Phase 1b Trial of Dinaciclib With Pembrolizumab for Advanced Breast Cancer

INCLUSION CRITERIA:

1. Histologically or cytologically documented, incurable, unresectable locally advanced,or metastatic breast cancer
2. Histologically documented metastatic or locally advanced unresectable breast cancerthat is ER and progesterone receptor (PR) <10% expression and does not over-expressHormone Estrogen Receptor-Positive (HER2) protein (Immunohistochemistry (IHC) 0, 1+,or 2+ and Fluorescent in situ hybridization (FISH) <2.0)
3. Patient must consent to a biopsy of a site of disease unless the only site of diseaseis lung/pleura, bone, or deemed unsafe by the principal investigator
4. Patient is male or female and ≥18 years of age on the day of signing informed consent.
5. Patient must have performance status of 0-1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale and life expectancy > 3 months
6. Patient must have evaluable disease
7. Patient must have adequate organ function as indicated by the following laboratoryvalues: Hematological

• Absolute neutrophil count (ANC) ≥ 1,500 /μL
• Platelets ≥ 100,000 /μL
• Hemoglobin ≥ 9 g/dL Renal
• Serum creatinine or calculated creatinine clearance ≤ 1.5 x upper limit of normal (ULN) OR
• ≥ 60 mL/min for patients with creatinine levels > 1.5 x institutional ULN Hepatic
• Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patients withtotal bilirubin levels > 1.5 x ULN
• Aspartate aminotransferase (AST) / serum glutamic-oxaloacetic transaminase (SGOT)and alanine aminotransferase (ALT) / serum glutamic-pyruvic transaminase (SGPT) ≤ 2.5 x ULN, ≤ 5 x ULN if liver metastasis Coagulation
• Prothrombin time (PT)/International Normalized Ratio (INR) ≤ 1.2 x ULN
• Partial thromboplastin time (PTT) ≤ 1.2 x ULN

8. Female patient of childbearing potential must have a negative serum or urine pregnancytest β-human chorionic gonadotropin (hCG) within 72 hours prior to first doses ofstudy medication . If the urine test is positive or cannot be confirmed as negative, aserum pregnancy test will be required.
9. Female subjects of childbearing potential must be willing to use an adequate method ofcontraception for the course of the study through 120 days after the last dose ofstudy medication. Note: Abstinence is acceptable if this is the usual lifestyle and preferredcontraception for the subject.
10. Male subjects of childbearing potential must agree to use an adequate method ofcontraception starting with the first dose of study therapy through 120 days after thelast dose of study therapy. Note: Abstinence is acceptable if this is the usuallifestyle and preferred contraception for the subject.
11. Patient has voluntarily agreed to participate by giving written informed consent
12. Concomitant use of bisphosphonates or nuclear factor-κB (RANK) ligand inhibitors isallowed.

EXCLUSION CRITERIA:

1. Patient who has had radiotherapy within 1 week (or unresolved radiation-relatedtoxicities), chemotherapy within 2 weeks or 5 half-lives, whichever is longer (6 weeksfor nitrosoureas, mitomycin C or bevacizumab), anti-cancer monoclonal antibody fordirect anti-neoplastic treatment within 3 weeks, or who has not recovered fromtoxicity due to previous agents administered. If the patient has residual toxicityfrom prior treatment, toxicity must be ≤ Grade 1 (except for neuropathy and alopecia).
2. > 2 lines of prior chemotherapy in the metastatic setting
3. Serum lactate dehydrogenase (LDH) > 1.5x institutional ULN
4. Patients less than 2 weeks post major surgical procedure (all surgical wounds must befully healed). For the purpose of this criterion, a major surgical procedure isdefined as one requiring the administration of general anesthesia.
5. Patient is currently participating in a study with an investigational compound ordevice.
6. Patient has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. However, patients with CNS metastases who have completed a course oftherapy would be eligible for the study provided they are clinically stable for atleast 4 weeks prior to entry as defined as: (1) no evidence of new or enlarging CNSmetastasis on brain imaging within 4 weeks of enrollment (2) off steroids for 2 weeks.Patients with clinically insignificant brain metastases that do not require treatmentare eligible.
7. Patient has a primary central nervous system tumor
8. Patient has known hypersensitivity to the components of study drug or its analogs.
9. Patient has a history or current evidence of clinically significant heart diseaseincluding:

• Clinically significant congestive heart failure, unstable angina pectoris,
• Clinically significant cardiac arrhythmia,
• Myocardial infarction during the last 6 months, and/or a current ECG tracing thatis abnormal in the opinion of the treating Investigator,
• QTc prolongation >480 msec (Bazett's Formula),
• Congenitally long QT syndrome, and/or current anti-arrhythmic therapy

10. Patient with evidence of clinically significant bradycardia (HR <50), or a history ofclinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degreeatrioventricular (AV) block (Mobitz Type 2), Patient with uncontrolled hypertension (≥140/90 mmHg). Patients who are controlled on antihypertensive medication will beallowed to enter the study.
11. Patient has a history or current evidence of any condition, therapy, or lababnormality that might confound the results of the study, interfere with the patient'sparticipation for the full duration of the study, or is not in the best interest ofthe patient to participate, in the opinion of the treating investigator.
12. Patient has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial
13. Patient is, at the time of signing informed consent, a regular user of any illicitdrugs or had a recent history (within the last year) of drug or alcohol abuse.
14. Patient is pregnant or breastfeeding, or expecting to conceive or father childrenwithin the projected duration of the study
15. Patient is known to be Human Immunodeficiency Virus (HIV)-positive
16. Patient has known history of active Hepatitis A, B, or C
17. Patients who have known allergic reactions to IV contrast dye despite standardprophylaxis
18. Patients who require medications that are strong CYP3A4 inhibitors or inducers.
19. Patients who have discontinued any of these medications must have a wash-out period ofat least 5 days or at least 5 half-lives of the drug (whichever is longer) prior tothe first dose of dinaciclib (Refer to Appendix 2 Drugs that interact strongly withCYP3A4).
20. Patients requiring warfarin therapy are excluded, low molecular weight heparin ispermitted.
21. Patient has a diagnosis of immunodeficiency or is receiving ongoing immunosuppressivetherapy, including systemic or enteric corticosteroids except for non-systemicallyabsorbed treatments (such as inhaled or topical steroid therapy for asthma, chronicobstructive pulmonary disease, allergic rhinitis). Patient must be off systemicsteroid or any other form of immunosuppressive therapy within 7 days prior to firstdose of trial treatment.
22. Patient is diagnosed with active autoimmune disease that has required systemictreatment in past 2 years (i.e., with use of disease modifying agents, corticosteroidsor immunosuppressive drugs). Note: replacement therapy (e.g., thyroxine, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)is not considered a form of systemic treatment.
23. Patient has history of interstitial lung disease or known history of, or any evidenceof active, noninfectious pneumonitis.
24. Patient has history of severe allergic, anaphylactic, or other hypersensitivityreactions to chimeric or humanized antibodies or prior allogeneic bone marrowtransplantation or prior solid organ transplantation.
25. Has received a live vaccine within 30 days of planned start of study therapy. Note:Seasonal influenza vaccines for injection are generally inactivated flu vaccines andare allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are liveattenuated vaccines, and are not allowed. Inclusion of women and minorities: Both men and women and members of all races and ethnic groups are eligible for this trial.