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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01676753
Recruitment Status : Active, not recruiting
First Posted : August 31, 2012
Last Update Posted : July 15, 2020
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Jo Chien, University of California, San Francisco

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Advanced or Metastatic Breast Cancer Triple Negative Breast Cancer Drug: Dinaciclib Drug: Pembrolizumab Phase 1

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 32 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Actual Study Start Date : December 28, 2016
Actual Primary Completion Date : June 30, 2020
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Dinaciclib & Pembrolizumab Treatment
Dinaciclib 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.
Drug: Dinaciclib

Given IV.

Dose Level = DL

DL1-12 mg/m2

DL2-18 mg/m2

DL3-25 mg/m2

DL4-33 mg/m2

DL5-50 mg/m2

Drug: Pembrolizumab
Given 200mg IV.

Primary Outcome Measures :
  1. 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). ]
    The MTD is measured (safety/tolerability) by clinical review of relevant AE parameters (i.e. laboratory tests, physical exams)

  2. Define dose-limiting toxicities (DLTs) [ Time Frame: Measured during each Cycle (21 Days), with number of cycles dependent on number of adverse events (AE) ]
    Toxicities will be graded in severity per CTCAE version 4.0, based on events occurring during the first Cycle for each cohort

Secondary Outcome Measures :
  1. 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) ]
    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)

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Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No


  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 values:


    • 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 device.
  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 including:

    • 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 prophylaxis
  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 CYP3A4).
  20. Patients requiring warfarin therapy are excluded, low molecular weight heparin is permitted.
  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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01676753

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United States, California
University of California, San Francisc
San Francisco, California, United States, 94143
Sponsors and Collaborators
Jo Chien
Merck Sharp & Dohme Corp.
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Principal Investigator: A Jo Chien, MD University of California, San Francisco
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Responsible Party: Jo Chien, UCSF Assistant Clinical Professor, University of California, San Francisco Identifier: NCT01676753    
Other Study ID Numbers: 16758
NCI-2018-01053 ( Registry Identifier: NCI Clinical Trials Reporting Program (CTRP) )
First Posted: August 31, 2012    Key Record Dates
Last Update Posted: July 15, 2020
Last Verified: July 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Breast Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Antineoplastic Agents, Immunological
Antineoplastic Agents