Parsaclisib for the Treatment of Newly Diagnosed Stage I-IIIC Triple-Negative or HER2-Positive Breast Cancer
This phase I trial studies the side effects and best dose of parsaclisib in treating patients with newly diagnosed stage I-IIIC triple-negative or HER2-postive breast cancer. Studies have shown that a good way to find out how cancer acts when exposed to anti-cancer drugs is through a pre-operative window study (window of opportunity). In this type of study, tissue and blood are collected before treatment. Then subjects receive a study drug for a few weeks before surgery. Blood is drawn during the course of treatment, and leftover tissue is collected during surgery. Comparing the tissue and blood before and after treatment shows the effects the study drug may have had on the tumor. Parsaclisib limits the effects of a protein called phosphatidylinositol 3-kinase delta (PI3K). By limiting P13K, parsaclisib may block certain cells that prevent the immune cells from working and may help the body’s immune system to fight tumors.
Inclusion Criteria
- Is able to understand and give written informed consent for removal of at least 2 cores of tissue via a pre-treatment research biopsy. Is able to understand and give written informed consent for either collection of leftover tissue at time of surgery and via an end of treatment (EOT) research biopsy
- Has histologically confirmed newly diagnosed stage I-IIIC invasive breast cancer that is triple negative (estrogen receptor [ER]/progesterone receptor [PR] < 1%, HER2 negative) or HER2-positive, and meets the criteria listed below: * HER 2 positive or overexpressed HER2 confirmed by immunohistochemistry (IHC), and florescence in situ hybridization (ISH) according to the 2018 American Society of Clinical Oncology (ASCO)-College of American Pathologists (CAP) guideline: ** IHC score of 3+ without ISH HER2/CEP17 OR ** ISH HER2/CEP17 amplified with ratio higher than 2.0 OR if reported average HER2 copy number >= 6 signals/cell * Scheduled for lumpectomy, mastectomy or neoadjuvant chemotherapy as first treatment for cancer * No prior or current therapy for breast cancer * Amenable to a baseline research breast biopsy * Amenable to a post-therapy research biopsy (for patients going on to neoadjuvant chemotherapy and not straight to surgery). For patients going directly to surgery, post-therapy biopsy will be obtained at the time of surgery
- Must have sufficient time to receive at least 7 consecutive days of parsaclisib therapy prior to definitive surgery or initiation of chemotherapy
- Has an Eastern Cooperative Oncology Group (ECOG) performance status =< 1
- Is able to swallow and retain oral medication
- Hemoglobin (Hgb) >= 10.0 g/dL (obtained within 72 hours [hr] of initiating study treatment)
- Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (obtained within 72 hr of initiating study treatment)
- Absolute lymphocyte count (ALC) > 500 cells/uL (obtained within 72 hr of initiating study treatment)
- Platelets >= 100 x 10^9/L (obtained within 72 hr of initiating study treatment)
- Creatinine =< 1.5 x upper limit of normal (ULN) OR calculated creatinine clearance (creatinine should be calculated per institutional standard) >= 60 mL/min for subject with creatinine levels > 1.5 x ULN (obtained within 72 hr of initiating study treatment)
- Bilirubin =< 1.5 x ULN or direct bilirubin =< ULN for subject with total bilirubin > 1.5 x ULN (obtained within 72 hr of initiating study treatment)
- Aspartate aminotransferase (AST) =< 2.5 x ULN (obtained within 72 hr of initiating study treatment)
- Alanine aminotransferase (ALT) =< 2.5 x ULN (obtained within 72 hr of initiating study treatment)
- Albumin >= 2.5 g/dL (obtained within 72 hr of initiating study treatment)
- International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT and partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants (obtained within 72 hr of initiating study treatment)
- Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT and PTT is within therapeutic range of intended use of anticoagulants (obtained within 72 hr of initiating study treatment)
- As determined by the enrolling physician or protocol designee, the subject is able to understand and comply with study procedures
- For female subjects of childbearing potential: has a negative serum pregnancy test at screening within 72 hours of receiving study treatment. In addition, female subjects must either: * Agree to the use of an approved method of contraception (i.e., two adequate barrier methods throughout the study starting with the screening visit) and to continue its use for the duration of the study treatment through 30 days after the last dose of parsaclisib if a female subject of child-bearing potential, or * Has documented inability to become pregnant (e.g., hysterectomy, bilateral tubal ligation or oophorectomy, or post-menopausal as defined as total cessation of menses for 2 years). 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 otherwise the subject must be willing to use 2 adequate barrier methods throughout the study
Exclusion Criteria
- Prior history of another known malignancy other than breast cancer within the previous 2 years with the exception of adequately treated basal cell carcinoma or cervical intraepithelial neoplasia, cervical carcinoma in situ or melanoma in situ
- Is pregnant or lactating
- Has a concomitant medical condition that precludes adequate study treatment compliance or assessment, such as bleeding disorders or any other medical condition that would increase risks of additional core biopsy for biomarkers
- Use of any potent CYP3A4 inhibitors or inducers (e.g., grapefruit or grapefruit juice) within 14 days or 5 half-lives (whichever is longer) before the first dose of parsaclisib
- Has allergy to inactive components of the study medication
- History of autoimmune disease or irritable bowel syndrome (IBS), or active colitis
- Inability to take oral medications (e.g., impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of oral medications such as ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel resection)
- Is participating in another therapeutic clinical trial or has received another investigational agent within 30 days prior to informed consent
- Known hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (with the exception of chronic or cleared HBV and HCV infection which is allowed)
- Has acute or currently active/requiring anti-viral therapy, hepatic or biliary disease (with the exception of subjects with Gilbert's syndrome, asymptomatic gallstones, or stable chronic liver disease per investigator assessment)
- Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the study
- Medical history of a disease that requires ongoing steroid therapy for > 14 days
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT04142554.
PRIMARY OBJECTIVE:
I. To determine the minimum dose of PI3K-delta inhibitor INCB050465 (parsaclisib), administered once daily for 14 consecutive days, in subjects with triple-negative or HER2-positive breast cancer resulting in either a 50% increase in the intratumoral CD8+ T cells/regulatory T-cell ratio or a 50% decrease in the percentage of intratumoral regulatory T cells as measured using single cell transcriptomics and/or flow cytometry.
SECONDARY OBJECTIVES:
I. To determine the minimum dose of parsaclisib, administered once daily for 14 consecutive days, in subjects with triple-negative or HER2 positive breast cancer resulting in either a 50% increase in the peripheral blood CD8+ T cells/regulatory T-cell ratio or a 50% decrease in the percentage of peripheral blood regulatory T cells as measured using single cell transcriptomics and/or flow cytometry.
II. To identify changes in the regulatory T cell signature following treatment with parsaclisib in subjects with triple-negative or HER2-positive breast cancer.
III. To identify changes in Ki-67 messenger ribonucleic acid (mRNA) expression following treatment with parsaclisib in subjects with triple-negative or HER2-positive breast cancer.
IV. To compare reduction in the regulatory T cell signature by dose of parsaclisib (10 mg, 3.0 mg or 1.0 mg).
EXPLORATORY OBJECTIVES:
I. To identify mRNA expression changes following treatment with parsaclisib in subjects with triple-negative or HER2-positive breast cancer.
II. To evaluate changes in the proliferation signature by mRNA expression following treatment with parsaclisib in subjects with triple-negative or HER2-positive breast cancer.
III. To perform cellular immunology assessment of peripheral blood mononuclear cells by evaluating changes in regulatory T cell (Treg) activation.
IV. To define and correlate molecular subtype with changes in the regulatory T cell signature by RNA-sequencing following parsaclisib treatment in subjects with triple-negative or HER2-positive breast cancer.
V. To correlate mutation and/or copy number variations by whole exome sequencing (WES) with mRNA gene expression changes and reduction of proliferation signature following treatment with parsaclisib in subjects with triple-negative or HER2-positive breast cancer.
VI. To evaluate if treatment with parsaclisib alters the presence of different populations of T-cells, B-cells, natural killer (NK) cells and/or myeloid cells using single cell RNA transcriptomics with V(D)J analysis for T and B-cells.
VII. To document safety of parsaclisib in subjects with triple-negative or HER2-positive breast cancer prior to their scheduled surgical resection per National Cancer Institute – Common Terminology for Adverse Events (NCI-CTCAE version [v] 5.0).
VIII. To perform metabolic mapping of kynurenine, tryptophan, arginine, ornithine, etc. using mass spectrometry.
OUTLINE:
Patients receive parsaclisib orally (PO) once daily (QD) for 14 days in the absence of disease progression or unacceptable toxicity.
After completion of study, patients are followed up at 30 days.
Trial PhasePhase I
Trial Typebasic science
Lead OrganizationUNC Lineberger Comprehensive Cancer Center
Principal InvestigatorLisa A. Carey
- Primary IDLCCC1820
- Secondary IDsNCI-2019-08258
- ClinicalTrials.gov IDNCT04142554