Metastatic Breast Cancer
Conditions
Keywords
Metastatic Breast Cancer, Amrubicin
Brief summary
Doxorubicin has been an integral part of the treatment of women with breast cancer for many years. Since amrubicin may have more activity than doxorubicin, as well as less cardiotoxicity, evaluation of amrubicin in the treatment of advanced breast cancer should be a priority. In this Phase II study, the investigators propose an evaluation of single-agent amrubicin as second- or third-line treatment for women with metastatic breast cancer.
Detailed description
This will be a phase I/II study where phase I will evaluate the maximum tolerated dose of amrubicin, and phase II will assess the progression free survival of patients with HER2-negative metastatic breast cancer using the dose established in the phase I portion.
Interventions
DRUGAmrubicin
Phase I: dose-escalating portion with the starting dose of amrubicin at 90mg/m\^2 IV q21 days. Dose escalations are as follows: DL2 - 100mg/m\^2; DL3 - 110mg/m\^2; and DL4 - 120mg/m\^2. All cycles are q21 days Phase II: Amrubicin will be administered at the maximum tolerated dose established in Phase I by IV every 21 days
Sponsors
Celgene
SCRI Development Innovations, LLC
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Females \>=18 years of age. 2. Histologic diagnosis of HER2-negative breast cancer. HER-2 negativity must be confirmed by one of the following: * FISH-negative (FISH ratio \<2.2), or * IHC 0-1+, or * IHC 2-3+ AND FISH-negative (FISH ratio \<2.2) 3. Evidence of metastatic or locally advanced, inoperable breast cancer. 4. Minimum of 1 and maximum of 2 prior metastatic breast cancer chemotherapy regimens. 5. Patients with prior anthracycline therapy are eligible, provided their previous anthracycline was ≥6 months prior to study entry. 6. Measurable disease per RECIST criteria version 1.1 7. Left ventricular ejection fraction (LVEF) ³50% by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA). 8. Patients must have QTc interval of \<=450 msec. 9. No intercurrent significant medical conditions or cardiac illness. 10. Patients must be \>=3 weeks since last chemotherapy, and recovered from all acute toxicities, with the exception of alopecia. 11. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-2. 12. Adequate organ function including the following: * ANC \>=1500 cells/mL * Platelet count \>=100,000 cells/mL * Hemoglobin \>=9 g/dL * Total bilirubin \<=1.5 x ULN; AST/ALT \<=2.5 x ULN, (except if due to hepatic metastases, then \<=5 x ULN) * Serum creatinine \<1.5 x ULN 13. Women of childbearing potential must have a negative serum or urine pregnancy test performed \<=7 days prior to start of treatment. If a woman becomes pregnant or suspects she is pregnant while participating in this study, she must agree to inform her treating physician immediately. 14. Patients must be accessible for treatment and follow-up. 15. Patients must be able to understand the investigational nature of this study and give written informed consent prior to study entry. 16. Patients who are on anticoagulation are acceptable if the therapeutic anticoagulation is stable. Additionally, the patient's INR must be adequate if the patient is receiving treatment with coumadin. 17. Prior hormonal therapy for metastatic breast cancer is permitted; however, the therapy must be discontinued prior to the patient's enrollment in this study.
Exclusion criteria
1. Any concurrent therapy with other investigational, chemotherapeutic, or hormonal therapy. 2. Prior treatment with \>=3 regimens of cytotoxic therapy in the advanced disease setting. (Any number of previous hormonal therapies are acceptable, as long as the therapy is discontinued prior to the patient's enrollment into this study). 3. Major surgery or systemic therapy \<=3 weeks of study treatment. 4. Prior high-dose chemotherapy requiring hematopoietic stem cell support. 5. Prior radiation therapy to \>25% of the bone marrow. 6. Uncontrolled brain metastases. Patients with treated brain metastases (resection or radiotherapy) are eligible if brain metastases have responded to treatment as documented by CT or MRI scan obtained at \>=2 weeks after completion of radiation therapy, neurologic symptoms are absent, and steroids have been discontinued. 7. Suspected, diffuse idiopathic interstitial lung disease or pulmonary fibrosis. 8. Diagnosis of second malignancy within the last 3 years (with the exception of carcinoma in situ of the cervix, squamous or basal cell skin cancer, thyroid cancer, ductal carcinoma in situ \[DCIS\], or lobular carcinoma in situ \[LCIS\]). 9. Any of the following \<=12 months prior to starting study treatment: * myocardial infarction; * severe unstable angina; * congestive heart failure; * ongoing cardiac dysrhythmia. 10. Family history of idiopathic cardiomyopathy or uncontrolled heart arrhythmia. 11. Patients with previous allergy or hypersensitivity to anthracyclines. 12. Patients who have had a ≥10% drop in LVEF on previous anthracycline therapy. 13. Palliative radiotherapy to areas of metastatic breast cancer must have been completed \>7 days prior to the first dose of study treatment. The exception is radiotherapy for brain metastases, which must be completed \>=21 days prior to study treatment. (Note: Any measurable lesion that has been previously irradiated will not be considered as a target lesion). 14. Concurrent severe, intercurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness/social situations that would limit compliance with study requirements. 15. History of seropositive HIV, or patients who are receiving immunosuppressive medications that increase the risk of neutropenic complications. 16. Mental condition that would prevent patient comprehension of the nature of, and risk associated with, the study. 17. Use of any non-approved or investigational agent \<=30 days of administration of the first dose of study drug. Patients may not receive any other investigational or anti-cancer treatments while participating in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-Free Survival (PFS) of MTD/Phase II Patients | every 6 weeks until progressive disease | Progression-free survival is measured from Day 1 of study drug administration to disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death on the study. Progression is defined in RECIST v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions. This outcome measure is reported for all patients treated at the same dose level and is not separated into Phase I and Phase II. The phase I and phase II results are not separated as the timing of enrollment (early in phase 1 or later phase II) is not relevant to the outcome measure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Patients With Adverse Events as a Measure of Safety and Tolerability | every 6 weeks until treatment discontinuation, up to 43 months | Assessments will be made through analysis of the reported incidence of treatment-emergent Serious Adverse Events (SAEs) and non-serious adverse events (AEs). |
| Overall Survival (OS) of MTD/Phase II Patients | every 6 weeks until treatment discontinuation, up to 43 months | Measured from Day 1 of study drug administration to date of death due to any cause. This outcome measure is reported for all patients treated at the same dose level and is not separated into Phase I and Phase II. The phase I and phase II results are not separated as the timing of enrollment (early in phase 1 or later phase II) is not relevant to this outcome measure. |
| Overall Response Rate (ORR) | every 6 weeks until treatment discontinuation, up to 43 months | The number of patients with observed complete response \[CR\] or partial response \[PR\]. 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; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. This outcome measure is reported for all patients treated at the same dose level and is not separated into Phase I and Phase II. The phase I and phase II results are not separated as the timing of enrollment (early in phase 1 or later phase II) is not relevant to the outcome measure. |
Countries
United States
Participant flow
Recruitment details
Patients were recruited at multiple dose levels into the Dose Escalation (Phase I) portion of this study to determine the safest dose of this regime (MTD - Maximum Tolerated Dose). Upon determination of this dose, patients being treated at the MTD proceeded to the Dose Expansion (Phase II) portion of the study and additional patients were recruited
Participants by arm
| Arm | Count |
|---|---|
| Phase I - Dose Level 1 Amrubicin -90 mg/m\^2 by intravenous(IV) every 21days | 3 |
| Phase I - Dose Level 2 Amrubicin -100 mg/m\^2 IV every 21days | 3 |
| Phase I - Dose Level 3 Amrubicin -110 mg/m\^2 IV every 21days | 3 |
| Phase I - Dose Level 4 Amrubicin -120 mg/m\^2 every 21 days | 6 |
| Phase II - Dose Level 3 Amrubicin -110 mg/m\^2 IV every 21days | 63 |
| Total | 78 |
Baseline characteristics
| Characteristic | Phase I - Dose Level 1 | Phase I - Dose Level 2 | Phase I - Dose Level 3 | Phase I - Dose Level 4 | Phase II - Dose Level 3 | Total |
|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 19 Participants | 20 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 3 Participants | 6 Participants | 44 Participants | 58 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 1 Participants | 1 Participants | 3 Participants | 5 Participants | 53 Participants | 63 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 7 Participants | 11 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 8 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 3 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 3 Participants | 6 Participants | 53 Participants | 67 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 3 Participants | 6 Participants | 63 Participants | 78 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 65 / 66 | 6 / 6 |
| serious Total, serious adverse events | 1 / 3 | 0 / 3 | 5 / 66 | 1 / 6 |
Outcome results
Primary
Progression-Free Survival (PFS) of MTD/Phase II Patients
Progression-free survival is measured from Day 1 of study drug administration to disease progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, or death on the study. Progression is defined in RECIST v1.1 as a 20% increase in the sum of the longest diameter of target lesions, a measurable increase in a non-target lesion, or the appearance of new lesions. This outcome measure is reported for all patients treated at the same dose level and is not separated into Phase I and Phase II. The phase I and phase II results are not separated as the timing of enrollment (early in phase 1 or later phase II) is not relevant to the outcome measure.
Time frame: every 6 weeks until progressive disease
Population: Patients who received the dose level 3 MTD dose/Phase II dose (Amrubicin -110 mg/m\^2) are included in the analysis. The 3, dose level 3 phase I pts and 63 phase II pts treated at this dose level are all combined to evaluate the efficacy of the MTD/phase II dose. The phase I and phase II results are not separated out as the timing of their enrollment (early in phase 1 or later phase II) is not relevant to the outcome measure. The other 12 phase I pts who were not treated at the MTD are excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amrubicin | Progression-Free Survival (PFS) of MTD/Phase II Patients | 4.0 months |
Secondary
Number of Patients With Adverse Events as a Measure of Safety and Tolerability
Assessments will be made through analysis of the reported incidence of treatment-emergent Serious Adverse Events (SAEs) and non-serious adverse events (AEs).
Time frame: every 6 weeks until treatment discontinuation, up to 43 months
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Amrubicin | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 3 Participants |
| Dose Level 2 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 3 Participants |
| Dose Level 3 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 65 Participants |
| Dose Level 4 | Number of Patients With Adverse Events as a Measure of Safety and Tolerability | 6 Participants |
Secondary
Overall Response Rate (ORR)
The number of patients with observed complete response \[CR\] or partial response \[PR\]. 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; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. This outcome measure is reported for all patients treated at the same dose level and is not separated into Phase I and Phase II. The phase I and phase II results are not separated as the timing of enrollment (early in phase 1 or later phase II) is not relevant to the outcome measure.
Time frame: every 6 weeks until treatment discontinuation, up to 43 months
Population: Patients who received the dose level 3 MTD dose/Phase II dose (Amrubicin -110 mg/m\^2) are included in the analysis. The 3, dose level 3 phase I pts and 63 phase II pts treated at this dose level are all combined to evaluate the efficacy of the MTD/phase II dose. The phase I and phase II results are not separated out as the timing of their enrollment (early in phase 1 or later phase II) is not relevant to the outcome measure. The other 12 phase I pts who were not treated at the MTD are excluded.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Amrubicin | Overall Response Rate (ORR) | 12 participants |
Secondary
Overall Survival (OS) of MTD/Phase II Patients
Measured from Day 1 of study drug administration to date of death due to any cause. This outcome measure is reported for all patients treated at the same dose level and is not separated into Phase I and Phase II. The phase I and phase II results are not separated as the timing of enrollment (early in phase 1 or later phase II) is not relevant to this outcome measure.
Time frame: every 6 weeks until treatment discontinuation, up to 43 months
Population: Patients who received the dose level 3 MTD dose/Phase II dose (Amrubicin -110 mg/m\^2) are included in the analysis. The 3, dose level 3 phase I pts and 63 phase II pts treated at this dose level are all combined to evaluate the efficacy of the MTD/phase II dose. The phase I and phase II results are not separated out as the timing of their enrollment (early in phase 1 or later phase II) is not relevant to the outcome measure. The other 12 phase I pts who were not treated at the MTD are excluded.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Amrubicin | Overall Survival (OS) of MTD/Phase II Patients | 14.4 months |