| Protocol No: | ECCT/22/11/03 | Date of Protocol: | 23-03-2022 |
| Study Title: |
A PHASE II/III MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE TARGETED THERAPIES AS TREATMENTS FOR PATIENTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) HARBORING ACTIONABLE SOMATIC MUTATIONS DETECTED IN BLOOD (BFAST: BLOOD FIRST ASSAY SCREENING TRIAL)
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| Study Objectives: |
Primary Efficacy Objective: To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed ORR based on confirmed objective response (indicated by two objective response assessments based on RECIST v1.1 separated by at least 4 weeks).
Secondary Efficacy Objective: To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints:
Investigator-assessed DOR, CBR, and PFS per RECIST v1.1
IRF-assessed ORR, DOR, CBR, and PFS per RECIST v1.1
OS.
Safety Objective: To evaluate the safety and tolerability of alectinib. Corresponding Endpoints:
Incidence, type, and severity of adverse events (based on the NCI CTCAE v4.0), including SAEs and AEs of special interest.
Changes in vital signs, physical findings, and clinical laboratory results during and following administration of protocol-specified IMPs.
PRO Objective: To evaluate the impact of alectinib on PROs in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints
Proportion of patients who improved compared with baseline in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain as measured by SILC
TTD in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain, as measured by SILC
Mean change from baseline in HRQoL, patient functioning, and symptoms as measured by the EORTC QLQ-C30 and SILC
PRO Objective: To evaluate and compare patients’ health status to generate utility scores for use in economic models for reimbursement. Corresponding endpoint: Health status as assessed by the EQ-5D-5L questionnaire.
Biomarker Objective: To assess prognostic effect and pharmacodynamics of exploratory
biomarkers in blood, and their association with disease status, mechanisms of resistance, and/or response to alectinib. Corresponding Endpoint: Relationship between circulating biomarkers related to alectinib efficacy.
Exploratory Objective: To explore the anti-tumor effect of alectinib in patients with CNS disease identified at baseline. Corresponding Endpoints:
Investigator-assessed ORR per RECIST v1.1 in patients with CNS disease
Investigator-assessed DOR per RECIST v1.1 in patients with CNS disease
Investigator-assessed CBR per RECIST v1.1 in patients with CNS disease
Exploratory Objective: To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed TIR according to RECIST.
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| Laymans Summary: |
This study will evaluate the efficacy and safety of multiple therapies that are selected using predictive biomarkers identified via a blood-based NGS assay in patients with advanced non-small cell lung cancer (NSCLC). Specific objectives and corresponding endpoints for the study are outlined for each cohort below.
This study will also characterize the natural history of patients with genomic alteration profiles of interest who do not enroll in any of the above treatment cohorts. Analyses will be exploratory in nature; there is no formal hypothesis testing in the natural history cohort.
Study BO29554 (BFAST) is a Phase II/III, global, multicenter, open-label, multi-cohort study designed to evaluate the safety and efficacy of targeted therapies or immunotherapy as single agents or in combination in patients with unresectable, advanced or metastatic NSCLC determined to harbor oncogenic somatic mutations (e.g., ALK, RET) or positive by tumor mutational burden (TMB) assay (above a prespecified cutoff) as identified by a blood-based NGS circulating tumor DNA (ctDNA) assay.
Male and female patients aged more than or equal to 18 years who meet the trial’s general inclusion/exclusion criteria will be eligible for blood-based screening. Blood specimens from patients meeting eligibility criteria for the blood-based screening part of the study will be prospectively tested for somatic alterations in a panel of oncogenes, including the targetable oncogenes and TMB.
The overarching structure of the BFAST study is an umbrella screening and interventional study, which will screen patient blood samples for the presence of potentially oncogenic somatic mutations and biomarker positivity via a blood-based NGS ctDNA assay, and will treat patients with a drug or drug regimen tailored to their results. Initially, three cohorts testing the efficacy and safety of therapy directed at specific mutations or biomarkers (ALK, RET, and biomarker positive for bTMB [bTMB-positive]) were implemented. Additional cohorts have been and will be added to address various identified somatic mutations or other biomarkers via future protocol amendments. Each cohort may have separate endpoints, screening, and treatment requirements.
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| Abstract of Study: |
A PHASE II/III MULTICENTER STUDY EVALUATING THE EFFICACY AND SAFETY OF MULTIPLE TARGETED THERAPIES AS TREATMENTS FOR PATIENTS WITH ADVANCED OR METASTATIC NON-SMALL CELL LUNG CANCER (NSCLC) HARBORING ACTIONABLE SOMATIC MUTATIONS DETECTED IN BLOOD (BFAST: BLOOD FIRST ASSAY SCREENING TRIAL)
PROTOCOL NUMBER: BO29554
VERSION NUMBER: 7
TEST PRODUCT: Alectinib (RO5424802), Atezolizumab (RO5541267), Entrectinib (RO7102122), Cobimetinib (RO5514041), Vemurafenib (RO5185426), GDC-6036 (RO7435846)
Lung cancer remains the leading cause of cancer death worldwide; it is the most common cancer in both men and women and is estimated to account for approximately 13% of all new cancers in 2016 (Miller et al. 2016). Non–small cell lung cancer (NSCLC), as a whole, is not rare (224,390 expected new cases in the United States in 2016) (Miller et al. 2016), and several treatments via a number of therapeutic mechanisms are approved for use. However, the disease is heterogeneous and comprises a number of rare or uncommon subgroups of patients, leaving considerable room for improvement in treating patients with a personalized approach.
Patients diagnosed with early-stage NSCLC have reasonable outcomes (5-year survival rate of 55%). However, the remaining 76% of the patient population who are diagnosed with regional or metastatic disease have poorer outcomes (5-year survival rates of 31% and 5% for regional and metastatic disease, respectively [Howlader et al. 2016]). Based on the Global Burden of Cancer Study (GLOBOCAN) 2012 data from the WHO Europe region, the overall age-standardized rate for lung cancer was 449 cases (313 cases in European Union) per 100,000 persons, with 36.5 deaths per 100,000 persons (International Agency for Cancer Research world population standard) (Ferlay et al. 2015). The GLOBOCAN database does not provide information on histology or cancer stage; thus, the proportion of the advanced or metastatic NSCLC could not be specifically determined for a European NSCLC population. NSCLC accounts for 80%-85% of all lung cancers in the Surveillance, Epidemiology and End Results (SEER) database; assuming a distribution similar to the data provided from SEER can be expected for the European Union, this would produce an expectation of 266 cases of NSCLC per 100,000 persons in the European Union per year.
Patients with advanced or metastatic NSCLC usually receive platinum-based doublet chemotherapy with or without a PD-L/PD-L1 inhibitor, unless they harbor tumors with activating EGFR, ALK, or ROS1 mutations and are treated with appropriately targeted therapy (based upon diagnostic selection) as first-line treatment (National Comprehensive Cancer Network [NCCN] 2016). These treatment options have produced response rates of up to 35% with chemotherapy (Schiller et al. 2002; Sandler et al. 2006; Scagliotti et al. 2008), 74% with crizotinib (ALK inhibitor; Xalkori®), and 65% with EGFR-targeted therapy (Rosell et al. 2012; Solomon et al. 2014). Additionally, the associated median progression-free survival (PFS) is approximately 6 months for chemotherapy and up to 14 months with targeted therapy, while the median overall survival (OS) is approximately 10 months with chemotherapy and up to 28 months with targeted therapy (Xalkori® and Tarceva® U.S. Prescribing Information). However, most patients will relapse as a result of inherent or acquired resistance and will require subsequent lines of therapy
The effectiveness of existing therapies declines in patients with advanced or metastatic disease who receive additional therapies beyond the first-line. While there are approved targeted therapies for previously treated patients with ALK- or EGFR-positive NSCLC, available approved treatment options for ALK- or EGFR-negative patients with previously treated advanced or metastatic NSCLC were limited to docetaxel, pemetrexed, and erlotinib prior to 2015. These agents have produced objective response rates (ORRs) of 5.5%-8.9% in pivotal trials in this patient population, with limited benefit in median PFS (range, 2-3 months) and median OS (range, 5.7-8.3 months) (Taxotere®, Alimta®, and Tarceva® U.S. Prescribing Information).
More recently, immunotherapy options such as atezolizumab (Tecentriq®), nivolumab (Opdivo) and pembrolizumab (Keytruda) have been approved in the United States, the European Union, and other countries for previously untreated (in the case of pembrolizumab) or previously treated advanced or metastatic NSCLC. In certain settings, patients are treated irrespective of biomarker information, while in others, patients are selected by a protein expression biomarker, largely regardless of driver mutation status (includes some, but not all patients with a specific mutation). The combination of ramucirumab (Cyramza®; VEGF-R2 antagonist) and docetaxel has also been recently approved in an unselected, previously treated NSCLC population. These recently approved agents have resulted in ORRs of 23% in unselected, previously treated NSCLC populations. While no single biomarker has, at this time, clearly discerned those patients who benefit from immunotherapies, it has been theorized that patients with high-mutation-load tumors are more likely to benefit thanas well as perhaps represent a distinct population from those patients who harbor driver mutations (Alexandrov et al. 2013; Rizvi et al. 2015).
Patients will be assigned to the appropriate cohort based on their identified oncogenic somatic mutation(s). If more than one mutation is identified, the priority for cohort assignment will be as follows:
ROS1 rearrangement (~1%): Cohort D (entrectinib) (Note: Cohort D has been closed to further enrollment)
BRAF V600 mutation (~1%2%): Cohort E (vemurafenib, cobimetinib, atezolizumab)
EGFR exon 20 mutation (~1%2%): Cohort F (atezolizumab, bevacizumab, carboplatin, pemetrexed)
RET rearrangement (~1.8%): Cohort B (alectinib) (Note: Cohort B has been closed to further enrollment.)
ALK rearrangement (~5%): Cohort A (alectinib) (Note: Cohort A has been closed to further enrollment.)
KRAS G12C mutation (~8 12%): Cohort G (GDC-6036 vs. docetaxel) bTMB positive (~23%36%): Cohort C (atezolizumab vs. chemotherapy)
(Note: Cohort C has been closed to further enrollment)
Patients who are screened using the ctDNA assay but who do not enroll in a treatment cohort are eligible to begin natural history follow-up (if consent is given) to document their cancer therapies (or therapy types), treatment response, and survival status. Additional information on other data that were collected as part of initial blood screening process for these patients is available in the body of the protocol. Patients with an alteration relevant to the BFAST trial or other key alteration profiles of interest (e.g., KRAS+, HER2+, MET+, PIK3CA+, other EGFR alterations, other ALK alterations, other RET alterations, other BRAF alterations, or other who pursue therapy or other management options outside of this study for any reason (e.g., failure to meet treatment-specific eligibility criteria, choosing not to enroll, physician decision to pursue alternative therapy, patient experiencing disease progression before they can enroll, etc.) will be the population of interest for this component of the study. Information will be obtained approximately every 3 months during routine doctor or healthcare appointments and/or telephone calls. For patients in the natural history follow-up, a blood sample will be collected at the time of disease progression for blood-based assay testing (if consent is given). These samples may be stored for future exploratory analyses.
Mandatory blood samples at baseline, during therapy (i.e., at each tumor assessment), and at progression of disease, as well as tissue (or results from tissue-based testing, when available or as required per protocol), will be collected in order to evaluate exploratory prognostic and/or predictive biomarkers, including but not limited to biomarkers related to driver oncogene signaling and NSCLC pathogenesis. For all patients, blood samples will be used as the only means of identifying driver mutations or TMB for inclusion in treatment cohorts, irrespective of tissue availability or tissue testing results. For patients who do not screen positive for an available cohort (or who are enrolled on the study but discontinue study treatment for reasons other than disease progression), or at the time of disease progression on study, treating physicians will have the option to receive access to a report of the FoundationOne Liquid Companion Diagnostic (F1LCDx) assay results (or Sponsor-designated assay results in China). To improve patient access to clinical trials and subject to informed consent, central F1LCDx results (or Sponsor-designated blood based NGS ctDNA assay results in China) for patients deemed not eligible for the enrollment in any active BFAST cohort, may be used to determine if patients are potentially eligible for other Sponsor's studies. The trial is designed to demonstrate clinical efficacy and safety in the target population, though dose-finding may be necessary in certain cohorts. Treatment will be assigned on the basis ofrelevant oncogenotype, will have cohort-specific inclusion/exclusion criteria, and unless otherwise specified, will continue until disease progression per Response Evaluation Criteria In Solid Tumors, Version 1.1 (RECIST v1.1), loss of clinical benefit (if applicable), unacceptable toxicity, patient or physician decision to discontinue, or death, whichever occurs first. If the
patient discontinues treatment prior to disease progression (because of adverse event, withdrawal of consent to treatment, or other reason), tumor assessment data collection will continue until disease progression per RECIST v1.1, death, withdrawal of consent, or study closure by the Sponsor, whichever occurs first. Follow-up data capture, including survival and subsequent anti-cancer therapies, will continue for each patient until death, loss to follow-up, study discontinuation, or study closure, whichever occurs first. Information regarding the nature and the duration of subsequent therapies will be collected.
OBJECTIVES AND ENDPOINTS
Primary Efficacy Objective:
To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed ORR based on confirmed objective response (indicated by two objective response assessments based on RECIST v1.1 separated by at least 4 weeks).
Secondary Efficacy Objective:
To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints:
Investigator-assessed DOR, CBR, and PFS per RECIST v1.1
IRF-assessed ORR, DOR, CBR, and PFS per RECIST v1.1
OS.
Safety Objective:
To evaluate the safety and tolerability of alectinib. Corresponding Endpoints:
Incidence, type, and severity of adverse events (based on the NCI CTCAE v4.0), including SAEs and AEs of special interest.
Changes in vital signs, physical findings, and clinical laboratory results during and following administration of protocol-specified IMPs.
PRO Objective:
To evaluate the impact of alectinib on PROs in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoints
Proportion of patients who improved compared with baseline in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain as measured by SILC
TTD in patient-reported lung cancer symptoms of cough, dyspnea, and chest pain, as measured by SILC
Mean change from baseline in HRQoL, patient functioning, and symptoms as measured by the EORTC QLQ-C30 and SILC
PRO Objective:
To evaluate and compare patients’ health status to generate utility scores for use in economic models for reimbursement. Corresponding endpoint: Health status as assessed by the EQ-5D-5L questionnaire.
Biomarker Objective:
To assess prognostic effect and pharmacodynamics of exploratory
biomarkers in blood, and their association with disease status, mechanisms of resistance, and/or response to alectinib. Corresponding Endpoint: Relationship between circulating biomarkers related to alectinib efficacy.
Exploratory Objective:
To explore the anti-tumor effect of alectinib in patients with CNS disease identified at baseline. Corresponding Endpoints:
Investigator-assessed ORR per RECIST v1.1 in patients with CNS disease
Investigator-assessed DOR per RECIST v1.1 in patients with CNS disease
Investigator-assessed CBR per RECIST v1.1 in patients with CNS disease
Exploratory Objective:
To evaluate the efficacy of alectinib in patients with ALK+ advanced or metastatic NSCLC as determined by the F1LCDX assay. Corresponding Endpoint: Investigator-assessed TIR according to RECIST.
Inclusion Criteria:
Exclusion Criteria:
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