Breast Cancer, Triple Negative Breast Cancer
Conditions
Keywords
Breast Cancer, Triple Negative Breast Cancer, CDK4/6 Inhibitor, trilaciclib dihydrochloride, Cosela, Immuno-oncology, Solid tumor, Chemotherapy-induced myelosuppression, Myeloprotective, Cyclin-dependent kinase 4/6 inhibitor, Neoadjuvant, HER2-negative, TNBC, Breast cancer surgery, Trilaciclib, Myeloprotection, pembrolizumab, carboplatin, doxorubicin, cyclophosphamide, Dose-dense anthracycline/cyclophosphamide, paclitaxel, Chemotherapy
Brief summary
The purpose of this study is to evaluate the mechanism of action, as well as the safety and efficacy of trilaciclib in combination with standard of care treatment in the neoadjuvant setting of early-stage triple negative breast cancer (TNBC). This study will have four phases: 1) Screening Phase, 2) Trilaciclib Lead-In Phase, 3) Treatment Phase, and 4) Surgery and Follow-Up Phase. After a screening phase of up to 21 day, each participant will receive trilaciclib single-dose monotherapy during the lead-in phase, followed by a tumor biopsy. During the treatment phase, each participant will receive trilaciclib with standard of care chemotherapy. Immunotherapy may be included during the treatment phase, per standard of care. 3-5 weeks following conclusion of the treatment phase, each participant will undergo definitive surgery. A 30-day Safety Follow-up Visit will occur 30 days after the last dose of trilaciclib and an End of Study Visit will occur within 14 days after definitive surgery.
Interventions
DRUGTrilaciclib
Trilaciclib is administered IV as monotherapy during the lead-in phase and administered prior to chemotherapy on each day chemotherapy is administered during the treatment phase.
DRUGCylophosphamide
Cyclophosphamide administered IV every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.
DRUGDoxorubicin
Doxorubicin administered as an IV bolus every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.
DRUGPaclitaxel
Paclitaxel administered weekly for the last 12 cycles (cycles 5-16), each cycle 1 week in length.
DRUGCarboplatin (Investigator discretion)
Carboplatin, if given, is administered IV weekly at the start of paclitaxel administration, for the last 12 cycles (cycles 5-16).
BIOLOGICALPembrolizumab (Investigator discretion)
Pembrolizumab, if given, is administered IV every 6 weeks throughout the treatment phase (cycles 1, 4, 9, 15).
Sponsors
G1 Therapeutics, Inc.
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
* Suitability of therapy and patient intends to undergo curative surgery * Documented diagnosis of estrogen receptor (ER)-negative and progesterone receptor (PR)-negative tumor * Primary tumor ≥ 1.5 cm with any nodal status * Provide archival tissue for the baseline tissue sample * ECOG performance status of 0 or 1 * Demonstrates adequate organ function * Research tumor biopsies including at least one on-treatment biopsy (and additional biopsy at baseline, if required) * Participants of child bearing potential must be willing to use 2 forms of contraception during the study and for 6 months following study treatment
Exclusion criteria
* Prior systemic therapies or radiation for current breast cancer * History of invasive malignancy ≤3 years prior to signing informed consent except for adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer * History of breast cancer including ipsilateral ductal carcinoma in situ (DCIS) treated with radiotherapy at any time * Previous exposure to doxorubicin of more than 200 mg/m2 (as lifetime exposure to doxorubicin is not to exceed 450 mg/m2) * For patients who will receive pembrolizumab: * History of active autoimmune disease that has required systemic treatment in past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy is not considered a form of systemic treatment * 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 study drugs * History of (non-infectious) pneumonitis that required steroids or current pneumonitis * Known history of active tuberculosis (Bacillus Tuberculosis) * History of severe hepatic impairment * Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure (Class II-IV as defined by the New York Heart Association \[NYHA\] functional classification system) * Known history of stroke, cerebrovascular accident, severe/unstable angina, myocardial infarction, or coronary angioplasty/stenting/bypass grafting within 6 months prior to enrollment * Known serious active infection (e.g., human immunodeficiency virus \[HIV\], hepatitis B or C, tuberculosis). * Women who are pregnant or breastfeeding * Participation in other studies involving active treatment with investigational drug(s) * Prior hematopoietic stem cell or bone marrow transplantation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immune-based Mechanism of Action | Up to 8 days after lead-in trilaciclib dose | Evaluated 7 days after a single-dose of trilaciclib, measured by the change in CD8+ T cells/regulatory T cells (Treg) ratio in tumor tissue; post-trilaciclib ratio minus pre-trilaciclib ratio. Research shows a correlation between immune cells, (tumor-infiltrating lymphocytes - TILs), and favorable outcomes. Both the presence of effector CD8+ T cells and the ratio of effector CD8+ T cells to immune-suppressive regulatory T cells (Treg) correlate with improved outcome and long-term survival in solid cancers. Therefore, the higher the ratio of CD8+ T cells/Tregs, the better the predicted outcome for a patient. This outcome measure is completed by looking at tumor tissue under a microscope. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Pathologic Complete Response (pCR) Rate | Up to 26 weeks | Rate of pCR using the definition of ypT0/Tis ypN0 (i.e., no invasive residual tumor in breast or nodes; noninvasive breast residuals allowed) as assessed by the local pathologist. |
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Up to 28 weeks | Safety/tolerability as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 |
Countries
United States
Participant flow
Recruitment details
Participants were recruited based on physician referral at 7 clinical locations, including academic, community, and hospital network locations. Recruitment occurred between November 2021 and August 2022. The first participant was enrolled on March 3rd, 2022. The last participant was enrolled on August 2nd, 2022.
Pre-assignment details
24 participants were enrolled. As an open-label study, all participants received trilaciclib during the monotherapy, lead-in phase, followed by trilaciclib plus doxorubicin/cyclophosphamide and paclitaxel (AC/T). Additions of pembrolizumab and/or carboplatin were at physician discretion.
Participants by arm
| Arm | Count |
|---|---|
| Trilaciclib Plus Chemotherapy All subjects received trilaciclib lead-in (240mg/m2) single dose monotherapy, followed by trilaciclib plus anthracycline/cyclophosphamide (Trilaciclib (240mg/m2) + doxorubicin (60 mg/m2) + cyclophosphamide (600 mg/m2) + pembrolizumab (per Investigator discretion; 400mg)), then trilaciclib plus taxane chemotherapy (Trilaciclib (240mg/m2) + paclitaxel (80 mg/m2) + carboplatin (per Investigator discretion; AUC 1.5) + pembrolizumab (per Investigator discretion; 400mg).
Trilaciclib: Trilaciclib is administered IV as monotherapy during the lead-in phase and administered prior to chemotherapy on each day chemotherapy is administered during the treatment phase.
Cylophosphamide: Cyclophosphamide administered IV every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.
Doxorubicin: Doxorubicin administered as an IV bolus every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.
Paclitaxel: Paclitaxel administered weekly for the last 12 cycles (cycles 5-16), each cycle 1 week in length.
Carboplatin (Investigator discretion): Carboplatin, if given, is administered IV weekly at the start of paclitaxel administration, for the last 12 cycles (cycles 5-16).
Pembrolizumab (Investigator discretion): Pembrolizumab, if given, is administered IV every 6 weeks throughout the treatment phase (cycles 1, 4, 9, 15). | 24 |
| Total | 24 |
Baseline characteristics
| Characteristic | Trilaciclib Plus Chemotherapy |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 22 Participants |
| Age, Continuous | 57.0 years |
| Body Mass Index (BMI) | 29.88 kg/m2 STANDARD_DEVIATION 9.219 |
| BRCA Mutation Status BRCA 1 | 1 Participants |
| BRCA Mutation Status BRCA 1/2 | 1 Participants |
| BRCA Mutation Status BRCA 2 | 0 Participants |
| BRCA Mutation Status Negative | 10 Participants |
| BRCA Mutation Status Not done/Other | 12 Participants |
| Easter Cooperative Oncology Group (ECOG) Score 0 | 22 Participants |
| Easter Cooperative Oncology Group (ECOG) Score 1 | 2 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Histologic Grade Grade 1 | 1 Participants |
| Histologic Grade Grade 2 | 3 Participants |
| Histologic Grade Grade 3 | 20 Participants |
| Histopathological type at diagnosis Ductal | 20 Participants |
| Histopathological type at diagnosis Lobular | 1 Participants |
| Histopathological type at diagnosis Other | 3 Participants |
| PD-L1 status Negative | 2 Participants |
| PD-L1 status Not done/Unknown | 21 Participants |
| PD-L1 status Positive | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 24 Participants |
| Sex: Female, Male Male | 0 Participants |
| Stage at diagnosis Stage I | 2 Participants |
| Stage at diagnosis Stage II | 19 Participants |
| Stage at diagnosis Stage III | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 24 |
| other Total, other adverse events | 24 / 24 |
| serious Total, serious adverse events | 4 / 24 |
Outcome results
Primary
Immune-based Mechanism of Action
Evaluated 7 days after a single-dose of trilaciclib, measured by the change in CD8+ T cells/regulatory T cells (Treg) ratio in tumor tissue; post-trilaciclib ratio minus pre-trilaciclib ratio. Research shows a correlation between immune cells, (tumor-infiltrating lymphocytes - TILs), and favorable outcomes. Both the presence of effector CD8+ T cells and the ratio of effector CD8+ T cells to immune-suppressive regulatory T cells (Treg) correlate with improved outcome and long-term survival in solid cancers. Therefore, the higher the ratio of CD8+ T cells/Tregs, the better the predicted outcome for a patient. This outcome measure is completed by looking at tumor tissue under a microscope.
Time frame: Up to 8 days after lead-in trilaciclib dose
Population: Full Analysis Set 1 (FAS1), defined as all enrolled participants who received trilaciclib during the Trilaciclib Lead-in Phase, for whom pre-trilaciclib and post-trilaciclib monotherapy biopsies were available for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trilaciclib Plus Chemotherapy | Immune-based Mechanism of Action | 0.3 CD8+/Tregs ratio |
p-value: 0.101Wilcoxon signed-rank test
Secondary
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)
Safety/tolerability as per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0
Time frame: Up to 28 weeks
Population: Full Analysis Set 2 (FAS2), included enrolled patients who had received at least one dose of a study drug during the Treatment Phase of the study.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trilaciclib Plus Chemotherapy | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Adverse Events CTCAE grade >/= 3 | 15 Participants |
| Trilaciclib Plus Chemotherapy | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Adverse Events CTCAE grade >/= 4 | 5 Participants |
| Trilaciclib Plus Chemotherapy | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Study drug related adverse event | 24 Participants |
| Trilaciclib Plus Chemotherapy | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Study drug related serious adverse event | 2 Participants |
| Trilaciclib Plus Chemotherapy | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Trilaciclib-related adverse event leading to discontinuation | 0 Participants |
| Trilaciclib Plus Chemotherapy | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Adverse event leading to death | 0 Participants |
| Trilaciclib Plus Chemotherapy | Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Trilaciclib adverse events of special interest (AESI) | 10 Participants |
Secondary
Pathologic Complete Response (pCR) Rate
Rate of pCR using the definition of ypT0/Tis ypN0 (i.e., no invasive residual tumor in breast or nodes; noninvasive breast residuals allowed) as assessed by the local pathologist.
Time frame: Up to 26 weeks
Population: Full Analysis Set (FAS), enrolled participants who received at least one dose of any study drug during the treatment period, where treatment period consists of Trilaciclib Lead-in Phase and the Treatment Phase.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Trilaciclib Plus Chemotherapy | Pathologic Complete Response (pCR) Rate | Achieved pCR | 10 Participants |
| Trilaciclib Plus Chemotherapy | Pathologic Complete Response (pCR) Rate | Did not achieve pCR | 14 Participants |