Brostallicin and Cisplatin in Treating Patients With Metastatic Breast Cancer

Study Overview
=================
Brief Summary
-----------------
This phase II trial studies how well brostallicin and cisplatin work in treating patients with breast cancer that has spread to other parts of the body (metastatic) and does not have estrogen receptors, progesterone receptors, or large amounts of human epidermal growth factor receptor 2 (HER2) on its cells (triple-negative). Drugs used in chemotherapy, such as brostallicin and cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from spreading.

Detailed Description
-----------------
PRIMARY OBJECTIVES: I. To identify any clinical efficacy of brostallicin and cisplatin in the treatment of breast cancer patients having a triple negative (estrogen receptor [ER]/progesterone receptor [PR]/HER2 negative) phenotype, as measured by progression-free survival (PFS) at 3 months. SECONDARY OBJECTIVES: I. To describe the confirmed tumor response rate of patients with measurable disease receiving brostallicin and cisplatin. II. To describe the duration of response in patients with measurable disease receiving brostallicin and cisplatin. III. To describe the 6-month progression-free survival of patients receiving brostallicin and cisplatin. IV. To describe the overall survival (OS) of patients receiving brostallicin and cisplatin. V. To evaluate the adverse event profile of the study regimen (adverse events graded using the Cancer Therapy Evaluation Program [CTEP] Active Version of the Common Terminology Criteria for Adverse Events [CTCAE]). OUTLINE: Patients receive cisplatin intravenously (IV) over 2 hours on day 1 and brostallicin IV over 10 minutes on day 2. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months until disease progression and then every 6 months for up to 5 years.

Official Title
-----------------
Phase II Trial of Brostallicin and Cisplatin in Patients With Metastatic Triple Negative Breast Cancer

Conditions
-----------------
Triple-negative Breast Cancer

Intervention / Treatment
-----------------
* Drug: brostallicin
* Drug: cisplatin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria Histologically or cytologically confirmed adenocarcinoma of the breast with clinical evidence of metastatic disease Triple negative breast cancer defined as HER2-(according to current American Society of Clinical Oncology [ASCO] College of American Pathologists [CAP] guidelines), ER- (defined as =< 1% by IHC) and PgR- (defined as =< 1% by IHC) 0 to 4 prior chemotherapy regimens in the metastatic setting Measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria Negative pregnancy test done =< 7 days prior to registration, for women of childbearing potential only Hemoglobin >= 10.0 g/dL Absolute neutrophil count (ANC) >= 1500/mm^3 Platelet count >= 100,000/mL Total bilirubin =< 1.5 x upper limit of normal (ULN) Serum creatinine =< 1.5 mg/dL Serum glutamic oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN or SGOT (AST) and SGPT (ALT) =< 5 x ULN if elevations are due to liver metastases Alkaline phosphatase =< 2.5 x ULN or alkaline phosphatase =< 5 x ULN if elevations are due to liver metastases Electrocardiogram (EKG) completed =< 15 days prior to registration Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2 Life expectancy > 3 months Has written informed consent Willingness to return to NCCTG enrolling institution for treatment and follow-up Patient willing to provide blood samples for research purposes Exclusion Criteria HER2 positive (3+ by IHC or fluorescence in situ hybridization [FISH] amplified) breast cancer by ASCO/CAP guidelines Estrogen receptor (ER) and/or progesterone receptor (PR/PgR) positive breast cancer (defined as > 1% of either receptor by IHC) Any of the following Pregnant women Nursing women Men or women of childbearing potential who are unwilling to employ adequate contraception (as determined by the treating physician) while on this study and for 30 days after end of treatment with the study drugs Stage III or IV invasive non-breast malignancy in =< 5 years prior to registration Pre-existing peripheral neuropathy of grade >= 2 (using the CTEP active version of the CTCAE) Major surgery =< 4 weeks prior to registration Chemotherapy or immunologic therapy =< 3 weeks prior to registration Radiotherapy =< 2 weeks prior to registration, except if to a non-target lesion only * NOTES: Prior radiation to a target lesion is permitted only if there has been clear progression of the lesion since radiation was completed If patient receives single dose radiation for palliation or radiation to non-target lesion, they may immediately proceed to registration without waiting 2 weeks Acute adverse events from radiation must have resolved to =< grade 1 (according to the CTEP active version of the CTCAE) Evidence of active brain metastasis including leptomeningeal involvement * NOTE: Central nervous system (CNS) metastasis controlled by prior surgery and/or radiotherapy is allowed; to be considered controlled, there must be at least 2 months of no symptoms or evidence of progression prior to study entry and corticosteroid therapy given to control brain edema must have been discontinued History of allergy or hypersensitivity to the drugs used in this study (or their excipients) including platinum compounds (cisplatin, carboplatin) Active, unresolved infection Uncontrolled intercurrent illness including, but not limited to psychiatric illness/social situations or co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or would interfere significantly with the proper assessment of safety of the prescribed regimens or would limit compliance with study requirements or would make it undesirable for patient to participate in the trial Clinically significant cardiovascular or cerebrovascular disease, including any history of the following =< 6 months prior to registration: Myocardial infarction Unstable angina New York Heart Association (NYHA) class II or greater congestive heart failure Uncontrolled or clinically significant cardiac arrhythmia (patients with controlled atrial fibrillation are eligible) Currently receiving treatment in a different clinical study in which investigational procedures are performed or investigational therapies are administered * NOTE: Patient may not enroll in such clinical trials while participating in this study; exception may be granted for trials related to symptom management (cancer control) which do not employ hormonal treatments or treatments that may block the path of the targeted agents used in this trial Immunocompromised patients (other than that related to the use of corticosteroids) including patients known to be human immunodeficiency virus (HIV) positive with an acquired immune deficiency syndrome (AIDS)-defining illness; HIV positive patients with cluster of differentiation (CD)4 count within institutional normal range and no history of an AIDS-defining illness are eligible

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (cisplatin and brostallicin)<br>Patients receive cisplatin IV over 2 hours on day 1 and brostallicin IV over 10 minutes on day 2. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Drug: brostallicin<br>* Given IV<br>Drug: cisplatin<br>* Given IV<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 3-month Progression-free Survival (3-mo PFS) Rate | A patient is considered to be a 3-month progression-free survivor if the patient is on study treatment 3 months from registration without a documentation of disease progression. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients and 95% confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner. If some patients are lost to follow-up not having been observed for at least 3 months, an estimate and confidence interval for the 3-month PFS rate incorporating censoring will be computed using the method of Kaplan-Meier. Progression is defined using the revised RECIST guideline (v1.1) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Confirmed Response Rate | A confirmed response is defined to be either a CR or PR noted as the objective status on 2 consecutive evaluations at least 6 weeks apart. All patients meeting the eligibility criteria who have signed a consent form and have begun treatment will be evaluable for response. The confirmed response rate will be estimated by the number of confirmed responses in evaluable patients with measurable disease divided by the total number of evaluable patients with measurable disease. The appropriate confidence interval will be calculated. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <1 cm.; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 5 years | 
| Duration of Response | Duration of response is defined for all evaluable patients with measurable disease who have achieved a confirmed response as the date at which the patient's earliest best objective status is first noted to be either a CR or PR to the earliest date progression is documented. If a patient dies subsequent to the confirmed response without a documentation of disease progression, the patient will be considered to have had disease progression at the time of their death. The distribution of duration of response will be estimated using the method of Kaplan-Meier. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <1 cm.; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | Up to 5 years | 
| 6-month Progression-free Survival (6-mo PFS) Rate | 6-month progression-free survival. A patient is considered to be a 6-month progression-free survivor if the patient is on study treatment 6 months from registration without a documentation of disease progression. The 6-month progression-free survival rate incorporating censoring will be computed using the method of Kaplan-Meier. Progression is defined using the revised RECIST guideline (v1.1) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | At 6 months | 
| Time to Disease Progression | Time to disease progression is defined as the time from registration to the earliest date of documentation of disease progression. If a patient dies without a documentation of disease progression the patient will be considered to have had disease progression at the time of their death. If the patient is declared to be a major treatment violation, the patient will be censored on the date the treatment violation was declared to have occurred. The distribution of time to progression will be estimated using the method of Kaplan-Meier. Progression is defined using the revised RECIST guideline (v1.1) as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. | up to 5 years | 
| Survival Time | Survival time is defined as the time from registration to death due to any cause. The distribution of survival time will be estimated using the method of Kaplan-Meier. | Up to 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
stage IV breast cancer, triple-negative breast cancer, male breast cancer