National Register of Actionable Mutations (RATIONAL)

• ClinicalTrials.gov Identifier: NCT05918666
• Recruitment Status: Recruiting
• First Posted: June 26, 2023
• Last Update Posted: June 26, 2023
• Sponsor: Federation of Italian Cooperative Oncology Groups
• Collaborators: Roche Pharma AG; AstraZeneca; Bayer; Bristol-Myers Squibb; Janssen, LP; Takeda; Amgen; Daiichi Sankyo; Eli Lilly and Company; Novartis; Clinical Research Technology S.r.l.
• Information provided by (Responsible Party): Federation of Italian Cooperative Oncology Groups

Tracking Information

• First Submitted Date: May 30, 2023
• First Posted Date: June 26, 2023
• Last Update Posted Date: June 26, 2023
• Actual Study Start Date: October 27, 2018
• Estimated Primary Completion Date: October 27, 2026 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 15, 2023)

rate of actionable mutations identified with NGS [ Time Frame: from October 2018 to study completion, 2 years after the last enrolled patient ]

information on somatic mutations obtained by analysis of neoplastic tissue samples and/or liquid biopsy (circulating tumor DNA extracted from the patient's plasma).

• Original Primary Outcome Measures: Same as current
• Change History: No Changes Posted
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: National Register of Actionable Mutations
• Official Title: National Register of Actionable Mutations - Rational Study

Brief Summary

The goal of this observational study is the creation of a national network of precision medicine, which allows to increase, for Italian patients suffering from solid tumors, the possibility of access to more innovative therapies and to collect retrospectively their clinical data.

For this purpose, a national register of actionable mutations in patients with solid tumors in advanced stage of disease will be created in which various individual, local and regional initiatives of genomic screening of cancer could merge.

Detailed Description

The primary objective of this observational study is to describe the frequency of actionable mutations in patients with solid tumors in advanced stage, receiving a genetic-molecular characterization with high throughput methods.

The secondary objectives are:

1. assess the correlation between genetic alterations and clinical and pathological characteristics of enrolled patients (gender, age, histological variant, location and extent of neoplasm, comorbidity, familiarity for neoplasms);
2. describe, where possible, any variation in the molecular profile for patients who are subjected to genetic screening analysis at different stages of the disease.
3. record retrospectively clinical efficacy and toxicity data when patients were treated with a target therapy based on the detected molecular alterations.

The national register of actionable mutations will be created collecting the following data:

1. Data extracted retrospectively from medical records of patients that have received during the study period a test with high-throughput technologies for the molecular characterization of their tumor, either by clinical routine or for research purposes.
2. Data collected prospectively from analysis of biological samples (FFPE and biopsy liquid) of patients that meet the elibility criteria and that perform the molecular-genetic screening using Foundation Medicine services or in selected italian laboratories.
3. Clinical data collected retrospectively (RR, DOR, PFS, OS, toxicity), in case where the patients are treated with a target therapy, based on the highlighted molecular alterations and on the choice of the clinician.

Only samples already available for clinical practice will be used in the study.

The register will be limited to collecting information on molecular alterations that can then be used for the insertion of patients in clinical studies already active, for the design of new studies proposed by members of the Steering Committee or of the participating sites, or for treatment with other modality.

• Study Type: Observational [Patient Registry]
• Study Design: Observational Model: Other; Time Perspective: Other
• Target Follow-Up Duration: 2 Years
• Biospecimen: Not Provided
• Sampling Method: Probability Sample
• Study Population: patients with solid tumors in advanced stage of disease
• Condition: Solid Tumours in Advanced Stages
• Intervention: Not Provided
• Study Groups/Cohorts: Not Provided

Publications *

• Barlesi F, Mazieres J, Merlio JP, Debieuvre D, Mosser J, Lena H, Ouafik L, Besse B, Rouquette I, Westeel V, Escande F, Monnet I, Lemoine A, Veillon R, Blons H, Audigier-Valette C, Bringuier PP, Lamy R, Beau-Faller M, Pujol JL, Sabourin JC, Penault-Llorca F, Denis MG, Lantuejoul S, Morin F, Tran Q, Missy P, Langlais A, Milleron B, Cadranel J, Soria JC, Zalcman G; Biomarkers France contributors. Routine molecular profiling of patients with advanced non-small-cell lung cancer: results of a 1-year nationwide programme of the French Cooperative Thoracic Intergroup (IFCT). Lancet. 2016 Apr 2;387(10026):1415-1426. doi: 10.1016/S0140-6736(16)00004-0. Epub 2016 Jan 15.
• Burrell RA, Swanton C. Tumour heterogeneity and the evolution of polyclonal drug resistance. Mol Oncol. 2014 Sep 12;8(6):1095-111. doi: 10.1016/j.molonc.2014.06.005. Epub 2014 Jul 10.
• Davis W, Makar G, Mehta P, Zhu GG, Somer R, Morrison J, Kubicek GJ. Next-Generation Sequencing in 305 Consecutive Patients: Clinical Outcomes and Management Changes. J Oncol Pract. 2019 Dec;15(12):e1028-e1034. doi: 10.1200/JOP.19.00269. Epub 2019 Aug 2.
• Garraway LA. Genomics-driven oncology: framework for an emerging paradigm. J Clin Oncol. 2013 May 20;31(15):1806-14. doi: 10.1200/JCO.2012.46.8934. Epub 2013 Apr 15.
• Kris MG, Johnson BE, Berry LD, Kwiatkowski DJ, Iafrate AJ, Wistuba II, Varella-Garcia M, Franklin WA, Aronson SL, Su PF, Shyr Y, Camidge DR, Sequist LV, Glisson BS, Khuri FR, Garon EB, Pao W, Rudin C, Schiller J, Haura EB, Socinski M, Shirai K, Chen H, Giaccone G, Ladanyi M, Kugler K, Minna JD, Bunn PA. Using multiplexed assays of oncogenic drivers in lung cancers to select targeted drugs. JAMA. 2014 May 21;311(19):1998-2006. doi: 10.1001/jama.2014.3741.
• Lopez-Chavez A, Thomas A, Rajan A, Raffeld M, Morrow B, Kelly R, Carter CA, Guha U, Killian K, Lau CC, Abdullaev Z, Xi L, Pack S, Meltzer PS, Corless CL, Sandler A, Beadling C, Warrick A, Liewehr DJ, Steinberg SM, Berman A, Doyle A, Szabo E, Wang Y, Giaccone G. Molecular profiling and targeted therapy for advanced thoracic malignancies: a biomarker-derived, multiarm, multihistology phase II basket trial. J Clin Oncol. 2015 Mar 20;33(9):1000-7. doi: 10.1200/JCO.2014.58.2007. Epub 2015 Feb 9.
• Meric-Bernstam F, Brusco L, Shaw K, Horombe C, Kopetz S, Davies MA, Routbort M, Piha-Paul SA, Janku F, Ueno N, Hong D, De Groot J, Ravi V, Li Y, Luthra R, Patel K, Broaddus R, Mendelsohn J, Mills GB. Feasibility of Large-Scale Genomic Testing to Facilitate Enrollment Onto Genomically Matched Clinical Trials. J Clin Oncol. 2015 Sep 1;33(25):2753-62. doi: 10.1200/JCO.2014.60.4165. Epub 2015 May 26.
• Normanno N, Rachiglio AM, Roma C, Fenizia F, Esposito C, Pasquale R, La Porta ML, Iannaccone A, Micheli F, Santangelo M, Bergantino F, Costantini S, De Luca A. Molecular diagnostics and personalized medicine in oncology: challenges and opportunities. J Cell Biochem. 2013 Mar;114(3):514-24. doi: 10.1002/jcb.24401.
• Pishvaian MJ, Blais EM, Brody JR, Lyons E, DeArbeloa P, Hendifar A, Mikhail S, Chung V, Sahai V, Sohal DPS, Bellakbira S, Thach D, Rahib L, Madhavan S, Matrisian LM, Petricoin EF 3rd. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol. 2020 Apr;21(4):508-518. doi: 10.1016/S1470-2045(20)30074-7. Epub 2020 Mar 2. Erratum In: Lancet Oncol. 2020 Apr;21(4):e182.
• Smyth LM, Zhou Q, Nguyen B, Yu C, Lepisto EM, Arnedos M, Hasset MJ, Lenoue-Newton ML, Blauvelt N, Dogan S, Micheel CM, Wathoo C, Horlings H, Hudecek J, Gross BE, Kundra R, Sweeney SM, Gao J, Schultz N, Zarski A, Gardos SM, Lee J, Sheffler-Collins S, Park BH, Sawyers CL, Andre F, Levy M, Meric-Bernstam F, Bedard PL, Iasonos A, Schrag D, Hyman DM; AACR Project GENIE Consortium. Characteristics and Outcome of AKT1 E17K-Mutant Breast Cancer Defined through AACR Project GENIE, a Clinicogenomic Registry. Cancer Discov. 2020 Apr;10(4):526-535. doi: 10.1158/2159-8290.CD-19-1209. Epub 2020 Jan 10.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: June 15, 2023): 3000
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: October 27, 2026
• Estimated Primary Completion Date: October 27, 2026 (Final data collection date for primary outcome measure)

Eligibility Criteria

General Inclusion Criteria for all patients:

• Age >18 years old
• Life expectancy 6 months
• ECOG performance status 2
• Diagnosis of malignant solid tumor, in advanced stage
• Informed consent to data registration and for privacy purposes

Additional inclusion criteria for patients that have already carried out a genetic characterisation extended by high throughput methods:

● Availability of the result of the broad spectrum analysis of genetic alterations carried out with high throughput methods on biological samples

Additional inclusion criteria for patients that perform the molecular-genetic screening using Foundation Medicine services or in selected italian laboratories:

• one of the following criteria:

  • Patients diagnosed with NSCLC not squamous, not pretreated;
  • Patients with biliary tract, pancreatic, esophagus, stomach, thymus, CNS, nasopharynx, salivary glands, endometrium and urothelium cancers;
  • Patients with any disease (including NSCLC) who are progressing disease after treatment with molecular target drugs. For these patients is the availability of a post- treatment biological sample is necessary;
  • Patients with cancer of unknown primary (CUP);
  • Young patients (<40 years) or patients who have exhausted standard lines of therapy, with any advanced/metastatic tumor which, in the opinion of the investigator, may benefit from a genetic-molecular characterization at broad spectrum aimed at a treatment with molecular target therapies.
• availability of biological material for testing.
• informed consent for testing.

Additional exclusion criteria for patients that perform the molecular-genetic screening using Foundation Medicine services or in selected italian laboratories:

● patients who have already received NGS or other high throughput in the same stage of disease.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Nicola Normanno, MD; 081.5903111; n.normanno@istitutotumori.na.it

• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT05918666
• Other Study ID Numbers: Rational study
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Federation of Italian Cooperative Oncology Groups
• Original Responsible Party: Same as current
• Current Study Sponsor: Federation of Italian Cooperative Oncology Groups
• Original Study Sponsor: Same as current

Collaborators

• Roche Pharma AG
• AstraZeneca
• Bayer
• Bristol-Myers Squibb
• Janssen, LP
• Takeda
• Amgen
• Daiichi Sankyo
• Eli Lilly and Company
• Novartis
• Clinical Research Technology S.r.l.

Investigators

• Principal Investigator: Nicola Normanno; INT- IRCCS Fondazione Pascale, Napoli

• PRS Account: Federation of Italian Cooperative Oncology Groups
• Verification Date: June 2023