PRESERVE 1: A phase 3, randomized, double-blind trial of trilaciclib versus placebo in patients receiving FOLFOXIRI/bevacizumab for metastatic colorectal cancer

Joleen M. Hubbard1; Matti Aapro2; Satish Shah3; Afshin Eli Gabayan4; Richard Siegel5; Yili Pritchett6; John Yi6; Janet Horton6; and Fortunato Ciardiello7

For questions regarding the PRESERVE 1 trial, please contact clinicalinfo@g1therapeutics.com. Copies of this e-Poster obtained through QR, AR, and/or text key codes are for personal use only and may not be reproduced without written permission of the authors.

Introduction
Introduction
Objectives
Objectives
Patients
Patients
Objectives
Study design
Objectives
Study Sites
References
References and
Acknowledgments
PDF
View PDF of
Poster

1Mayo Clinic, Rochester, MN, USA; 2Genolier Cancer Center, Clinique de Genolier, Genolier, Switzerland; 3Gettysburg Cancer Center, Gettysburg, PA, USA; 4Beverly Hills Cancer Center, Beverly Hills, CA, USA; 5Illinois Cancer Specialists, Arlington Heights, IL, USA; 6G1 Therapeutics, Inc., Research Triangle Park, NC, USA; 7University of Campania Luigi Vanvitelli, Naples, Italy

ESMO Congress 2021 | September 16–21, 2021 | Virtual

 

Introduction

  • Multiagent chemotherapy remains the cornerstone of treatment for metastatic colorectal cancer (mCRC), with most patients receiving some combination of leucovorin, fluorouracil, oxaliplatin, and irinotecan in the first-line setting, often in combination with a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) pathways1,2
  • Improvements in overall survival (OS) and progression-free survival (PFS) gained from combining leucovorin, fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI) with bevacizumab have come at the expense of increased chemotherapy-induced toxicity, including myelosuppression, diarrhea, and mucositis1-3
    • As a result, the use of FOLFOXIRI is frequently limited to younger patients with fewer comorbidities
  • Chemotherapy-induced myelosuppression, which commonly manifests as neutropenia, anemia, and/or thrombocytopenia, is a dose-limiting and potentially fatal complication of treatment that can result in hospitalization and the need for supportive care interventions
    • Symptoms of fatigue, and the development of infections and bleeding can seriously affect quality of life, and dose reductions and treatment delays may affect treatment response and long-term survival4,5
  • Trilaciclib is an intravenous cyclin-dependent kinase 4/6 inhibitor indicated to decrease the incidence of chemotherapy-induced myelosuppression in adult patients when administered prior to a platinum/etoposide- or topotecan-containing chemotherapy regimen for extensive-stage small cell lung cancer6
  • Data from 3 randomized, placebo-controlled, phase 2 clinical trials showed that administering trilaciclib prior to chemotherapy reduced the incidence of chemotherapy-induced myelosuppression, and reduced the need for supportive care interventions and chemotherapy dose reductions/delays7-9
  • Additionally, in a randomized phase 2 trial in patients with metastatic triple-negative breast cancer, administering trilaciclib prior to gemcitabine plus carboplatin significantly improved OS compared with chemotherapy alone, potentially through protection and direct activation of immune function10,11
Diagram 1
Next Section
Back to home
 

Objectives

PRESERVE 1 STUDY

  • PRESERVE 1 (NCT04607668) is a phase 3, multicenter, randomized, double-blind, placebo-controlled study evaluating the myeloprotective and antitumor efficacy of trilaciclib versus placebo administered prior to FOLFOXIRI/bevacizumab for patients receiving first-line treatment for proficient mismatch repair/microsatellite stable (pMMR/MSS) mCRC
  • FOLFOXIRI is more efficacious and more myelosuppressive than other fluorouracil-based regimens used in the treatment of mCRC; therefore, patients should benefit from a reduction in the incidence of chemotherapy-induced myelosuppression and use of this regimen at the standard-of-care dose and schedule

STUDY OBJECTIVES

Diagram 2
Next Section
Back to home
 

Patient Eligibility Criteria

Diagram 3
Next Section
Back to home
 

Study Design

Figure 1
5FU, fluorouracil; CI, continuous infusion; FOLFOXIRI, leucovorin, fluorouracil, oxaliplatin, and irinotecan; mCRC, metastatic colorectal cancer; pMMR/MSS, proficient mismatch repair/microsatellite stable.

ENDPOINTS

Diagram 4

STATISTICS

  • To ensure strong control of family-wise type I error rate at the level of 2-sided 0.05, the following statistical considerations are specified in the protocol:
    1. Overall alpha (α) will be split for analyses between 2 groups:
    • Group 1: analyses of the 2 primary myelosuppression endpoints and time to first confirmed deterioration in fatigue (TTCD-fatigue) using α1 = 0.04
    • Group 2: analyses of PFS and OS using α2 = 0.01

    2. Hierarchical procedures are specified to test treatment effects within each group:
    • As coprimary endpoints, duration of severe (grade 4) neutropenia (DSN) in cycle 1, and occurrence of severe neutropenia (SN) during induction will each be tested at the 2-sided 0.04 level; if both are positive, α1 will be passed to test treatment effect on TTCD-fatigue
    • Treatment effect for OS will be tested after the treatment effect for PFS is established at the α2 level

    3. Recycling of α from Group 1 to Group 2:
    • If the treatment effects are established for all 3 endpoints in Group 1, PFS and OS will be tested at the 2-sided 0.05 level; otherwise, they will be tested at the 0.01 level
  • The sample size is determined to support the primary efficacy analysis for the 2 primary efficacy endpoints:
    • 282 patients will be needed to detect treatment effect on DSN using a Mann-Whitney-Wilcoxon test, and on occurrence of SN using a chi-square test, with 90% power at the 2-sided significance level of 0.04
    • Assuming 5% of randomized patients will not have any postbaseline data, a total of 296 patients (148 per group) will be required for the study
Next Section
Back to home
 

Study Sites

Diagram 5
Next Section
Back to home
 

References and Acknowledgments

REFERENCES

  • 1. Montagnani F, et al. Colorectal Dis. 2011;13:846–52.
  • 2. Loupakis F, et al. N Engl J Med. 2014;371:1609–18.
  • 3. Sastre J, et al. J Clin Oncol. 2019;37:3507
  • 4. Epstein RS, et al. Adv Ther. 2020;37:3606–18.
  • 5. Epstein RS, et al. Patient Prefer Adherence. 2021;15:453–65.
  • 6. COSELA™ (trilaciclib). Prescribing Information. https://www.g1therapeutics.com/cosela/pi/. Accessed August 2021.
  • 7. Daniel D, et al. Int J Cancer. 2021;148:2557–70.
  • 8. Weiss JM, et al; G1T28-02 Study Group. Ann Oncol. 2019;30:1613–21.
  • 9. Hart LL, et al. Adv Ther. 2021;38:350–65.
  • 10. Tan AR, et al. Lancet Oncol. 2019;20:1587–601.
  • 11. O’Shaughnessy J, et al. SABCS poster presentation. 2020; abstract #PD1-06.
  • 12. He S, et al. Sci Transl Med. 2017;9:eaal3986.
  • 13. Li C, et al. Cancer Chemother Pharmacol. 2021;87:689–700.
  • 14. Lai AY, et al. J Immunother Cancer. 2020;8:e000847

ACKNOWLEDGMENTS

Study sponsored by G1 Therapeutics. Medical writing assistance was provided by Farhana Burnett, PhD, from Alligent Europe (Envision Pharma Group), funded by G1 Therapeutics, Inc.

Back to home