Dinaciclib and Epirubicin Hydrochloride in Treating Patients With Metastatic Triple-Negative Breast Cancer

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

This phase I clinical trial studies the side effects and the best dose of dinaciclib when given together with epirubicin hydrochloride (epirubicin) in patients with metastatic (cancer that has spread to other parts of the body) triple-negative breast cancer. Dinaciclib is designed to stop cancer cells from dividing into new cancer cells. Epirubicin is designed to block the way cancer cells grow and divide and may slow or stop cancer cells from spreading throughout the body. Researchers want to find out what is the highest tolerable dose of the experimental drug dinaciclib that can be given in combination with epirubicin in patients with metastatic triple negative breast cancer.

Study Overview

• Status: Completed
• Conditions: Recurrent Breast Carcinoma; Estrogen Receptor Negative; HER2/Neu Negative; Progesterone Receptor Negative; Triple-Negative Breast Carcinoma; Male Breast Carcinoma; Stage IV Breast Cancer AJCC v6 and v7
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Dinaciclib; Drug: Epirubicin Hydrochloride

Detailed Description

PRIMARY OBJECTIVES:

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

SECONDARY OBJECTIVES:

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 terminal deoxynucleotidyl transferase (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.

• Study Type: Interventional
• Enrollment (Actual): 40
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
• 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
• 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 glutamate 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
• 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 family 3, subfamily A, polypeptide 4/5 (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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Treatment (dinaciclib and epirubicin hydrochloride); Patients receive dinaciclib 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.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Dinaciclib; Given IV; Other Names: SCH 727965; MK-7965; CDK Inhibitor SCH 727965; Drug: Epirubicin Hydrochloride; Given IV; Other Names: Ellence; IMI-28; Pharmorubicin PFS

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	The number (%) of DLTs will tabulate by dose level of dinaciclib.	21 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Predictive value of MCL-1, LMW-E, and tumor grade as predictors of biologic response (i.e. induction of apoptosis) in tumors treated with therapy	A logistic regression model will be used to assess whether the expression level of LMW-E can predict clinical benefit, adjusted for dose level and other potential prognostic factors: visceral organ involvement (present vs. absent), number of prior therapies for metastatic breast cancer (0-2 or > 2), age (< 60 vs. > 60) and ECOG performance status (0-1 vs. 2).	Up to 30 days after completion of study treatment
Clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD]), assessed using Response Evaluation Criteria in Solid Tumors (RECIST)	The overall clinical benefit rate for patients treated at the MTD will be estimated with a 90% credible interval.	At 6 months
Changes in proliferation as measured by Ki67 and apoptosis as measured by TUNEL	For the patients with pre- and post- treatment biopsies, summary statistics used to describe change in apoptotic index pre- to post-treatment, and boxplots to illustrate distribution pre- and post-treatment, as well as distribution of change. Mean change estimated with 95% confidence interval. MCL-1, LMW-E, and Ki67 similarly analyzed. Analyses also performed stratified by tumor grade. Correlation between changes in MCL-1 and LMW-E pre- to post-treatment estimated with 95% confidence interval. Number of tumors in 4 categories (negative, low, medium, high) tabulated by % of TUNEL+ tumor cells.	From baseline to 2 weeks

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Stacy Moulder, M.D. Anderson Cancer Center

Publications and helpful links

General Publications

• Mitri Z, Karakas C, Wei C, Briones B, Simmons H, Ibrahim N, Alvarez R, Murray JL, Keyomarsi K, Moulder S. A phase 1 study with dose expansion of the CDK inhibitor dinaciclib (SCH 727965) in combination with epirubicin in patients with metastatic triple negative breast cancer. Invest New Drugs. 2015 Aug;33(4):890-4. doi: 10.1007/s10637-015-0244-4. Epub 2015 May 7.

Study record dates

Study Major Dates

• Study Start (Actual): August 21, 2012
• Primary Completion (Actual): September 10, 2013
• Study Completion (Actual): September 10, 2013

Study Registration Dates

• First Submitted: June 18, 2012
• First Submitted That Met QC Criteria: June 19, 2012
• First Posted (Estimate): June 20, 2012

Study Record Updates

• Last Update Posted (Actual): March 30, 2018
• Last Update Submitted That Met QC Criteria: March 29, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Breast Diseases; Breast Neoplasms; Carcinoma; Triple Negative Breast Neoplasms; Breast Neoplasms, Male; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Epirubicin
• Other Study ID Numbers: NCI-2012-00950 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA016672 (U.S. NIH Grant/Contract); U01CA062461 (U.S. NIH Grant/Contract); 2012-0229 (M D Anderson Cancer Center); 9138 (Other Identifier: CTEP); R01CA152228 (U.S. NIH Grant/Contract)