Clinical Trials /

The Rome Trial From Histology to Target: the Road to Personalize Target Therapy and Immunotherapy

NCT04591431

Description:

This is a randomized, prospective, multicenter, Proof of Concept, Phase II clinical trial Study. The main objective of the study is to evaluate the efficacy (meant as overall response rate ORR) of TT (targeted Therapy) vs SoC (standard of Care) in patients with progressive disease (recurrent and/or metastatic) of breast cancer, metastatic gastro-intestinal tumors, non small cell lung cancer (NSCLC) or others. Patients should have completed at least 1 line of treatment and no more than 2 as defined by the current version of the AIOM (Italian Association of Medical Oncology) guidelines. Patients are included if surgery is contraindicated.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: The Rome Trial From Histology to Target: the Road to Personalize Target Therapy and Immunotherapy
  • Official Title: The Rome Trial From Histology to Target: the Road to Personalize Target Therapy and Immunotherapy

Clinical Trial IDs

  • ORG STUDY ID: MAR-BAS-18-005
  • SECONDARY ID: 2018-002190-21
  • NCT ID: NCT04591431

Conditions

  • Breast Cancer
  • Gastrointestinal Cancer
  • Non Small Cell Lung Cancer
  • Other Cancer

Interventions

DrugSynonymsArms
ErlotinibTailored Therapy
TrastuzumabTailored Therapy
Trastuzumab emtansineTailored Therapy
PertuzumabTailored Therapy
LapatinibTailored Therapy
EverolimusTailored Therapy
VemurafenibTailored Therapy
CobimetinibTailored Therapy
AlectinibTailored Therapy
BrigatinibTailored Therapy
PalbociclibTailored Therapy
PonatinibTailored Therapy
VismogedibTailored Therapy
ItacitinibTailored Therapy
IpatasertibTailored Therapy
EntrectinibTailored Therapy
AtezolizumabTailored Therapy
NivolumabTailored Therapy
IpilimumabTailored Therapy
PemigatinibTailored Therapy
Oncology DrugsStandard of Care

Purpose

This is a randomized, prospective, multicenter, Proof of Concept, Phase II clinical trial Study. The main objective of the study is to evaluate the efficacy (meant as overall response rate ORR) of TT (targeted Therapy) vs SoC (standard of Care) in patients with progressive disease (recurrent and/or metastatic) of breast cancer, metastatic gastro-intestinal tumors, non small cell lung cancer (NSCLC) or others. Patients should have completed at least 1 line of treatment and no more than 2 as defined by the current version of the AIOM (Italian Association of Medical Oncology) guidelines. Patients are included if surgery is contraindicated.

Detailed Description

      Personalizing cancer medicine depends on the implementation of personalized diagnostics and
      therapeutics. Detailed genomic and gene expression signatures screening are likely to play a
      central role in this. Personalized Medicine has been widely depicted as a striking
      innovation, that is able to reform the standard approach to disease management, replacing the
      one-size-fits-all scheme of medicine with a single-patient-sized medical intervention.

      Personalized medicine promoters usually highlight its potential to combine a more effective
      health-care with costs containment, according to the following rules:

        -  monitoring of disease risks and more effective prevention;

        -  early intervention;

        -  selection of optimal therapy;

        -  reduction of trial-and-error prescribing and reduction of adverse drug reactions;

        -  exclusion of unnecessary drugs;

        -  therapeutic drug monitoring and disease progression/remission monitoring;

        -  increased patient compliance with therapy. In spite of expectations, many unsolved
           practical issues, from technical and scientific to ethical, legal and economic topics,
           are slowing down the translation of personalized medicine principles into medical
           practice. Furthermore, wide adoption of personalized strategies also has to deal with
           the peculiar rules, policy and reimbursement system of each country.

      Application of Personalized Medicine in the real world seems entangled by the unmet need to
      develop evidence-based guidelines.

      The benefits of personalized medicine in routine clinical practice have firstly emerged in
      oncology. The power of precision medicine in the field of anticancer therapy resides in the
      possibility to characterize the genomic profile of both the disease (eg somatic mutations in
      the tumor tissue or blood sample) and the patient (eg the germinal genomic profile). The
      first piece of information allows stratification of patients in responder and non-responder
      to specific drugs, improving efficacy and avoiding wasting of expensive medications as
      biological drugs. Personalized medicine for cancer can be classified in:

        -  targeted therapy (which bloks the growth of cancer cells by interfering with specific
           molecular targets of cancer cells) or

        -  immunotherapy (which use the body'immune system to fight cancer cells by stimulating the
           immune system) Targeted therapy belongs to Personalized Medicine approach and the study
           of genetic mutations on tumor tissue or blood sample (CTC or cfDNA ) are changing the
           scenario of the treatment approach of cancer patients.

      In clinical practice, the use of target therapies driven by mutation's assessment has
      radically changed the survival of patients affected by breast cancer, NSCLC, melanoma,
      colo-rectal cancer, while the clinical application of specific gene expression signatures is
      driving the choice of the best adjuvant strategy in early breast cancer.

      Despite the efficacy of such approach its use is restricted to a relatively small fraction of
      patients and the evaluation of mutation is conditioned by the primary site of the cancer,
      i.e. by the tumor histology. The current biological understanding leads to hypothesize that
      the cancer behavior is highly dependent from the underlying driver genetic alterations
      independently from the histology. It's widely demonstrated that such molecular alterations
      are detected regardless of the histology, and this has already modified the treatment
      approach of some cancers.

      Furthermore, several studies have demonstrated the efficacy of the choice of treatment
      according to genomic evaluation regardless of its histology with acceptable
      cost-effectiveness profile.

      In the context of precision medicine the Immuno-oncology is becoming Precision
      Immuno-oncology and the efforts of science are directed towards the identification of
      predictive biomarkers of response to immune checkpoint inhibitors.

      Promising biomarkers are Microsatellite Instability (MSI) and the tumour mutational load
      (TMB). In particular TMB is a quantitative biomarker that reflects the total number of
      mutations carried by tumor cells. TMB is well-known to reflect neoantigens burden potentially
      recognized by the immune system. This has been shown to correlate with better anti-PD-1
      response in particular for both pembrolizumab and nivolumab combined with ipilimumab .

      The same findings were demonstrated in the OAK study considering peripheral blood mutational
      load and response to atezolizumab.

      High tumor mutation burden (defined as tumors that have high ≥10 mutations/megabase, mut/mb)
      allows to identify 45% of patients who can benefit from immunotherapy regardless of PD-L1
      expression. So, ever keeping in mind that although many evidences are available, the
      relationship between histology and genomic alterations is still under definition, as well as
      the relationship between the latter and gene expression.

      The aim of the present investigation is to combine all of the information available to drive
      the therapy selection according to the genomic alteration profile. Therefore, the main
      objective of our study is to evaluate the efficacy of therapy according to genomic profile
      (TT - Tailored Treatment) versus Standard of Care (SoC). A molecular profile of the cancer
      will be evaluated on tumor tissue biopsy (using the Foundation One (with updated gene panel
      324 gene reflecting CDx) at the time of patient inclusion in the trial and on circulating DNA
      fragments (i.e. using FoundationOne Liquid test) at the time of patient inclusion in the
      trial and at progression of disease.

      This study is a Phase II, randomized, multicenter, Proof of Concept, clinical trial. Patients
      with progressive disease (recurrent and/or metastatic) of breast cancer, metastatic
      gastro-intestinal tumors, non small cell lung cancer (NSCLC) or others will be included.
      Patients should have completed at least 1 line of treatment and no more than 2 as defined by
      the current version of the AIOM guidelines. Patients are included if surgery is
      contraindicated.

      Patients could have received targeted therapy for metastatic disease. A molecular profile of
      the cancer will be evaluated on tumor tissue biopsy and on ctDNA of around 1280 patients at
      patient inclusion.

      After FO evaluations patients with actionable mutations, not previous identified with other
      methods, for which approved drugs according to histotype are available, will be excluded.

      Once identified molecular abnormalities (not only those that are disease-specific), that can
      be modulated with target or immunotherapeutic intervention available within the present
      study, patients will be randomized to receive:

      ARM A: Therapy at choice of physician, according to Standard of Care (SoC) ARM B: Tailored
      treatment according to genomic profile (Tailored Treatment, TT)

      The Molecular Tumor Board (MTB) will define the target therapy and immunotherapy while
      standard treatment will be decided by study physicians.

      Patients should remain in the treatment phase of the study until investigator assesses
      radiographic or clinical progressive disease, unmanageable toxicity, or study termination.

      Tumor assessments will be conducted every 12 weeks from the date of randomization until any
      of the above events occurs.

      Delays in treatment administration will not impact the timing of the tumor assessments. If a
      tumor assessment must be performed early/late, subsequent assessments will be conducted
      according to the original schedule of every 12 weeks from the date of randomization.

      At the time of the first progression of disease:

        -  blood sample will be collected to evaluate the molecular profile of the cancer on
           circulating DNA fragments (i.e. using FoundationOne Liquid test)

        -  Study treatment (SoC or TT) will be interrupted waiting for the evaluations for the
           Rescue/Switched Phase

      Tumor assessments must be conducted until progressive disease (PD for RECIST 1.1 or iCPD for
      iRECIST if clinically indicated), even if treatment has been discontinued due to
      investigator-determined PD or unacceptable toxicity.

      After discontinuation of study treatment for reason different from progressive disease and
      withdrawal of consent, tumor assessments will continue until progression.

      In addition, patients will be followed for survival until death, loss to follow-up,
      withdrawal of consent, or study termination.
    

Trial Arms

NameTypeDescriptionInterventions
Tailored TherapyExperimentalPatients will be treated with target therapy and/or immunotherapy according to their genomic profile evidenced by the FO (Foundation One) profiling. Patients will be treated with one or more drugs of the following list according to their genomic profile and independently from their type of cancer: TARGETED THERAPY (MOLECULAR TARGET) ERLOTINIB (EGFR mutation) TRASTUZUMAB, PERTUZUMAB, TDM1, LAPATINIB (ERBB2 amplifications/mut) EVEROLIMUS (mTOR mutations, AKT mut) VEMURAFENIB, COBIMETINIB (BRAFV600E mutations) ALECTINIB, BRIGATINIB (ALK, RET) PALBOCICLIB (CDK4/6, CDKN2A/p16) PONATINIB (Bcr-abl) VISMODEGIB (SMO/PTCH1) ITACITINIB (JAK mutation) INCB054828 (FGFR1/2/3) IPATASERTIB (PI3K, AKT, PTEN) ENTRECTINIB (NTRK1/2/3 -TRK fusion proteins-, ROS1) IMMUNOTHERAPY (BIOMARKERS) ATEZOLIZUMAB, NIVOLUMAB, IPILIMUMAB (MSI, HIGH TUMOR MUTATIONAL BURDEN, OTHER ) Drugs will be administered according to their respective SmPCs (or IBs in case of drugs under development).
  • Erlotinib
  • Trastuzumab
  • Trastuzumab emtansine
  • Pertuzumab
  • Lapatinib
  • Everolimus
  • Vemurafenib
  • Cobimetinib
  • Alectinib
  • Brigatinib
  • Palbociclib
  • Ponatinib
  • Vismogedib
  • Itacitinib
  • Ipatasertib
  • Entrectinib
  • Atezolizumab
  • Nivolumab
  • Ipilimumab
  • Pemigatinib
Standard of CareActive ComparatorPatients will be treated according the current version of the AIOM (Italian Association of Medical Oncology) guidelines for their type of cancer. As an example, patients could be treated with standard chemotherapy and/or targeted therapy according to the histological results.
  • Oncology Drugs

Eligibility Criteria

        Inclusion Criteria:

          1. Age ≥ 18 at time of signing Informed Consent Form

          2. Patients able and willing to provide a written informed consent to participate to the
             study

          3. Patients with recurrent/metastatic breast, gastrointestinal cancer,non small cell lung
             cancer or others

          4. Patients not treatable with potentially curative surgery ot other loco-regional
             treatments.

          5. Patients should have been completed at least 1 line of treatment for breast cancer,
             gastro-intestinal, non small cell lung cancer or other cancer

          6. ECOG performance status from 0 to 1

          7. Molecular target not actionable with approved drugs identified during screening by
             profiling with Foundation One on biopsy and Foundation ACT on blood

          8. Biopsiable disease (tumor biopsy mandatory for tumor profiling). The biopsy must be
             performed during the screening period, when patients complete the conventional therapy
             for their recurrent/metastatic cancer. Historical samples will be considered for the
             study if collected within 3 months before the ICF signature of the patient. Samples
             older than 3 months, with a maximum timeframe of 6 months, will be considered upon
             clinical judgement of the Investigator.

          9. Measurable disease, eligible to standard treatment. Patients must have measurable or
             evaluable disease defined, per RECIST 1.1 or irCS (immune related Response Criteria),
             as at least one lesion that can be accurately measured in at least one dimension
             (longest diameter to be recorded for non-nodal lesions and short axis for nodal
             lesions) as ≥20 mm with conventional techniques or as ≥10 mm with spiral computed
             tomography (CT) scan, Magnetic Resonance Imaging (MRI), or a subcutaneous or
             superficial lesion that can be measured with calipers by clinical exam. For lymph
             nodes, the short axis must be ≥15 mm. Patients who have assessable disease by physical
             or radiographic examination but do not fully meet the above definitions of measurable
             disease (but still remains measurable) are eligible and will be considered to have
             evaluable disease. Patient's whose disease cannot be objectively measured by physical
             or radiographic examination (e.g., elevated serum tumor marker only) are NOT eligible.
             PET scan could be performed, if clinically indicated. For PET response evaluation
             PERCIST criteria will be applied.

         10. Adequate renal function defined by a serum creatinine <1.5xUNL (upper normal limit).

         11. Adequate liver function test defined by SGOT & SGPT <3xUNL (5xUNL in case of liver
             metastases), and bilirubin level <1.5xUNL

         12. Adequate bone marrow function defined by platelets >100,000/mm3, hemoglobin >10 g/dL,
             and neutrophils >1,000/mm3

         13. For female of child-bearing potential and for all women < 1 years after the onset of
             menopause: a negative pregnancy test <72 hours before starting study treatment is
             required. If sexually active, female of childbearing potential must use "highly
             effective" methods of contraception for the study duration. Contraception should
             continue after the last treatment for 3 months or for longer periods according to what
             reported in the Appendix 1 of the Protocol

         14. For male of reproductive potential: any sexually active male patient must use a condom
             while on study treatment. Contraception should continue after the last treatment for 3
             months or for longer periods according to what reported in the Appendix 1 of the
             Protocol.

        Exclusion Criteria:

          1. Patients who have only bone and/or brain metastases

          2. Patients treated with more than 2 lines for breast cancer, gastro-intestinal, non
             small cell lung cancer and other cancer

          3. Patients whose brain metastases have not been monitored for >2 months

          4. Patients with well-established actionable targets for which approved and marketed
             targeted drugs are available (i.e. lung cancer with EGFR mutation, or ALK
             translocation, B-RAF mutant melanoma, GIST with KIT mutations or breast cancer with
             HER2 amplification)

          5. Patient participating in another clinical trial with an experimental drug

          6. Anticoagulation with anti-vitamin K (Low Molecular Weight Heparin [LMWH] is allowed)

          7. Patients with other concurrent severe and/or uncontrolled medical disease which could
             compromise participation in the study, including uncontrolled diabetes, cardiac
             disease, uncontrolled hypertension, congestive cardiac failure, ventricular
             arrhythmias, active ischemic heart disease, myocardial infarction within one year,
             chronic liver or renal disease, active gastrointestinal tract ulceration, severely
             impaired lung function

          8. Pregnant and/or breastfeeding women

          9. Patients with any psychological, familial, sociological or geographical condition
             potentially hampering compliance with the study protocol and follow-up schedule

         10. HIV, HBV, or HCV infection as per specific test performed at the screening visit or
             known as per Medical History

         11. Patients with documented contraindication to any of the IMPs that will be used for the
             study, as reported in the respective SmPcs/IBs and in Appendix 2

         12. Patients treated with the following drugs, because of the risk of immunosuppression:
             Chronic or high-dose oral corticosteroid therapy, TNF-inhibitors and Anti-T cell
             antibodies
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:OVERALL RESPONSE RATE (ORR)
Time Frame:42 months
Safety Issue:
Description:Evaluation of the ORR of the Treatment at choice of physicians, according to Standard of Care (SoC) or of the Tailored Treatment (TT). The ORR will be constructed according to the specific design of the study, therefore including also the Rescue Therapy Phase data. This means that the ORR will take into account 3 evaluations: on the original final population ( i.e 384 patients divided into the 4 groups of type of cancer) on the TT patients, which will include the original randomized TT patients and the patients switched from the standard of care therapy (SoC therapy) to the TT Therapy, this latter within the Rescue Therapy Phase (patients switching upon the first documented progression) on the population composed by the original TT patients, the original SoC patients and the switched TT patients. This means that the total population analyzed will include the original 384 population data (as per randomization) and the additional switched TT patients.

Secondary Outcome Measures

Measure:Progression Free Survival (PFS) of SoC vs TT
Time Frame:42 months
Safety Issue:
Description:
Measure:Time to Treatment Failure (TTF) of SoC vs TT
Time Frame:42 months
Safety Issue:
Description:
Measure:Time to Next Treatment (TTNT) of SoC vs TT
Time Frame:42 months
Safety Issue:
Description:
Measure:Concordance between molecular profile on tumor tissue and ctDNA
Time Frame:42 months
Safety Issue:
Description:Will be evaluated the concordance between Foundation One results on tumor tissue and blood sample. Overlapping mutational results will be considered as "concordant" otherwise will be considered as "discordant". Both qualitative and quantitative differences in mutational status will be considered.
Measure:QoLs included in the two arms of the study of SoC vs TT
Time Frame:42 months
Safety Issue:
Description:The QoL score will be measured in the two arms of the study (SoC and TT), using the EORTC QLQ-C30, a validated questionnaire designed to assess different aspects of health and quality of life for cancer patients. Data from the two Quality of Life (QoL) questionnaires will be descriptively analyzed.
Measure:The safety profile between the two treatment arms of SoC vs TT
Time Frame:42 months
Safety Issue:
Description:Percentage of Participants with Adverse Events (AEs) or Serious AEs (SAEs).
Measure:Overall survival (OS)
Time Frame:42 months
Safety Issue:
Description:● Overall survival (OS) is defined as the time from randomization to death from any cause. Data for patients with no record of death will be censored at the last date they were known to be alive. The analysis of OS will follow the same methodology as the primary endpoint.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Fondazione per la Medicina Personalizzata

Last Updated

November 9, 2020