CISPLATIN + AZD-1775 In Breast Cancer
Condition: Triple-negative Metastatic Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Cisplatin; AZD1775
Intervention description: chemotherapy; Wee1 tyrosine kinase inhibitor
Intervention MeSH terms: Adavosertib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 34.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Triple-negative metastatic breast cancer

Summary:

      This research study is studying a combination of drugs as a possible treatment for
      triple-negative breast cancer that has spread to other areas of the body. The names of the
      study interventions involved in this study are:

        -  Cisplatin

        -  AZD1775
    

Eligibility criteria:

        Inclusion Criteria:

          -  Participants must have histologically or cytologically confirmed invasive breast
             cancer, with stage IV disease. Patients without pathologic or cytologic confirmation
             of metastatic disease should have unequivocal evidence of metastasis from physical
             examination or radiologic evaluation.

          -  Either the primary invasive tumor and/or the metastasis must be triple-negative,
             defined as:

               -  hormone-receptor poor, ER- and PR-negative, or staining present in <1% by
                  immunohistochemistry (IHC)

               -  HER2-negative: 0 or 1+ by IHC, or FISH<2.0

          -  Participants must have at least one lesion that is not within a previously radiated
             field that is measurable on computerized tomography (CT) or magnetic resonance imaging
             (MRI) scan per RECIST version 1.1. Bone lesions are not considered measurable by
             definition. See Section 11 for the evaluation of measurable disease.

          -  Prior chemotherapy: Patients may have received 0-1 prior chemotherapeutic regimen for
             metastatic breast cancer and must have been off treatment with chemotherapy for at
             least 21 days before enrollment in the study. The number of patients with 0 prior
             chemotherapeutic regimen will be limited to a maximum of n = 20.

          -  Prior biologic therapy: Patients must have discontinued all biologic therapy at least
             21 days before participation.

          -  Prior radiation therapy: Patients may have received prior radiation therapy in either
             the metastatic or early-stage setting. Radiation therapy must be completed at least 14
             days prior to study participation and patients should have recovered from adverse
             effects of radiation to grade ≤1.

          -  Age ≥18

          -  ECOG performance status ≤1

          -  Participants must have normal organ and marrow function as defined below:

               -  Absolute neutrophil count ≥ 1500/mm3

               -  Platelets ≥100,000/mm3

               -  Hemoglobin ≥ 9 g/dL

               -  Total Bilirubin ≤ 1.5 mg/dL

               -  Serum creatinine ≤1.5 mg/dL OR measured creatinine clearance (CrCl) ≥45 mL/min as
                  calculated by the Cockcroft-Gault method OR 24-hour measured urine CrCl ≥45mL/min

               -  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times
                  the upper limit of normal. For patients with documented liver metastases, AST/ALT
                  ≤ 5.0 times the upper limit of normal.

          -  Patients on bisphosphonates may continue receiving bisphosphonate therapy during study
             treatment.

          -  Availability of a tissue block from initial breast cancer diagnosis and/or metastatic
             recurrence. If a tissue block is not available, 10-20 unstained slides may be provided
             as an alternative. If unstained slides will be provided, they should not be sent until
             specifically requested by the DFCI study coordinator. If archival tumor tissue is not
             available, a fresh biopsy may be performed.

          -  In the first stage of the trial, at least 10 patients with biopsy-accessible disease
             must be willing to undergo paired research biopsies. These biopsies will occur 5-48
             hours after the C1D1 cisplatin dose (ie. C1D2or C1D3) and 5-8hrs (+/- 24hrs) after the
             last dose of AZD1775 on C2D3. The exact timing of the biopsy relative to receipt of
             study treatment should be accurately recorded.

               -  Biopsies may be done with local anesthesia or intravenous conscious sedation,
                  according to standard institutional guidelines.

               -  Research biopsies requiring general anesthesia are not allowed on this protocol
                  unless a biopsy is being obtained simultaneously for clinical reasons, in the
                  judgment of the patients' treating physician.

               -  Patients who undergo an attempted on-treatment research biopsy and in whom
                  inadequate tissue is obtained are still eligible to continue protocol therapy.
                  They will not be required to undergo a repeat biopsy attempt.

               -  If dosing is delayed placing the biopsy outside of the allowable window, the
                  biopsy should be rescheduled to be within the window. If not feasible, the biopsy
                  should be obtained as close to within the window as possible.

               -  Fine needle aspirates (FNA) is not allowed

          -  Female subjects of childbearing potential must have a negative serum pregnancy test at
             screening.

          -  The effects of AZD1775 on the developing human fetus are unknown. Women of
             child-bearing potential and men must agree to use enhanced methods of contraception.
             All women are considered to be of childbearing potential unless they fulfill one of
             the following criteria at screening:

               -  Post-menopausal defined as age ≥50 and amenorrheic for at least 12 months OR
                  Women age <50 if they have been amenorrheic for at least 12 months and have a
                  serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) level in
                  the postmenopausal range (per institutional standards).

               -  If women have documentation of irreversible surgical sterilisation by
                  hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, or bilateral
                  tubal ligation, they are considered post-menopausal.

          -  Appropriate contraception should be used from the time of screening, throughout the
             duration of study participation, and for four months after the last dose of AZD1775.
             Acceptable methods of contraception include abstinence, tubal ligation, intra-uterine
             devices, and vasectomised partner. All methods of contraception (with the exception of
             total abstinence) should be used in combination with the use of a condom by the male
             sexual partner for intercourse. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, the participants
             treating physician should be informed immediately. Additionally, male patients should
             refrain from donating sperm from the start of dosing until 6 months after
             discontinuing AZD1775. If male patients wish to father children they should be advised
             to arrange for freezing of sperm samples prior to the start of study treatment.

          -  Participant must be able to swallow pills.

          -  Participant may not have a percutaneous endoscopic gastrostomy (PEG) tube or be
             receiving total parenteral nutrition (TPN).

          -  Ability to understand and the willingness to sign a written informed consent document.

        Exclusion Criteria:

          -  Participants who are receiving any other investigational agents within 21 days of the
             first dose of study drug.

          -  Major surgical procedures <28 days from beginning study treatment.

          -  Participants who have received a prior inhibitor of Wee1 kinase activity

          -  Participants who have received prior platinum chemotherapy

          -  Known brain metastases that are untreated, symptomatic, or require therapy to control
             symptoms. Patients with a history of treated central nervous system (CNS) metastases
             are eligible. Treated brain metastases are defined as those having no evidence of
             progression for ≥ 1 month after treatment, or hemorrhage for ≥ 2 weeks after treatment
             and no ongoing requirement for corticosteroids, as ascertained by clinical examination
             and brain imaging (magnetic resonance imaging or CT scan) during the screening period.
             Any corticosteroid use for brain metastases must have been discontinued without the
             subsequent appearance of symptoms for ≥2 weeks before the first study drug. Treatment
             for brain metastases may include whole brain radiotherapy, radiosurgery, or a
             combination as deemed appropriate by the treating physician. Patients with CNS
             metastases treated by neurosurgical resection or brain biopsy performed within 1 month
             before day 1 of study treatment will be excluded.

          -  Patients with grade >1 neuropathy or grade >1 toxicity (except alopecia or anorexia)
             from prior therapy

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to AZD1775 or Cisplatin.

          -  Participants receiving any medications, substances, or foods (ie, grapefruit juice)
             listed below are ineligible (Please refer to Section 5.4 for list of restricted
             co-medications):

               -  prescription or non-prescription drugs or other products known to be sensitive
                  CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be
                  moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2
                  weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks
                  after the last dose of study drug. sensitive substrates of CYP2C8, CYP2C9,
                  CYP2C19, or substrates of these enzymes with narrow therapeutic range

               -  inhibitors or substrates of P-gp

          -  Participants who have an uncontrolled intercurrent illness, including, but not limited
             to, ongoing or active infection, uncontrolled hypertension, unstable angina pectoris,
             uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association
             Class III or IV (Appendix B), active ischemic heart disease, myocardial infarction
             within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal
             ulceration diagnosed within the previous 6 months, chronic liver or renal disease, or
             severe malnutrition. In addition, patients are ineligible if they have a psychiatric
             illness or a social situation that could limit their ability to comply with the study
             requirements.

          -  Participants who have refractory nausea and vomiting, chronic gastrointestinal
             diseases, or previous significant bowel resection that would preclude adequate
             absorption of AZD1775.

          -  Pregnant women are excluded from this study because AZD1775 is a Wee1 inhibitor agent
             with the potential for teratogenic or abortifacient effects.

          -  Lactating or breastfeeding women are excluded because there is an unknown but
             potential risk for adverse events in nursing infants secondary to treatment of the
             mother with AZD1775, breastfeeding should be discontinued prior to being treated with
             AZD1775. These potential risks may also apply to other agents used in this study.

          -  Known HIV-positive participants are ineligible because these participants are at
             increased risk of lethal infections when treated with marrow-suppressive therapy.

          -  Participant with mean resting corrected QT interval (specifically QTc calculated using
             the Fridericia formula [QTcF]) > 450 msec for males and > 470 msec for females, from 3
             electrocardiograms (ECGs) performed within 2-5 minutes apart at study entry, or
             congenital long QT syndrome.