Study Of Single-dose Cyclophosphamide +Pembrolizumab In Patients With Metastatic Triple Negative Breast Cancer

This phase II, single-arm, multicenter study will evaluate efficacy and toxicity of administration of pembrolizumab following cyclophosphamide therapy, in advanced stage triple-negative breast cancer.

Duration of Therapy

Treatment may continue until one of the following occurs:

• Disease progression
• Inter-current illness that prevents further administration of treatment
• Unacceptable adverse event(s)
• Pregnancy
• Patient decides to withdraw from study treatment,
• General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator
• Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication, whichever is later

Duration of Follow Up

• Subjects will be followed for up to 3 years after removal from study treatment or until death, whichever occurs first.
• Patients removed from study for unacceptable adverse events (AEs) will be followed until resolution or stabilization of the event(s).

Inclusion criteria

• Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
• Age ≥ 18 years at the time of consent.
• Have measurable disease based on RECIST 1.1 (see section 6.7 for details).
• ECOG Performance Status ≤ 1 as defined in the protocol ECOG Performance Status.
• Subject must have histologically confirmed stage IV TNBC (ER-, PR-, HER2-negative) and have received at least 1 prior line of systemic therapy.

• ER- and PR-negative: defined as < 1% staining by immunohistochemistry (IHC)
• HER2-negative disease, defined as IHC 0-1+ or fluorescence in situ hybridization (FISH) ratio < 2.0
• Patients with stable brain metastases will be allowed provided the following criteria are met:

• Brain radiation was already provided at least 4 weeks prior to initiating study treatment
• The subject has no new or progressive neurologic symptoms AND neurological symptom stability for the last 4 weeks prior to the study
• The subject has been off of corticosteroids for at least 7 days prior to trial treatment
• The subject does not have carcinomatous meningitis
• Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 72 h of initiating study treatment.
• Females of childbearing potential must have a negative serum pregnancy test within 72 hrs prior to treatment. NOTE: Females are considered of child bearing potential unless they are surgically sterile, have a congenital acquired condition that prevents childbearing (have undergone a hysterectomy, bilateral tubal ligation/occlusion, bilateral salpingectomy or bilateral oophorectomy at least 6 weeks prior to screening) or they are naturally postmenopausal for at least 12 consecutive months without an alternative medical cause. In women < 45 years of age a high follicle stimulating hormone level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
• Female patients of childbearing potential should be willing to use appropriate birth control as outlined in Section 5.2.8, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.
• Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 5.2.8, starting with the first dose of study therapy through 120 days after the last dose of study therapy.
• Consent for the use of any residual material from biopsy (archival tissue) and serial blood draws will be required for enrollment; fresh biopsy (pre and post dose) of tumor tissue will be optional. NOTE: Patients without adequate tissue for bio correlates will not be excluded or required to have a repeat biopsy.
• As determined by the enrolling physician or protocol designee, the subject should be able to understand and comply with study procedures for the entire length of the study.
• Has a LVEF within the normal institutional range (or ≥ 50%) based on ECHO or MUGA.

Exclusion criteria

• Active infection requiring systemic therapy
• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study).
• Has a known history of active Bacillus Tuberculosis (TB)
• Hypersensitivity to pembrolizumab or any of its excipients.
• Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years.
• Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to receipt of study medication or who has not recovered (i.e., ≤ Grade 1 or at baseline; excludes alopecia and Grade 2 neuropathy) from adverse events due to a previously administered agent.

• If subject had major surgery, they must have recovered adequately from the toxicity and complications from the intervention prior to starting therapy
• Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer.
• Has had monoclonal antibody therapy within 4 weeks prior to study Day 1 or who has not recovered (ie, ≤ Grade 1 at baseline; excludes alopecia and Grade 2 neuropathy) from adverse events due to agent(s) administered more than 4 weeks earlier.
• Treatment with any investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study medication.
• Used an investigational device within 4 weeks of the first dose of treatment.
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
• Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
• Has known history of, or any evidence of active, non-infectious pneumonitis requiring treatment with steroids; has history of, or any evidence of, active interstitial lung disease.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
• Has participated in a previous trial and received pembrolizumab therapy
• Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
• Has received a live vaccine within 30 days prior to the first dose of trial treatment.

• Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed
• Cyclophosphamide is a substrate for cytochromes 2B6, 2C9, 3A4 and 2C19. Patients must not have received any drug that is a moderate or strong inhibitor of 2B6, 2C9, 3A4, and 2C19 within 1 week prior to receiving cyclophosphamide dosing through 72 hours after cyclophosphamide dosing. Patients must not have received any drug that is a moderate or strong inducer of 3A4 within 2 weeks prior to cyclophosphamide dosing.