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A Phase 1 Study With Dose Expansion of Dinaciclib (SCH 727965) in Combination With Epirubicin in Patients With Metastatic Triple Negative Breast Cancer

Phase 1
18 Years
Open (Enrolling)
Estrogen Receptor-negative Breast Cancer, HER2-negative Breast Cancer, Male Breast Cancer, Progesterone Receptor-negative Breast Cancer, Recurrent Breast Cancer, Stage IV Breast Cancer, Triple-negative Breast Cancer

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Trial Information

A Phase 1 Study With Dose Expansion of Dinaciclib (SCH 727965) in Combination With Epirubicin in Patients With Metastatic Triple Negative Breast Cancer


I. To determine the maximum tolerated dose (MTD) of dinaciclib given in combination with
epirubicin in patients with metastatic triple negative breast cancer.


I. To determine the predictive value of myeloid cell leukemia sequence 1 protein (MCL-1),
low molecular weight cyclin E (LMW-E), and tumor grade as predictors of biologic response
(i.e. induction of apoptosis) in tumors treated with therapy.

II. To evaluate the efficacy of combination therapy. III. To determine the effects of
therapy on proliferation as measured by proliferation-related Ki-67 antigen (Ki67) and
apoptosis as measured by TdT-mediated dUTP nick end labeling assay (TUNEL).

OUTLINE: This is a dose-escalation study of dinaciclib.

Patients receive dinaciclib intravenously (IV) over 2 hours on day 1 and epirubicin
hydrochloride IV over 30 minutes on day 2. Treatment repeats every 21 days for up to 12
courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for 30 days.

Inclusion Criteria:

- Patients must have histologically confirmed estrogen receptor (ER)/progesterone
receptor (PR)/human epidermal growth factor receptor 2 (HER2) negative carcinoma of
the breast that is metastatic or unresectable and for which standard curative or
palliative measures do not exist or are no longer effective; for purposes of this
study, triple negative disease will be tumors that have ER/PR < 10% and HER2 =< 1+ by
immunohistochemistry (IHC) or HER2 fluorescent in situ hybridization (FISH)
non-amplified (ratio < 2)

- Patients must have an Eastern Cooperative Oncology Group (ECOG) performance status of
0, 1 or 2

- Patients must have no more than two prior chemotherapy regimens for metastatic breast
cancer; in patients who develop disease recurrence within 6 months of adjuvant or
neoadjuvant chemotherapy, the adjuvant or neoadjuvant therapy will be considered one
prior regimen for metastatic disease

- ECOG performance status =< 2 (Karnofsky >= 60%)

- Life expectancy of greater than 3 months

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 100,000/mcL

- Total bilirubin within normal limits unless clinical diagnosis of Gilbert's syndrome

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT])
=< 2.5 X institutional upper limit of normal

- Creatinine within normal institutional limits OR creatinine clearance >= 60
mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- Patients must be disease free of prior malignancy for >= 5 years with the exception
of curatively treated squamous cell carcinomas of the skin or carcinoma in situ of
the cervix or breast

- Must have at least one site of objective measurable or evaluable disease; baseline
measurements and evaluations must be obtained within 4 weeks of start of therapy

- Patients must have no history of prior therapy with dinaciclib

- Concurrent use of hormonal therapy is not permitted; concurrent radiation therapy is
not permitted; bisphosphonates are allowed, provided that they were started no less
than two weeks prior to initiating protocol therapy

- Patients must have completed and recovered from the effects of prior chemotherapy (=<
grade 2 toxicity) excluding alopecia

- Women of child-bearing potential and men must agree to use adequate contraception
(barrier method of birth control; abstinence) prior to study entry and for the
duration of study participation; should a woman become pregnant or suspect she is
pregnant while she or her partner is participating in this study, she should inform
her treating physician immediately; men treated or enrolled on this protocol must
also agree to use adequate contraception prior to the study, for the duration of
study participation, and 4 months after completion of dinaciclib administration

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events

- Patients who are receiving any other investigational agents

- Patients with untreated brain metastases should be excluded from this clinical trial
because they may develop progressive neurologic dysfunction that would confound the
evaluation of neurologic and other adverse events

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition as epirubicin or dinaciclib

- Patients receiving any medications or substances that are inhibitors or inducers of
cytochrome P450 3A4/5 (CYP3A4/5) are ineligible

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements

- Pregnant women are excluded from this study; breastfeeding should be discontinued if
the mother is treated with dinaciclib

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible

- Patients who have had prior organ allograft or require immunosuppressive therapy

- Patients who have received a cumulative dose of doxorubicin of greater than 360
mg/m^2 or epirubicin of greater than 600 mg/m^2; patients who have received > 240
mg/m^2 of doxorubicin or > 400 mg/m^2 of epirubicin should be advised to undergo
evaluation of left ventricular ejection fraction (LVEF) with echocardiogram or multi
gated acquisition scan (MUGA) prior to initiating therapy

- Patients with a history of New York Heart Association class 3 or 4 heart failure, or
history of myocardial infarction, unstable angina or cerebral vascular accident (CVA)
within 6 months of protocol registration

- LVEF < 50% by MUGA or echocardiogram (ECHO)

- Patients who have history of PR prolongation or atrioventricular (AV) block

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

MTD of dinaciclib given in combination with epirubicin hydrochloride, determined according to incidence of dose-limiting toxicity (DLT) graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4

Outcome Description:

We will tabulate the number (%) of DLTs by dose level of dinaciclib.

Outcome Time Frame:

21 days

Safety Issue:


Principal Investigator

Stacy Moulder

Investigator Role:

Principal Investigator

Investigator Affiliation:

M.D. Anderson Cancer Center


United States: Food and Drug Administration

Study ID:




Start Date:

August 2012

Completion Date:

Related Keywords:

  • Estrogen Receptor-negative Breast Cancer
  • HER2-negative Breast Cancer
  • Male Breast Cancer
  • Progesterone Receptor-negative Breast Cancer
  • Recurrent Breast Cancer
  • Stage IV Breast Cancer
  • Triple-negative Breast Cancer
  • Breast Neoplasms
  • Breast Neoplasms, Male



M D Anderson Cancer CenterHouston, Texas  77030