 beats per minute (bpm)
  • Absolute neutrophil count (ANC) >= 1,500/mm^3. Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 4 weeks before obtaining sample
  • Platelets >= 100,000/mm^3. Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 4 weeks before obtaining sample
  • Hemoglobin >= 9.0 g/dL. Patients must be able to meet the criteria without transfusion or receipt of colony stimulating factors within 4 weeks before obtaining sample
  • Creatinine clearance >= 60 mL/min based on Cockcroft-Gault equation
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x the upper normal limit of institution's normal range. For subjects with liver metastases, AST and ALT =< 5 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
  • Total bilirubin =< 1.5 x the upper normal limit of institution's normal range. For subjects with liver metastases, total bilirubin > 1.5 - 3.0 x the upper normal limit of institution's normal range are acceptable as long as there is no persistent nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or eosinophilia
  • Prothrombin time (PT) and partial thromboplastin time (PTT) must be =< 2 X the upper limit of the institution's normal range
  • International normalized ratio (INR) < 2. Subjects on anticoagulation (such as coumadin) will be permitted to enroll as long as the INR is in the acceptable therapeutic range as determined by the investigator
  • Patients may have received an unlimited number of prior therapies. The last dose of systemic therapy must have occurred a minimum of 2 weeks prior to cycle 1, day 1 (C1D1)
  • Patients must have fully recovered from all effects of surgery. Patients must have had at least two weeks after minor surgery and four weeks after major surgery before starting therapy. Minor procedures requiring conscious sedation such as endoscopies or mediport placement may only require a 24-hour waiting period, but this must be discussed with an investigator
  • Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to initiation of treatment and/or postmenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential
  • Patient is capable of swallowing pills whole
  • Subject is capable of understanding and complying with parameters as outlined in the protocol and able to sign and date the informed consent, approved by the Institutional Review Board (IRB), prior to the initiation of any screening or study-specific procedures
  • Patient must consent to multiple biopsies during study

Exclusion Criteria

  • Prior disease progression while receiving anti-PD-1 or anti-PD-L1 therapy within 6 months of use
  • Prior PARP inhibitor-based therapy
  • Known or suspected central nervous system (CNS) metastases, unless at least one month has passed since last local CNS therapy and there is no evidence for recurrent or progressive CNS disease on follow up imaging. Participants may remain on steroids for CNS disease if they are taking a stable dose that is less than 10 mg of prednisone per day, or the equivalent
  • Patient has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy (including but not limited to prednisone, cyclophosphamide, azathioprine, methotrexate, thalidomide, and TNFalpha antagonists) within 7 days prior to the first dose of study treatment * Patients who have received acute, low-dose, systemic immunosuppressant medications (e.g., a one-time dose of dexamethasone for nausea) may be enrolled in the study after discussion with and approval by the study principal investigators (PIs) * The use of inhaled, intranasal, ophthalmic or topical corticosteroids is allowed * The use of mineralocorticoids (e.g., fludrocortisone) for patients with orthostatic hypotension is allowed * Physiologic doses of systemic corticosteroids at doses which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid * High dose steroid pre-treatment for CT contrast dye allergy is allowed, provided the dose(s) of steroids is(are) given at least 1 week prior to starting the study medications
  • Known chronic infection with human immunodeficiency virus (HIV) or hepatitis B virus (testing not required prior to enrollment) * Patients with chronic hepatitis C virus may be enrolled if there is no clinical/laboratory evidence of cirrhosis AND the patient’s liver function tests fall within the parameters set
  • Active tuberculosis OR known history of previous clinical diagnosis of tuberculosis
  • Severe infections within 4 weeks prior to day 1 of study therapy, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia * Any course of oral or IV antibiotics must have been completed at least 2 weeks prior to the first dose of study medications
  • Signs or symptoms of infection within 2 weeks prior to cycle 1, day 1
  • Prior allogeneic bone marrow transplantation or prior solid organ transplantation
  • Patient has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., use of disease-modifying agents, corticosteroids, or immunosuppressive drugs), including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, vascular thrombosis associated with antiphospholipid syndrome, Wegener’s granulomatosis, Sjogren’s syndrome, auto-immune Bell’s palsy, Guillain-Barre syndrome, multiple sclerosis, vasculitis, or glomerulonephritis with the following caveats: * Replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment * Patients with Grave’s disease, vitiligo, autoimmune alopecia, or psoriasis not requiring systemic treatment (within the past 2 years) are eligible upon consultation with the study PIs * Patients with questionable diagnosis of autoimmune disease who have never been treated with immunosuppressive regimen and have no ongoing symptoms at the time of enrollment may be eligible after discussion with medical monitor and PI
  • History of idiopathic pulmonary fibrosis, pneumonitis (including drug induced), organizing pneumonia (i.e., bronchiolitis obliterans, cryptogenic organizing pneumonia, etc.), or evidence of active pneumonitis on screening chest CT scan * History of radiation pneumonitis in the radiation field (fibrosis) is permitted
  • Cardiovascular disease problems including unstable angina, therapy for life-threatening ventricular arrhythmia, or myocardial infarction, stroke, or congestive heart failure within the last 6 months. Additionally, patients must not have QT prolongation greater than or equal to 481 milliseconds
  • Life-threatening visceral disease or other severe concurrent disease that would, in the investigator’s judgment, cause unacceptable safety risks, contraindicate patient participation in the clinical study or compromise compliance with the protocol (e.g. chronic active hepatitis, active untreated or uncontrolled fungal, bacterial or viral infections, etc.)
  • Patient has impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of the study drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
  • Patient has received a live vaccine within 30 days of planned start of study therapy
  • Presence of a psychiatric illness or social situation that would limit compliance with study requirements
  • Women who are pregnant or breastfeeding
  • The subject must not have had diagnosis, detection, or treatment of another type of cancer =< 2 years prior to randomization (except basal or squamous cell carcinoma of the skin that has been definitively treated). Questions regarding the inclusion of individual subjects should be directed to the principal investigators, Dr. Collins
  • Patients must not have had investigational therapy administered =< 4 weeks, or within a time interval less than at least 5 half-lives of the investigational agent, whichever is longer, prior to the first scheduled day of dosing in this study
  • Patients must not have had radiotherapy encompassing > 20% of the bone marrow
  • Patients must not have a known hypersensitivity to the components of talazoparib, avelumab or the excipients
  • Patients must not have current evidence of any condition, therapy, or laboratory abnormality (including active or uncontrolled myelosuppression [ie, anemia, leukopenia, neutropenia, thrombocytopenia]) that might confound the results of the study or interfere with the patient's participation for the full duration of the study treatment or that makes it not in the best interest of the patient to participate
  • Patients must not be considered a poor medical risk due to a serious, uncontrolled medical disorder, nonmalignant systemic disease, or active, uncontrolled infection. Examples include, but are not limited to, uncontrolled ventricular arrhythmia, recent (within 90 days) myocardial infarction, uncontrolled major seizure disorder, unstable spinal cord compression, superior vena cava syndrome, or any psychiatric disorder that prohibits obtaining informed consent
  • Current use of potent P-glycoprotein (gp) inhibitors within 7 days prior to randomization

District of Columbia

Washington
MedStar Georgetown University Hospital
Status: ACTIVE
Contact: Julie Collins
Phone: 202-444-2223

Utah

Salt Lake City
Huntsman Cancer Institute / University of Utah
Status: ACTIVE
Contact: Adam Louis Cohen

PRIMARY OBJECTIVE:

I. To evaluate the safety and tolerability of induction talazoparib followed by combination avelumab and talazoparib.

SECONDARY OBJECTIVE:

I. To assess the anti-tumor efficacy of combined therapy as determined by measurement of objective response rate (ORR), overall survival (OS), progression-free survival (PFS), duration of response (DOR) and disease control rate (DCR) as a total cohort and BRCA1/2 carriers versus (vs) non BRCA1/2 carriers.

EXPLORATORY OBJECTIVE:

I. To define the effect of BRCA1/2 status, talazoparib alone, and talazoparib plus avelumab on immunomodulation as measured by immune cell infiltration and activation in plasma/serum assays and tissue.

OUTLINE:

Patients receive talazoparib orally (PO) once daily (QD) on days 1-28. Beginning cycle 2, patients also receive avelumab intravenously (IV) over 1 hour on days 1 and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 12 weeks.

Trial Phase Phase I/II

Trial Type Treatment

Lead Organization
MedStar Georgetown University Hospital

Principal Investigator
Julie Collins

  • Primary ID STUDY00000023
  • Secondary IDs NCI-2019-06240
  • Clinicaltrials.gov ID NCT03964532