Trilaciclib, a CDK4/6 Inhibitor, in Patients With Early-Stage Triple Negative Breast Cancer

Study Overview
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Brief Summary
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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.

Official Title
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A Phase 2, Open-Label, Single-Arm Study of Single-Dose Lead-In and Neoadjuvant Trilaciclib and Chemotherapy in Patients With Early-Stage Triple Negative Breast Cancer (TNBC)

Conditions
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Triple Negative Breast Cancer, Breast Cancer

Intervention / Treatment
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* Drug: Trilaciclib
* Drug: Cylophosphamide
* Drug: Doxorubicin
* Drug: Paclitaxel
* Drug: Carboplatin (Investigator discretion)
* Biological: Pembrolizumab (Investigator discretion)


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Trilaciclib plus chemotherapy<br>Trilaciclib lead-in, followed by trilaciclib plus anthracycline/cyclophosphamide, then trilaciclib plus taxane chemotherapy: Lead-in trilaciclib (240mg/m2) single dose monotherapy Trilaciclib (240mg/m2) + doxorubicin (60 mg/m2) + cyclophosphamide (600 mg/m2) + pembrolizumab (per Investigator discretion; 400mg) Trilaciclib (240mg/m2) + paclitaxel (80 mg/m2) + carboplatin (per Investigator discretion; AUC 1.5) | Drug: Trilaciclib<br>* 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.<br>* Other names: G1T28;Drug: Cylophosphamide<br>* Cyclophosphamide administered IV every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.<br>* Other names: CYTOXAN®;Drug: Doxorubicin<br>* Doxorubicin administered as an IV bolus every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.<br>* Other names: ADRIAMYCIN®;Drug: Paclitaxel<br>* Paclitaxel administered weekly for the last 12 cycles (cycles 5-16), each cycle 1 week in length.<br>* Other names: TAXOL®;Drug: Carboplatin (Investigator discretion)<br>* Carboplatin, if given, is administered IV weekly at the start of paclitaxel administration, for the last 12 cycles (cycles 5-16).<br>* Other names: PARAPLATIN®;Biological: Pembrolizumab (Investigator discretion)<br>* Pembrolizumab, if given, is administered IV every 6 weeks throughout the treatment phase (cycles 1, 4, 9, 15).<br>* Other names: KEYTRUDA®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 8 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Up to 26 weeks | 
| Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) | Safety/tolerability as per CTCAE version 5.0 | Up to 28 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cosela, Chemotherapy-induced myelosuppression, TNBC, Breast Cancer, Triple Negative Breast Cancer, CDK4/6 Inhibitor, trilaciclib dihydrochloride, Immuno-oncology, Solid tumor, Myeloprotective, Cyclin-dependent kinase 4/6 inhibitor, Neoadjuvant, HER2-negative, Breast cancer surgery, Trilaciclib, Myeloprotection, pembrolizumab, carboplatin, doxorubicin, cyclophosphamide, Dose-dense anthracycline/cyclophosphamide, paclitaxel, Chemotherapy