E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally Advanced Unresectable or Metastatic Triple Negative Breast Cancer |
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E.1.1.1 | Medical condition in easily understood language |
Advanced or Metastatic Breast Cancer |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10075566 |
E.1.2 | Term | Triple negative breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 23.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10084066 |
E.1.2 | Term | Triple negative breast cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072740 |
E.1.2 | Term | Locally advanced breast cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Cohort 1: First-Line Population: To evaluate the effect of trilaciclib on OS compared with placebo
NA since protocol 5.0 (Cohort 2: Second-line, Previously Treated with a PD-1/PD-L1 Inhibitor Population: To evaluate the effect of trilaciclib on OS compared with placebo) (for full wording see protocol)
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E.2.2 | Secondary objectives of the trial |
Both cohorts * To assess the effect of trilaciclib compared with placebo on: - OS in the PD-L1-positive or negative subgroup (Cohort 1 only) - progression-free survival - anti-tumor activity - quality of life related to fatigue - chemotherapy-induced myelosuppression related symptoms - myelopreservation effects - healthcare utilization - standard of care dosing - safety and tolerability
*Cohort 2 is closed to enrollment as of 24 January 2022. (for full wording see protocol)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study: 1. Female or male patients with evaluable locally advanced unresectable or metastatic TNBC 2. Age ≥18 years 3. Documentation of histologically or cytologically confirmed hormone (estrogen and progesterone) receptor negative tumor by immunohistochemistry (IHC) assessment (defined as <1% nuclei staining) and HER2-negative, non-overexpressing (by IHC [0 or 1+] OR in situ hybridization [ratio <2.0] OR average HER2 gene copy number of <4 signals/nucleus) on most recent biopsy per 2018 American Society of Clinical Oncology and the College of American Pathologists (ASCO CAP) criteria. 4. Prior systemic therapies (Cohort 1 only): a. No prior systemic therapy in the locally advanced unresectable/metastatic setting including chemotherapy, targeted therapy, immunotherapy, or investigational agents. b. Time between completion of last treatment with curative intent and first metastatic recurrence must be ≥ 6 months. Note, prior PD-1/PD-L1 inhibitor in the (neo)adjuvant/ curative setting does not have time/interval restrictions. Washout of at least 14 days from prior PD-1/PDL1 inhibitor to the first dose of study drug is required. c. Only patients for whom treatment with a PD-1/PD-L1 inhibitor is not an option, either based on clinical eligibility or drug availability, will be enrolled in Cohort 1. 5. Prior systemic therapies (Cohort 2 only, Cohort 2 is closed to enrollment as of 24 January 2022). a. Documentation of PD-L1 positive status b. Treated with a PD-1/PDL1 inhibitor for a minimum duration of 4 months in the locally advanced unresectable/metastatic setting and as the most recent therapy. Washout of at least 14 days from prior PD-1/PDL1 inhibitor to the first dose of study drug is required. 6. Radiation therapy for metastatic disease is permitted. There is no required minimum washout period for these therapies. Patients should be recovered from the effects of radiation. 7. Archival tumor tissue must be available or a fresh biopsy must be obtained, unless approved by the Medical Monitor. If archival tissue is used, representative formalin-fixed paraffin embedded (FFPE) tumor specimens in paraffin blocks (75-micron) or at least 15 (5-micron) unstained slides are required. a. For Cohort 1 only, some of the tumor tissue noted above will be used for determination of tumor PD-L1 status using the Ventana SP-142 IVD assay which can be assay locally or centrally. Testing should be conducted on a recurrent/metastatic tumor; however, a primary lesion is acceptable. Documentation of PD-L1 status is acceptable for randomization if testing was done using the Ventana SP-142 IVD assay. 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 9. Adequate organ function as demonstrated by the following laboratory values: a. Hemoglobin ≥9.0 g/dL in the absence of RBC transfusion or ESA administration within 14 days prior to first dose of study drug b. Absolute neutrophil count (ANC) ≥1.5 × 10^9/L in the absence of G-CSF/ GM-CSF administration within 14 days prior to first dose of study drug c. Platelet count ≥100 × 10^9/L in the absence of platelet transfusion within 14 days prior to the first dose of study drug d. Estimated glomerular filtration rate ≥30 mL/minute/1.73 m2 (or calculated per institutional standards and local practice) e. Total bilirubin ≤1.5 × upper limit of normal (ULN) (<3 ULN if Gilbert’s disease) f. ALT and AST ≤2.5 × ULN (<5 ULN if documented liver metastases) 10. Resolution of nonhematologic toxicities from prior systemic therapy, radiation therapy, or surgical procedures to ≤Grade 1 (except alopecia) 11. Predicted life expectancy of ≥3 months 12. Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. Please see Section 17.3 for detailed instructions on methods of contraception requirements 13. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form and in this protocol 14. Patients who consent to optional biopsy collection (at baseline and one on-treatment timepoint): Acceptable samples for both baseline and on-treatment timepoint include core needle biopsies (minimum three cores) or excisional, incisional, punch, or forceps biopsies for cutaneous, subcutaneous, or mucosal lesions. Tumor tissue should be from a locally recurrent or metastatic site and be of good quality based on total and viable tumor content. Fine-needle aspiration, brushing, cell pellet from pleural effusion, bone metastases, and lavage samples are not acceptable. A minimum of three cores is acceptable.
(see protocol for full information) |
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E.4 | Principal exclusion criteria |
A patient will not be eligible for participation in this study if any of the following criteria apply: 1. Prior treatment with gemcitabine in any setting. 2. Prior treatment with carboplatin in the locally advanced unresectable/metastatic setting. Prior carboplatin in the (neo)adjuvant/curative setting is permitted as long as it was completed ≥ 6 months prior to the first metastatic recurrence 3. Malignancies other than TNBC within 3 years prior to randomization: Patients with malignancies of a negligible risk of metastasis or death (e.g., risk of metastasis or death <5% at 5 years as determined by the investigator) are eligible provided they meet all of the following criteria: a. Malignancy treated with expected curative intent (e.g., adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ treated surgically with curative intent) b. No evidence of recurrence or metastasis by follow-up imaging and any disease-specific tumor markers 4. Presence of central nervous system (CNS) metastases and/or leptomeningeal disease requiring immediate treatment with radiation therapy or steroids. Patient must be off steroids administered for brain metastases for at least 14 days prior to the first dose of study drugs. No stereotactic radiation within 7 days or whole-brain radiation within 14 days prior to first dose of study drugs 5. Receipt of any cytotoxic chemotherapy within 14 days prior to the first dose of study drugs 6. Receipt of any investigational medication within 30 days, or at least 5 half-lives, whichever is greater, prior to the first dose of study drugs 7. QTcF interval >480 msec at Screening. For patients with ventricular pacemakers, QTcF >500 msec 8. Uncontrolled ischemic heart disease or uncontrolled symptomatic congestive heart failure (Class III or IV as defined by the New York Heart Association [NYHA] functional classification system) 9. Known history of stroke or cerebrovascular accident within 6 months prior to first dose of study drugs 10. Known serious active infection (e.g., human immunodeficiency virus [HIV], hepatitis B or C, tuberculosis). Patients with past hepatitis B virus (HBV) infection or resolved HBV infection (defined as having a negative HBsAg test and a positive antibody to hepatitis B core antigen [anti-HBc] antibody test) are eligible. Patients positive for hepatitis C virus (HCV) antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 11. Known hypersensitivity to carboplatin or other platinum-containing compounds, or mannitol 12. Pregnant or lactating women 13. Prior hematopoietic stem cell or bone marrow transplantation 14. Other uncontrolled serious chronic disease or psychiatric condition that in the Investigator’s opinion could affect patient safety, compliance, or follow-up in the protocol 15. Major surgical procedure, open biopsy, or significant traumatic injury within 30 days prior to first dose of study drugs, or anticipation of the need for major surgical procedure during the course of the study 16. Receipt of a live, attenuated vaccine within 30 days prior to the first dose of study drugs or anticipation that such a live, attenuated vaccine will be required during the study treatment period |
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E.5 End points |
E.5.1 | Primary end point(s) |
Cohort 1: - OS in the ITT population defined as time from randomization to death due to any cause for those who died; or time to last contact known as alive for those who survived in the study (censored cases).
Cohort 2: - OS in the ITT population defined as time from randomization to death due to any cause for those who died; or time to last contact known as alive for those who survived in the study (censored cases). NOTE: The objectives, endpoints and planned analyses in Cohort 2 as of protocol v.5.0 are no longer applicable, and data from Cohort 2 will be summarized as appropriate. Cohort 2 is closed to enrollment as of 24 January 2022. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cohort 1: randomization to up to 39 months Cohort 2: randomization to up to 28 months
NOTE: The objectives, endpoints and planned analyses in Cohort 2 as of protocol v.5.0 are no longer applicable, and data from Cohort 2 will be summarized as appropriate. Cohort 2 is closed to enrollment as of 24 January 2022. |
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E.5.2 | Secondary end point(s) |
both Cohorts: • OS in PD-L1-positive subgroup (cohort 1 only) • OS in PD-L1-negative subgroup (cohort 1 only) • PFS in ITT population using RECIST v1.1, defined as time from randomization to disease progression or death due to any cause, whichever occurs first; for patients without disease progression or death, PFS will be calculated per censoring rules. • ORR, as defined as percentage of patients with confirmed CR and PR per RECIST v1.1 • CBR, as defined as percentage of patients with confirmed CR, PR, and SD lasting 24 weeks or longer, as per RECIST v1.1 • Duration of objective response per RECIST v1.1 • Time to first confirmed deterioration of fatigue (TTCD-fatigue), as measured by the FACIT-F. • Change from baseline and/or time to deterioration in: a. FACT-G domain scores (physical, social/family, emotional, and functional well-being) b. FACT-An: Anemia c. EQ-5D-5L • Percent of patients reporting deterioration and improvement using: a. PGIC fatigue item b. PGIS fatigue item • Occurrence and severity of AEs by NCI CTCAE v5 • Trilaciclib AESIs • Changes in laboratory parameters (hematology and serum chemistry), vital signs and ECG parameters • Grade 3 or 4 abnormalities in serum chemistry laboratory parameters • Trilaciclib infusion interruptions • Chemotherapy dose modifications • Relative dose intensity for gemcitabine and carboplatin
Secondary Objectives: to evaluate the myelopreservation effect of trilaciclib compared with placebo • Duration of severe (Grade 4) neutropenia in Cycle 1 • Occurrence of severe (Grade 4) neutropenia • Occurrence of febrile neutropenia AEs • Occurrence of G-CSF administration • Occurrence of Grade 3 or 4 decreased hemoglobin laboratory values • RBC transfusions on or after Week 5 (occurrence and number of transfusions) • Occurrence of ESA administration • Occurrence of Grade 3 or 4 decreased platelet count laboratory values • Platelet transfusions (occurrence and number of transfusions) • Occurrence and number of hospitalizations due to chemotherapy-induced myelosuppression • All-cause dose reductions (occurrence and number of reductions) • All-cause cycle delays (occurrence and number of delays)
NOTE: The objectives, endpoints and planned analyses in Cohort 2 as of protocol v.5.0 are no longer applicable, and data from Cohort 2 will be summarized as appropriate. Cohort 2 is closed to enrollment as of 24 January 2022. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
thorough the study as per the schedule of assessments in the protocol |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 38 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Australia |
United States |
Georgia |
Moldova, Republic of |
Russian Federation |
Ukraine |
Serbia |
Bulgaria |
France |
Poland |
Spain |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of study is event driven. That is, each cohort will continue until the targeted number of deaths is observed. There is an interim analysis for OS in Cohort 1. If the interim results demonstrate a statistically significant effect of trilaciclib over placebo for OS based on pre-specified criterion, Cohort 1 will be stopped early due to success. In that event, Cohort 2 will continue until the targeted number of deaths is observed.
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 3 |
E.8.9.2 | In all countries concerned by the trial days | 1 |