| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | | Untreated Extensive-Stage Small Cell Lung Cancer | |
| E.1.1.1 | Medical condition in easily understood language | | Untreated Extensive-Stage Small Cell Lung Cancer | |
| 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 | 21.1 | | E.1.2 | Level | PT | | E.1.2 | Classification code | 10041068 | | E.1.2 | Term | Small cell lung cancer extensive stage | | E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) | |
| 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 | | Evaluate the potential of trilaciclib, compared with placebo, to reduce chemotherapy-induced myelosuppression in patients with SCLC undergoing treatment with E/P/A | |
| E.2.2 | Secondary objectives of the trial | Evaluate potential of trilaciclib, compared with placebo, to reduce chemotherapy-induced myelosuppression and its consequences in patients with SCLC undergoing treatment with E/P/A
Evaluate the antitumor activity of trilaciclib or placebo administered in combination with E/P/A to patients with SCLC
Determine the safety and tolerability of trilaciclib or placebo administered in combination with E/P/A in patients with SCLC
Evaluate potential of trilaciclib to reduce chemotherapy-induced myelosuppression by assessing effects on multiple lineages and current standard of care interventions to treat myelosuppression (neutrophils, RBC, platelets, lymphocytes)
Describe the PK of trilaciclib, carboplatin, and etoposide in a subset of patients; and atezolizumab in all patients | |
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria | For a patient to be eligible for participation in this study, all of the following criteria must
apply.
1. Age ≥ 18 years
2. Unequivocally confirmed diagnosis of SCLC by histology or cytology, preferably
including the presence of neuroendocrine features by immunohistochemistry
3. Extensive-stage SCLC
4. At least 1 target lesion that is measurable by RECIST v1.1 (Eisenhauer 2009)
5. Hemoglobin ≥ 9.0 g/dL
6. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
7. Platelet count ≥ 100 × 109/L
8. Creatinine ≤ 1.5 mg/dL or glomerular filtration rate (GFR) of ≥ 60 mL/minute
9. Total bilirubin ≤ 1.5 × ULN; < 3 × ULN if the patient has documented Gilbert’s disease
10. AST and ALT ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases
11. ECOG performance status of 0 to 2
12. Predicted life expectancy of ≥ 3 months
13. Contraception:
a. For females: All females of childbearing potential must have a negative serum beta human chorionic gonadotropin (β-hCG) test result
at screening. Females must be either postmenopausal, surgically sterile, or agree to use 2 forms of highly effective contraception during the study and for 6 months following discontinuation of study treatment
i. Postmenopausal is defined as (1) at least 60 years of age, (2) medically confirmed ovarian failure, or (3) younger than 60 years of age
and have had cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause, and/or serum levels of estradiol and follicle stimulating hormone within the laboratory's reference range for postmenopausal females
ii. Acceptable surgical sterilization techniques are complete or partial hysterectomy, bilateral tubal ligation with surgery at least 6 months
prior to dosing, or bilateral oophorectomy with surgery at least 2 months prior to dosing
iii. Highly effective methods of contraception are those that result in a low failure rate (ie, less than 1% per year) when used consistently and correctly. These include the following:
1.Established use of oral, injected or implanted hormonal methods of contraception (stable dose at least 3 months prior to dosing)
2. Placement of an intrauterine device or intrauterine system
3. Barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository. Barrier methods alone (without spermicide) are not acceptable methods. Likewise, spermicide alone is not an acceptable method
4. Male sterilization (with the appropriate post-vasectomy documentation of the absence of sperm in the ejaculate). For female subjects on the study, the vasectomized male partner should be the sole partner for that subject
5. True abstinence, when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
b. For males: For males: Males must be surgically sterile or have a female partner who is either postmenopausal, surgically sterile, or using
2 forms of highly effective contraception as noted above. Acceptable surgical sterilization techniques are vasectomy with surgery at least 6 months prior to dosing. Males must also refrain from sperm donation during the study and for 6 months following discontinuation of treatment
14. Able to understand and sign an informed consent | |
| E.4 | Principal exclusion criteria | A patient will not be eligible for participation in this study if any of the following criteria
apply.
1. Limited-stage SCLC
2. Prior chemotherapy for limited or extensive-stage SCLC
3. Prior treatment with immunotherapies including but not limited to cluster of differentiation 137 (CD137) agonists or immune checkpoint blockade therapies (such as anti-PD-1, anti-PD-L1, CTLA4 therapeutic antibodies)
4. Presence of symptomatic brain metastases requiring immediate treatment with radiation therapy or steroids
5. Malignancies other than SCLC within 3 years prior to randomization, with the exception of those with a negligible risk of metastasis or death treated with expected curative outcome
6. History of idiopathic pulmonary fibrosis, organizing pneumonia, drug induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis on screening chest CT scan (history of radiation pneumonitis in the radiation field [fibrosis] is permitted)
7. Active, known, or suspected autoimmune disease that has required systemic treatment in the past 2 years (ie, with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Exceptions include vitiligo, controlled asthma, type I diabetes, Graves’ disease, Hashimoto’s disease, or with medical monitor approval. Stable replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) for well-controlled disease is not
considered a form of systemic treatment.
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 enrollment
10. Serious active infection at the time of enrollment
11. Psychiatric illness/social situations that would limit study compliance
12. Other uncontrolled serious chronic disease or conditions that in the investigator’s opinion
could affect compliance or follow-up in the protocol
13. Known human immunodeficiency virus (HIV), known active Hepatitis B (eg, HBsAg
reactive or HBV DNA detected) or Hepatitis C (eg, HCV RNA [qualitative] is detected)
14. Radiotherapy to any site within 2 weeks prior to enrollment
15. Receipt of any investigational medication within 4 weeks prior to enrollment
16. Administration of a live attenuated vaccine within 4 weeks before enrollment or anticipation that such a live attenuated vaccine will be required during the study
17. Influenza vaccination should be given during influenza season only (approximately October to March). Patients must not receive live, attenuated influenza vaccine (eg, FluMist) within 4 weeks prior to enrollment, at any time during the study, and at least 5 months after the last dose of atezolizumab
18. Patients with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications (including but not limited to cyclophosphamide, azathioprine, methotrexate, thalidomide,
and anti-tumor necrosis factor [TNF] agents) within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
19. Hypersensitivity to any of the components of the formulation of etoposide or etoposide phosphate
20. Hypersensitivity to carboplatin or other platinum-containing compounds, or mannitol
21. History of severe allergic, anaphylactic, or other hypersensitivity reactions to chimeric or humanized antibodies or fusion proteins
22. Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies
23. Legal incapacity or limited legal capacity
24. Pregnant or lactating women | |
| E.5 End points |
| E.5.1 | Primary end point(s) | •Duration of severe (Grade 4) neutropenia in Cycle 1
•Occurrence of severe (Grade 4) neutropenia | |
| E.5.1.1 | Timepoint(s) of evaluation of this end point | The final analysis of primary endpoint will be conducted after all patients have had the opportunity to receive at least 12 weeks of treatment (ie, randomized induction treatment part of the study). All study data collected through the time of the final analysis data cut, will be included in the final analysis. This includes, but is not limited to, the final myelosuppression analysis, final ORR analysis, and interim PFS/OS analyses.
| |
| E.5.2 | Secondary end point(s) | •Occurrence of RBC transfusions on/after Week 5 (proportion of patients)
•Occurrence of G-CSF administration (proportion of patients)
•A composite endpoint (MAHE) defined to include:
•All-cause hospitalizations (number of events)
•All-cause dose reductions (number of events)
•Febrile neutropenia (number of events)
•RBC transfusions on/after Week 5 (number of events)
•Prolonged severe (Grade 4) neutropenia (duration > 5 days; number of events) | |
| E.5.2.1 | Timepoint(s) of evaluation of this end point | The final analysis of secondary endpoint will be conducted after all patients have had the opportunity to receive at least 12 weeks of treatment (ie, randomized induction treatment part of the study). All study data collected through the time of the final analysis data cut, will be included in the final analysis. This includes, but is not limited to, the final myelosuppression analysis, final ORR analysis, and interim PFS/OS analyses.
Patients will be followed for survival until at least 70% of the patients have died at which time an end of study analysis for OS and PFS will be done. | |
| 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 | No |
| 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 | | Immunogenicity (ATA (anti-therapeutic antibody)) | |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 30 |
| 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 | | Bulgaria | | Estonia | | France | | Georgia | | Latvia | | Spain | | Ukraine | | United States | |
| 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 | | Completion of Survival Follow-up Phase, or termination of the study by the sponsor | |
| 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
