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

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)

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.

Study Overview

• Status: Completed
• Conditions: Breast Cancer; Triple Negative Breast Cancer
• Intervention / Treatment: Drug: Trilaciclib; Drug: Cylophosphamide; Drug: Doxorubicin; Drug: Paclitaxel; Drug: Carboplatin (Investigator discretion); Biological: Pembrolizumab (Investigator discretion)

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Alamitos, California, United States, 90720
      • Cancer and Blood Specialty Clinic
    • Santa Monica, California, United States, 90404
      • UCLA Department of Medicine - Hematology/Oncology
    • Whittier, California, United States, 90602
      • PIH Health
  • Nebraska
    • Lincoln, Nebraska, United States, 68506
      • Nebraska Hematology-Oncology, P.C.
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center
  • Texas
    • Dallas, Texas, United States, 75246
      • Texas Oncology - Baylor Charles A. Sammons Cancer Center
  • Virginia
    • Norfolk, Virginia, United States, 23502
      • Virginia Oncology Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Trilaciclib plus chemotherapy; 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; 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.; Other Names: G1T28; COSELA®; Drug: Cylophosphamide; Cyclophosphamide administered IV every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.; Other Names: CYTOXAN®; Drug: Doxorubicin; Doxorubicin administered as an IV bolus every 2 weeks for the first 4 cycles (1-4), each cycle 2 weeks in length.; Other Names: ADRIAMYCIN®; Drug: Paclitaxel; Paclitaxel administered weekly for the last 12 cycles (cycles 5-16), each cycle 1 week in length.; Other Names: TAXOL®; Drug: Carboplatin (Investigator discretion); Carboplatin, if given, is administered IV weekly at the start of paclitaxel administration, for the last 12 cycles (cycles 5-16).; Other Names: PARAPLATIN®; Biological: Pembrolizumab (Investigator discretion); Pembrolizumab, if given, is administered IV every 6 weeks throughout the treatment phase (cycles 1, 4, 9, 15).; Other Names: KEYTRUDA®

What is the study measuring?

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; 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.	Up to 8 days after lead-in trilaciclib dose

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 Common Terminology Criteria for Adverse Events (CTCAE) version 5.0	Up to 28 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intratumoral immune profile characterization following trilaciclib	Characterization of molecular and immune changes based on CD8+ T cell and Treg infiltration, quantified by RNA profiling of tumor tissue before study treatment, during study treatment, and at definitive surgery.	Up to 26 weeks
Kinetics of the immune response in peripheral blood	Longitudinal immune changes in peripheral blood, measured by frequency of immune subsets and profiling of activation, maturation, and exhaustion status.	Up to 26 weeks
Kinetics of T cell function and polyfunctionality	Ex-vivo measurement of cytokine production to determine T cell function and polyfunctionality.	Up to 26 weeks
Molecular biomarkers for clinical responsiveness	pCR in patients by gene signatures determined in the tumor at baseline.	Up to 26 weeks
CDK4/6 dependence for clinical responsiveness	pCR in patients by subgroups according to CDK4/6 dependence signatures.	Up to 26 weeks
PD-L1 status and clinical responsiveness	pCR in patients by subgroups according to PD-L1 status, as measured by IHC.	Up to 26 weeks
Immune response and clinical responsiveness	pCR in patients by frequency of immune subsets, immunological markers, and cytokines.	Up to 26 weeks

Collaborators and Investigators

• Sponsor: G1 Therapeutics, Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 3, 2022
• Primary Completion (Actual): October 31, 2022
• Study Completion (Actual): March 13, 2023

Study Registration Dates

• First Submitted: October 6, 2021
• First Submitted That Met QC Criteria: October 27, 2021
• First Posted (Actual): November 9, 2021

Study Record Updates

• Last Update Posted (Actual): March 12, 2024
• Last Update Submitted That Met QC Criteria: March 11, 2024
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Breast Cancer; paclitaxel; carboplatin; cyclophosphamide; Chemotherapy; Solid tumor; TNBC; Neoadjuvant; Triple Negative Breast Cancer; pembrolizumab; Immuno-oncology; doxorubicin; HER2-negative; Breast cancer surgery; Trilaciclib; Cyclin-dependent kinase 4/6 inhibitor; Chemotherapy-induced myelosuppression; Myeloprotective; CDK4/6 Inhibitor; trilaciclib dihydrochloride; Cosela; Myeloprotection; Dose-dense anthracycline/cyclophosphamide
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Triple Negative Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antineoplastic Agents, Immunological; Antibiotics, Antineoplastic; Immune Checkpoint Inhibitors; Carboplatin; Paclitaxel; Pembrolizumab; Doxorubicin
• Other Study ID Numbers: G1T28-212

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No