Triple Negative Breast Cancer
Conditions
Keywords
Pembrolizumab, cyclophosphamide
Brief summary
The purpose of this study is to evaluate pembrolizumab therapy in patients with triple-negative breast cancer (TNBC) who have received at least one prior line of therapy.
Detailed description
This phase II, single-arm, multicenter study will evaluate efficacy and toxicity of administration of pembrolizumab following cyclophosphamide therapy, in advanced stage triple-negative breast cancer. Duration of Therapy Treatment may continue until one of the following occurs: * Disease progression * Inter-current illness that prevents further administration of treatment * Unacceptable adverse event(s) * Pregnancy * Patient decides to withdraw from study treatment, * General or specific changes in the patient's condition render the patient unacceptable for further treatment in the judgment of the investigator * Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study medication, whichever is later Duration of Follow Up * Subjects will be followed for up to 3 years after removal from study treatment or until death, whichever occurs first. * Patients removed from study for unacceptable adverse events (AEs) will be followed until resolution or stabilization of the event(s).
Interventions
DRUGPembrolizumab
Subjects will be treated every 3 weeks with 200 mg of pembrolizumab via a 30 minute infusion.
DRUGCyclophosphamide
A single 300 mg/m2 dose of cyclophosphamide IV over 30-60 minutes will be administered on Day 1 of this study.
Sponsors
Merck Sharp & Dohme LLC
UNC Lineberger Comprehensive Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Written informed consent and HIPAA authorization for release of personal health information. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. 2. Age ≥ 18 years at the time of consent. 3. Have measurable disease based on RECIST 1.1 (see section 6.7 for details). 4. ECOG Performance Status ≤ 1 as defined in the protocol ECOG Performance Status. 5. Subject must have histologically confirmed stage IV TNBC (ER-, PR-, HER2-negative) and have received at least 1 prior line of systemic therapy. * ER- and PR-negative: defined as \< 1% staining by immunohistochemistry (IHC) * HER2-negative disease, defined as IHC 0-1+ or fluorescence in situ hybridization (FISH) ratio \< 2.0 6. Patients with stable brain metastases will be allowed provided the following criteria are met: * Brain radiation was already provided at least 4 weeks prior to initiating study treatment * The subject has no new or progressive neurologic symptoms AND neurological symptom stability for the last 4 weeks prior to the study * The subject has been off of corticosteroids for at least 7 days prior to trial treatment * The subject does not have carcinomatous meningitis 7. Demonstrate adequate organ function as defined in the table below; all screening labs to be obtained within 72 h of initiating study treatment. 8. Females of childbearing potential must have a negative serum pregnancy test within 72 hrs prior to treatment. NOTE: Females are considered of child bearing potential unless they are surgically sterile, have a congenital acquired condition that prevents childbearing (have undergone a hysterectomy, bilateral tubal ligation/occlusion, bilateral salpingectomy or bilateral oophorectomy at least 6 weeks prior to screening) or they are naturally postmenopausal for at least 12 consecutive months without an alternative medical cause. In women \< 45 years of age a high follicle stimulating hormone level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. In the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. 9. Female patients of childbearing potential should be willing to use appropriate birth control as outlined in Section 5.2.8, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication. 10. Male subjects of childbearing potential must agree to use an adequate method of contraception as outlined in Section 5.2.8, starting with the first dose of study therapy through 120 days after the last dose of study therapy. 11. Consent for the use of any residual material from biopsy (archival tissue) and serial blood draws will be required for enrollment; fresh biopsy (pre and post dose) of tumor tissue will be optional. NOTE: Patients without adequate tissue for bio correlates will not be excluded or required to have a repeat biopsy. 12. As determined by the enrolling physician or protocol designee, the subject should be able to understand and comply with study procedures for the entire length of the study. 13. Has a LVEF within the normal institutional range (or ≥ 50%) based on ECHO or MUGA.
Exclusion criteria
1. Active infection requiring systemic therapy 2. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the mother is being treated on study). 3. Has a known history of active Bacillus Tuberculosis (TB) 4. Hypersensitivity to pembrolizumab or any of its excipients. 5. Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years. 6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to receipt of study medication or who has not recovered (i.e., ≤ Grade 1 or at baseline; excludes alopecia and Grade 2 neuropathy) from adverse events due to a previously administered agent. • If subject had major surgery, they must have recovered adequately from the toxicity and complications from the intervention prior to starting therapy 7. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. 8. Has had monoclonal antibody therapy within 4 weeks prior to study Day 1 or who has not recovered (ie, ≤ Grade 1 at baseline; excludes alopecia and Grade 2 neuropathy) from adverse events due to agent(s) administered more than 4 weeks earlier. 9. Treatment with any investigational drug within 4 weeks or 5 half-lives, whichever is shorter, prior to the first dose of study medication. 10. Used an investigational device within 4 weeks of the first dose of treatment. 11. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 12. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. 13. Has known history of, or any evidence of active, non-infectious pneumonitis requiring treatment with steroids; has history of, or any evidence of, active interstitial lung disease. 14. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 15. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment. 16. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator. 17. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 19. Has participated in a previous trial and received pembrolizumab therapy 20. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA \[qualitative\] is detected). 21. Has received a live vaccine within 30 days prior to the first dose of trial treatment. • 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 22. Cyclophosphamide is a substrate for cytochromes 2B6, 2C9, 3A4 and 2C19. Patients must not have received any drug that is a moderate or strong inhibitor of 2B6, 2C9, 3A4, and 2C19 within 1 week prior to receiving cyclophosphamide dosing through 72 hours after cyclophosphamide dosing. Patients must not have received any drug that is a moderate or strong inducer of 3A4 within 2 weeks prior to cyclophosphamide dosing.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Progression Free Survival (PFS) | Up to 5 years | PFS is defined as the time from day1 of the study treatment until disease progression or death. Disease progression is defined as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST)1.1 based on computerized tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) images or assessment of the physician. RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), 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. |
| Quantification of the Change in Regulatory T Cells (Tregs) During the Study Treatment. | Up to 2 years | Regulatory T cells (Tregs) are counted before the treatment start and during the treatment. Methods: Blood Sample collection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) | Up to 2 years | DCR is defined as the percentage of participants, who achieve \[compete response (CR) + partial response (PR) and stable disease (SD) per RECIST1.1. If best response is SD, then it must last more than 6 months to be included in calculation of DCR, to be considered to have received clinical benefit from the treatment regimen. RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), 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. |
| Overall Response Rate (ORR) | Up to 2 years | ORR is defined as the percentage of patients with \[compete response (CR) + partial response (PR)\] per RECIST1.1 based on computerized tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) images. RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; |
| Treatment Associated Toxicity | Up to 3 years | Treatment Associated Toxicity is defined as the number of participants with Grade 3-4 adverse events associated with study treatment. Adverse Events were classified and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4 based on changes in laboratory parameters, vital signs, and other safety assessments per standard of care. |
| Overall Survival (OS) | Up to 3 years | OS is defined as the time from D1 of study treatment to death from any cause. |
| Duration of Response (DOR) | Up to 3 years | DOR is defined as the time from documentation of tumor response by RECIST1.1 \[(CR) + (PR)\] to disease progression by RECIST 1.1. It will be measured from when the time measurement criteria are first met for complete response or partial response (whichever status is recorded first) until the first date of progressive disease or death. Patients who neither progress nor die will be censored on the date of their last tumor assessment. |
Countries
United States
Participant flow
Recruitment details
Subjects were enrolled at five institutions (UNC-Chapel Hill, University of Pittsburgh, Moses Cone, UNC-Rex Cancer Center, and George Washington University) from November, 2016 to February, 2018. All subjects started to receive study treatment in November 2016 although 2 subjects signed informed consent in October 2016.
Pre-assignment details
A total of forty-nine subjects consented to the study, but eight were deemed to be ineligible and one subject has withdrawn the consent during screening. Forty subjects were enrolled and evaluable for toxicity and survival, and 39 subjects were evaluable for response.
Participants by arm
| Arm | Count |
|---|---|
| Experimental: Single Arm Subjects will receive a single dose (300 mg/m2) of cyclophosphamide given the day before cycle 1 of pembrolizumab (200 mg), which will be administered every 3 weeks.
Pembrolizumab: Subjects will be treated every 3 weeks with 200 mg of pembrolizumab via a 30 minute infusion.
Cyclophosphamide: A single 300 mg/m2 dose of cyclophosphamide IV over 30-60 minutes will be administered on Day 1 of this study. | 40 |
| Total | 40 |
Baseline characteristics
| Characteristic | Experimental: Single Arm |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 32 Participants |
| ECOG performance status 0 | 24 Participants |
| ECOG performance status 1 | 16 Participants |
| Prior (neo)adjuvant therapy No | 7 Participants |
| Prior (neo)adjuvant therapy Yes | 33 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants |
| Race (NIH/OMB) More than one race | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 28 Participants |
| Region of Enrollment United States | 40 participants |
| Sex: Female, Male Female | 40 Participants |
| Sex: Female, Male Male | 0 Participants |
| Sites of metastatic disease Bone | 18 Participants |
| Sites of metastatic disease Brain | 1 Participants |
| Sites of metastatic disease Liver | 12 Participants |
| Sites of metastatic disease Lung | 14 Participants |
| Sites of metastatic disease Lymph node | 4 Participants |
| Stage at diagnosis 0-III | 30 Participants |
| Stage at diagnosis IV | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 5 / 40 |
| other Total, other adverse events | 40 / 40 |
| serious Total, serious adverse events | 18 / 40 |
Outcome results
Primary
Quantification of the Change in Regulatory T Cells (Tregs) During the Study Treatment.
Regulatory T cells (Tregs) are counted before the treatment start and during the treatment. Methods: Blood Sample collection.
Time frame: Up to 2 years
Population: The subjects received two doses of the study treatment.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental: Single Arm | Quantification of the Change in Regulatory T Cells (Tregs) During the Study Treatment. | -3.3 Percent Change in Tregs |
| C1D1-C2D1 | Quantification of the Change in Regulatory T Cells (Tregs) During the Study Treatment. | 10 Percent Change in Tregs |
| C1D2-C2D1 | Quantification of the Change in Regulatory T Cells (Tregs) During the Study Treatment. | 21.7 Percent Change in Tregs |
Primary
The Progression Free Survival (PFS)
PFS is defined as the time from day1 of the study treatment until disease progression or death. Disease progression is defined as per Response Evaluation Criteria In Solid Tumors Criteria (RECIST)1.1 based on computerized tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) images or assessment of the physician. RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), 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.
Time frame: Up to 5 years
Population: The subjects received at least one dose of the study treatment were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental: Single Arm | The Progression Free Survival (PFS) | 1.8 months |
Secondary
Disease Control Rate (DCR)
DCR is defined as the percentage of participants, who achieve \[compete response (CR) + partial response (PR) and stable disease (SD) per RECIST1.1. If best response is SD, then it must last more than 6 months to be included in calculation of DCR, to be considered to have received clinical benefit from the treatment regimen. RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no response or less response than Partial or Progressive; or Progressive Disease (PD), 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.
Time frame: Up to 2 years
Population: The subjects received the study treatment, treatments response was assessed and/or followed up for more than 6 months.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Experimental: Single Arm | Disease Control Rate (DCR) | 28 Participants |
Secondary
Duration of Response (DOR)
DOR is defined as the time from documentation of tumor response by RECIST1.1 \[(CR) + (PR)\] to disease progression by RECIST 1.1. It will be measured from when the time measurement criteria are first met for complete response or partial response (whichever status is recorded first) until the first date of progressive disease or death. Patients who neither progress nor die will be censored on the date of their last tumor assessment.
Time frame: Up to 3 years
Population: The subjects received at least one dose of the study treatment and treatments response was assessed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental: Single Arm | Duration of Response (DOR) | 20.4 months |
Secondary
Overall Response Rate (ORR)
ORR is defined as the percentage of patients with \[compete response (CR) + partial response (PR)\] per RECIST1.1 based on computerized tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) images. RECIST v.1.1: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions;
Time frame: Up to 2 years
Population: The subjects received at least one dose of the study treatment and treatments response was assessed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Experimental: Single Arm | Overall Response Rate (ORR) | 21 percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as the time from D1 of study treatment to death from any cause.
Time frame: Up to 3 years
Population: All subjects who received at least one dose of treatment were included.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Experimental: Single Arm | Overall Survival (OS) | 6.3 months |
Secondary
Treatment Associated Toxicity
Treatment Associated Toxicity is defined as the number of participants with Grade 3-4 adverse events associated with study treatment. Adverse Events were classified and graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v.4 based on changes in laboratory parameters, vital signs, and other safety assessments per standard of care.
Time frame: Up to 3 years
Population: Participants who received at least one cycle of study treatment were included.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Experimental: Single Arm | Treatment Associated Toxicity | Gastrointestinal disorders | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Fatigue | 3 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Anemia | 2 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | White blood cell decreased | 2 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Pericardial tamponade | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Pain | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Neutrophil count decreased | 2 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Lymphocyte count decreased | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Immune system disorders | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Hypoalbuminemia | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Headache | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Generalized muscle weakness | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Dyspnea | 2 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Dry mouth | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Diarrhea | 2 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Colitis | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Blood bilirubin increased | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Aspartate aminotransferase increased | 2 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Anorexia | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Alkaline phosphatase increased | 1 Participants |
| Experimental: Single Arm | Treatment Associated Toxicity | Alanine aminotransferase increased | 1 Participants |