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



The purpose of this trial is to determine the safety and tolerability (maximum tolerated dose (MTD)) of weekly dinaciclib in combination with pembrolizumab in patients with advanced breast cancer. Once this is defined, dose expansion will be performed at this MTD in patients with metastatic or locally advanced and unresectable triple negative breast cancer, to evaluate the efficacy of combined dinaciclib and pembrolizumab.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Active, not recruiting


Phase 1

Trial Eligibility



  • Brief Title: Phase 1b Trial of Dinaciclib With Pembrolizumab for Advanced Breast Cancer
  • Official Title: A Phase 1b Trial of the Cyclin-dependent Kinase Inhibitor Dinaciclib in Combination With Pembrolizumab in Patients With Advanced Breast Cancer and Assessment of MYC Oncogene Overexpression

Clinical Trial IDs

  • ORG STUDY ID: 16758
  • SECONDARY ID: NCI-2018-01053
  • NCT ID: NCT01676753


  • Advanced or Metastatic Breast Cancer
  • Triple Negative Breast Cancer


DinaciclibDinaciclib & Pembrolizumab Treatment
PembrolizumabDinaciclib & Pembrolizumab Treatment


The purpose of this trial is to determine the safety and tolerability (maximum tolerated dose (MTD)) of weekly dinaciclib in combination with pembrolizumab in patients with advanced breast cancer. Once this is defined, dose expansion will be performed at this MTD in patients with metastatic or locally advanced and unresectable triple negative breast cancer, to evaluate the efficacy of combined dinaciclib and pembrolizumab.

Detailed Description

      This is an open-label phase Ib trial of weekly dinaciclib in combination with every 3 week
      pembrolizumab in patients with advanced triple negative breast cancer. Any number of prior
      therapies is allowed. Pembrolizumab will be administered every 3 weeks at a fixed dose of 200
      mg IV. Dinaciclib will be administered D1 and D8 of a 21 day cycle by 2-hour intravenous
      infusion. The starting dose level of this study will be dinaciclib 12 mg/m2 in combination
      with pembrolizumab 200 mg IV. The dose of dinaciclib will be escalated following a toxicity
      probability interval (TPI) design which targets a DLT rate of ~ 25% . The primary objective
      is to define the maximum tolerated and recommended phase 2 dose (MTD and RP2D) of dinaciclib
      when given weekly in this combination and schedule. The primary endpoint is safety and
      tolerability. MTD will be defined in at least 6 patients. Secondary objectives include
      evaluation of the preliminary efficacy of this combination using RECIST 1.1 and irRECIST.
      Exploratory studies characterizing and correlating PDL-1 and MYC overexpression with clinical
      response will be performed. Tumor biopsies are mandatory unless otherwise specified.

Trial Arms

Dinaciclib & Pembrolizumab TreatmentExperimentalDinaciclib is administered on days 1 and 8 of a 21-day cycle in combination with pembrolizumab administered on day 1 of each 21-day cycle.
  • Dinaciclib
  • Pembrolizumab

Eligibility Criteria


          1. Histologically or cytologically documented, incurable, unresectable locally advanced,
             or metastatic breast cancer

          2. Histologically documented metastatic or locally advanced unresectable breast cancer
             that is ER and progesterone receptor (PR) <10% expression and does not over-express
             Hormone 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 disease
             is 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 laboratory


               -  Absolute neutrophil count (ANC) ≥ 1,500 /μL

               -  Platelets ≥ 100,000 /μL

               -  Hemoglobin ≥ 9 g/dL


               -  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


               -  Serum total bilirubin ≤ 1.5 x ULN OR direct bilirubin ≤ ULN for patients with
                  total 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


               -  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 pregnancy
             test β-human chorionic gonadotropin (hCG) within 72 hours prior to first doses of
             study medication . If the urine test is positive or cannot be confirmed as negative, a
             serum pregnancy test will be required.

          9. Female subjects of childbearing potential must be willing to use an adequate method of
             contraception for the course of the study through 120 days after the last dose of
             study medication.

             Note: Abstinence is acceptable if this is the usual lifestyle and preferred
             contraception for the subject.

         10. Male subjects of childbearing potential must agree to use an adequate method of
             contraception starting with the first dose of study therapy through 120 days after the
             last dose of study therapy. Note: Abstinence is acceptable if this is the usual
             lifestyle and preferred contraception for the subject.

         11. Patient has voluntarily agreed to participate by giving written informed consent

         12. Concomitant use of bisphosphonates or RANK-ligand inhibitors is allowed


          1. Patient who has had radiotherapy within 1 week (or unresolved radiation-related
             toxicities), chemotherapy within 2 weeks or 5 half-lives, whichever is longer (6 weeks
             for nitrosoureas, mitomycin C or bevacizumab), anti-cancer monoclonal antibody for
             direct anti-neoplastic treatment within 3 weeks, or who has not recovered from
             toxicity due to previous agents administered. If the patient has residual toxicity
             from 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 be
             fully healed). For the purpose of this criterion, a major surgical procedure is
             defined as one requiring the administration of general anesthesia.

          5. Patient is currently participating in a study with an investigational compound or

          6. Patient has known active central nervous system (CNS) metastases and/or carcinomatous
             meningitis. However, patients with CNS metastases who have completed a course of
             therapy would be eligible for the study provided they are clinically stable for at
             least 4 weeks prior to entry as defined as: (1) no evidence of new or enlarging CNS
             metastasis on brain imaging within 4 weeks of enrollment (2) off steroids for 2 weeks.
             Patients with clinically insignificant brain metastases that do not require treatment
             are 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 disease

               -  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 that
                  is 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 of
             clinically significant bradyarrhythmias such as sick sinus syndrome, 2nd degree
             atrioventricular (AV) block (Mobitz Type 2), Patient with uncontrolled hypertension
             (≥140/90 mmHg). Patients who are controlled on antihypertensive medication will be
             allowed to enter the study.

         11. Patient has a history or current evidence of any condition, therapy, or lab
             abnormality that might confound the results of the study, interfere with the patient's
             participation for the full duration of the study, or is not in the best interest of
             the patient to participate, in the opinion of the treating investigator.

         12. Patient has known psychiatric or substance abuse disorders that would interfere with
             cooperation with the requirements of the trial

         13. Patient is, at the time of signing informed consent, a regular user of any illicit
             drugs 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 children
             within 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 standard

         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 of
             at least 5 days or at least 5 half-lives of the drug (whichever is longer) prior to
             the first dose of dinaciclib (Refer to Appendix 2 Drugs that interact strongly with

         20. Patients requiring warfarin therapy are excluded, low molecular weight heparin is

         21. Patient has a diagnosis of immunodeficiency or is receiving ongoing immunosuppressive
             therapy, including systemic or enteric corticosteroids except for non-systemically
             absorbed treatments (such as inhaled or topical steroid therapy for asthma, chronic
             obstructive pulmonary disease, allergic rhinitis). Patient must be off systemic
             steroid or any other form of immunosuppressive therapy within 7 days prior to first
             dose of trial treatment.

         22. Patient is diagnosed with active autoimmune disease that has required systemic
             treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids
             or immunosuppressive drugs). Note: replacement therapy (e.g., thyroxine, insulin, or
             physiologic 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 evidence
             of active, noninfectious pneumonitis.

         24. Patient has history of severe allergic, anaphylactic, or other hypersensitivity
             reactions to chimeric or humanized antibodies or prior allogeneic bone marrow
             transplantation 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 and
             are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live
             attenuated 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.
Maximum Eligible Age:85 Years
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:Measured during each Cycle (21 Days), with number of cycles dependent on number of adverse events (AE). MTD is defined as the dose at which no more than 1/6 patients experience a DLT (dose-limiting toxicity).
Safety Issue:
Description:The MTD is measured (safety/tolerability) by clinical review of relevant AE parameters (i.e. laboratory tests, physical exams)

Secondary Outcome Measures

Measure:Anti-tumor activity in patients with advanced triple negative breast cancer
Time Frame:Assessed every 9 weeks, from date of screening assessment (within 4 weeks of enrollment) until the date of ceased treatment (whether due to disease progression, death, adverse events or withdrawal), for the period of the study (estimated 2-3 years)
Safety Issue:
Description:Response and progression will be evaluated by diagnostic anatomic imaging and clinical exam. Overall tumor response and time to progression will be assessed using RECIST (Response Evaluation Criteria in Solid Tumors) 1.1 criteria and immune-related RECIST (irRECIST)


Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Jo Chien

Last Updated

July 26, 2021