<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04410653</url>
  </required_header>
  <id_info>
    <org_study_id>NCT/DKTK PMO-1604</org_study_id>
    <nct_id>NCT04410653</nct_id>
  </id_info>
  <brief_title>Afatinib in Advanced NRG1-Rearranged Malignancies</brief_title>
  <official_title>Afatinib in Advanced NRG1-Rearranged Malignancies: the NCT/DKTK PMO-1604 Phase-II Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>German Cancer Research Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>German Consortium for Translational Cancer Research</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>German Cancer Research Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Whole-genome and transcriptome sequencing of patients with advanced solid tumors enrolled in&#xD;
      the NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program&#xD;
      revealed recurrent NRG1 fusions in a substantial proportion of patients with KRAS wild-type&#xD;
      (KRASwt) pancreatic adenocarcinoma (PDAC) and a case of signet-ring cell carcinoma of the&#xD;
      appendix. NRG1 rearrangements drive tumor development through ERBB receptor-mediated&#xD;
      signaling, as evidenced by objective response to ERBB inhibition in two cases of&#xD;
      NRG1-rearranged PDAC in the MASTER cohort. Recently, NRG1 fusions have also been identified&#xD;
      as a therapeutic target in a substantial number of the invasive mucinous subtype of lung&#xD;
      adenocarcinoma (IMA) as well as in cholangiocellular carcinoma and, at low incidence, other&#xD;
      tumor entities, suggesting oncogenic properties across a broader spectrum of malignancies.&#xD;
&#xD;
      Within this phase II clinical trial, the investigators aim to investigate the efficacy of the&#xD;
      pan-ERBB inhibitor afatinib in advanced-stage NRG1-rearranged malignancies across all tumor&#xD;
      entities following progression on standard therapy. Due to the enrichment of&#xD;
      NRG1-rearrangements observed in KRASwt PDAC and IMA, two separate study arms will focus on&#xD;
      these tumor entities while a third arm will allow inclusion of patients with any other NRG1&#xD;
      rearranged malignancy. Recruitment of adequate patient numbers in this well-defined molecular&#xD;
      subgroup will be achieved by a multicenter approach including all DKTK partner sites and&#xD;
      on-site pre-screening of PDAC for KRAS mutational status. Eligible patients will be&#xD;
      identified by in-depth molecular characterization of tumors within the NCT/DKTK MASTER&#xD;
      program or identification of a NRG1-rearranged tumor by another method for fusion detection&#xD;
      (e.g. gene fusion panel).&#xD;
&#xD;
      Patients with NRG1-rearranged tumors fulfilling eligibility criteria will be offered to&#xD;
      participate in the trial and receive afatinib monotherapy until tumor progression or&#xD;
      discontinuation for other reasons. To assess mechanisms of secondary resistance and to&#xD;
      investigate the clinical impact of liquid biopsies in this setting, blood samples for exome&#xD;
      sequencing will be taken prior to initiation of the study treatment as well as at the time of&#xD;
      progression.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">July 31, 2022</start_date>
  <completion_date type="Anticipated">December 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Disease Control Rate</measure>
    <time_frame>6 months</time_frame>
    <description>Primary objective of the study is to assess clinical activity of afatinib in adult patients with (locally) advanced or recurrent solid tumors harboring NRG1-rearrangments. Clinical efficacy is determined by disease control rate (DCR) including CR, PR, and SD according to RECIST v1.1 criteria.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>To assess progression-free survival (PFS) of afatinib in adult patients with advanced solid tumors harboring NRG1-rearrangments.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>through study completion, an average of 1 year</time_frame>
    <description>To assess OS (overall survival) of afatinib in adult patients with advanced solid tumors harboring NRG1-rearrangments.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and Tolerability: Toxic effects are graded according to the National Cancer Institute Common Toxicity Criteria (CTCAE) version 5.0</measure>
    <time_frame>6 months</time_frame>
    <description>This endpoint includes all AEs, their severity, SAEs, the relation of AEs to the study treatment, dose modifications for toxicity and discontinuation of study treatment during the trial phase. Toxic effects are graded according to the National Cancer Institute Common Toxicity Criteria (CTCAE) version 5.0.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Patient reported Outcomes</measure>
    <time_frame>6 months</time_frame>
    <description>Patient Reported Outcomes including quality of life (QLQ) of patients treated with afatinib.&#xD;
Patient-Reported Outcomes (PROs) including health-related quality of life (QoL) are calculated as the new European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Summary Score recommended by the EORTC Quality of Life Group. In addition, the EORTC QLQ function and symptom scores will be calculated according to the actual EORTC Scoring Manual.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Metastatic and Locally Advanced NRG1-rearranged Malignancies</condition>
  <arm_group>
    <arm_group_label>Arm 1 (KRASwt PDAC)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 2 (IMA)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm 3 (other)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Afatinib 40 MG</intervention_name>
    <description>single oral dose of afatinib each day starting at a dose of 40 mg on day 1, continuously, until the development of progressive disease or unacceptable adverse events</description>
    <arm_group_label>Arm 1 (KRASwt PDAC)</arm_group_label>
    <arm_group_label>Arm 2 (IMA)</arm_group_label>
    <arm_group_label>Arm 3 (other)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provision of a written informed consent&#xD;
&#xD;
          2. Patient is able to understand and comply with the protocol for the duration of the&#xD;
             study including undergoing treatment and scheduled visits and examinations&#xD;
&#xD;
          3. Progressive metastatic or locally advanced NRG1-Rearranged Malignancy as determined by&#xD;
             investigator&#xD;
&#xD;
          4. At least one measurable lesion that can be accurately assessed at baseline by CT or&#xD;
             MRI and is suitable for repeated assessment&#xD;
&#xD;
          5. Prior administration of at least one standard treatment for primary and/or relapsed&#xD;
             malignancy according to current guidelines&#xD;
&#xD;
          6. Eastern Cooperative Oncology Group Performance Status ≤ 1&#xD;
&#xD;
          7. Male or female patient aged ≥ 18, no upper age limit&#xD;
&#xD;
          8. Postmenopausal or evidence of non-childbearing status. For women of childbearing&#xD;
             potential: negative urine pregnancy test at baseline and highly effective forms of&#xD;
             contraception in place thereafter as well as confirmed negative urine pregnancy test&#xD;
             prior to treatment on day 1 of every cycle and at end of treatment period.&#xD;
&#xD;
             Evidence of childbearing potential is defined as:&#xD;
&#xD;
             o Fertile, following menarche and until becoming post-menopausal unless permanently&#xD;
             sterile&#xD;
&#xD;
             Postmenopausal or evidence of non-childbearing status is defined as:&#xD;
&#xD;
               1. Amenorrheic for 1 year or more without an alternative medical cause following&#xD;
                  cessation of exogenous hormonal treatments PLUS Follicle stimulating hormone&#xD;
                  (FSH) levels in the postmenopausal range in women not using hormonal&#xD;
                  contraception or hormonal replacement therapy&#xD;
&#xD;
               2. Surgical sterilisation (bilateral oophorectomy, hysterectomy or bilateral&#xD;
                  salpingectomy)&#xD;
&#xD;
          9. Female patients of child bearing potential and male patients with partners of child&#xD;
             bearing potential, who are sexually active, must agree to the use of two highly&#xD;
             effective forms of contraception. This should be started from the signing of the&#xD;
             informed consent and continue throughout period of taking study treatment and for 1&#xD;
             month (female patients) / 3 months (male patients) after last dose of study drug.&#xD;
&#xD;
         10. Identification of NRG1 rearrangements within NCT/DKTK MASTER (Heidelberg Ethics&#xD;
             Committee Reference No.: S-206/2011) or identification of a NRG1 fusion by another&#xD;
             method for fusion detection (e.g. gene fusion panel)&#xD;
&#xD;
         11. Adequate bone marrow, renal, and hepatic function defined by laboratory tests within&#xD;
             14 days prior to study treatment:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) ≥1500 / mm3. (ANC &gt;1000/mm3 may be considered in&#xD;
                  special circumstances such as benign cyclical neutropenia as judged by the&#xD;
                  investigator and in discussion with the sponsor).&#xD;
&#xD;
               2. Platelet count ≥75,000 / mm3.&#xD;
&#xD;
               3. Estimated creatinine clearance &gt; 45ml / min (according to&#xD;
                  Crockroft-Gault-formula).&#xD;
&#xD;
               4. Total Bilirubin ≤ 1.5 times upper limit of normal (Patients with Gilbert's&#xD;
                  syndrome total bilirubin must be ≤4 times institutional upper limit of normal&#xD;
                  (ULN)).&#xD;
&#xD;
               5. Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ three&#xD;
                  times the ULN (if related to liver metastases ≤ five times ULN).&#xD;
&#xD;
         12. Left ventricular function with resting ejection fraction ≥ 50% or above the LLN.&#xD;
&#xD;
         13. Recovered from any previous therapy related toxicity to ≤Grade 1 at study entry&#xD;
             (except for stable sensory neuropathy ≤Grade 2 and alopecia)&#xD;
&#xD;
         14. Written informed consent that is consistent with ICH-GCP guidelines&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Other malignancy within the last 5 years except: adequately treated non-melanoma skin&#xD;
             cancer, curatively treated in situ cancer of the cervix, ductal carcinoma in situ&#xD;
             (DCIS), Stage 1, grade 1 endometrial carcinoma, or other solid tumours including&#xD;
             lymphomas (without bone marrow involvement) curatively treated with no evidence of&#xD;
             disease for ≥5 years&#xD;
&#xD;
          2. Concurrent or previous treatment within 4 weeks in another interventional clinical&#xD;
             trial with an investigational anticancer therapy&#xD;
&#xD;
          3. Prior treatment with afatinib&#xD;
&#xD;
          4. Hormonal treatment within 2 weeks prior to start of study treatment (continued use of&#xD;
             anti-androgens and/or gonadorelin analogues for treatment of prostate cancer&#xD;
             permitted)&#xD;
&#xD;
          5. Radiotherapy within 4 weeks prior to randomization , except as follows:&#xD;
&#xD;
             i.) Palliative radiation to target organs may be allowed up to 2 weeks prior to&#xD;
             randomisation, and&#xD;
&#xD;
             ii.) Single dose palliative treatment for symptomatic metastasis outside above&#xD;
             allowance to be discussed with coordinating investigator/ scientific investigator&#xD;
             prior to enrolling.&#xD;
&#xD;
          6. Major surgery within 4 weeks before starting study treatment or scheduled for surgery&#xD;
             during the projected course of the study&#xD;
&#xD;
          7. Known hypersensitivity to afatinib or the excipients of any of the trial drugs&#xD;
&#xD;
          8. History or presence of clinically relevant cardiovascular abnormalities such as&#xD;
             uncontrolled hypertension, congestive heart failure NYHA classification of ≥ 3,&#xD;
             unstable angina or poorly controlled arrhythmia as determined by the investigator.&#xD;
             Myocardial infarction within 6 months prior to randomisation.&#xD;
&#xD;
          9. Women of child-bearing potential (WOCBP) and men who are able to father a child,&#xD;
             unwilling to be abstinent or use highly effective methods of birth control that result&#xD;
             in a low failure rate of less than 1% per year when used consistently and correctly&#xD;
             prior to study entry, for the duration of study participation and for 1 month (female&#xD;
             patients)/ 3 months (male patients) after last dose of study drug (after EOT).&#xD;
&#xD;
         10. Women who are pregnant, nursing, or who plan to become pregnant while in the trial&#xD;
&#xD;
         11. Any history of or concomitant condition that, in the opinion of the Investigator,&#xD;
             would compromise the patient's ability to comply with the study or interfere with the&#xD;
             evaluation of the efficacy and safety of the test drug&#xD;
&#xD;
         12. Known pre-existing interstitial lung disease (ILD)&#xD;
&#xD;
         13. Any history or presence of poorly controlled gastrointestinal disorders that could&#xD;
             affect the absorption of the study drug (e.g. Crohn's disease, ulcerative colitis,&#xD;
             chronic diarrhoea, malabsorption)&#xD;
&#xD;
         14. Leptomeningeal carcinomatosis&#xD;
&#xD;
         15. Patients with brain or subdural metastases are not eligible, unless they have&#xD;
             completed local therapy and have discontinued the use of corticosteroids,&#xD;
             anti-convulsants or have been on stable dose of corticosteroids for at least 4 weeks&#xD;
             before starting study treatment. Any symptoms attributed to brain metastases must be&#xD;
             stable for at least 4 weeks before starting study treatment.&#xD;
&#xD;
         16. Persistent toxicity (≥Grade 2 according to Common Terminology Criteria for Adverse&#xD;
             Events [CTCAE] version 5.0) caused by previous cancer therapy, excluding alopecia&#xD;
&#xD;
         17. Clinical signs of active infection (&gt;Grade 2 according to CTCAE version 5.0)&#xD;
&#xD;
         18. History of HIV infection and immunocompromised patients&#xD;
&#xD;
         19. Viral active or chronic hepatitis (HBV or HCV)&#xD;
&#xD;
         20. Dementia or significant impairment of cognitive state&#xD;
&#xD;
         21. Epilepsy requiring pharmacologic treatment&#xD;
&#xD;
         22. Heart failure NYHA III/IV&#xD;
&#xD;
         23. Severe obstructive or restrictive ventilation disorder&#xD;
&#xD;
         24. Concomitant use of P-gp- inhibitors (e.g. ritonavir, ciclosporin A, ketoconazole,&#xD;
             itraconazole, erythromycin, verapamil, quinidine, tacrolimus, nelfinavir, saquinavir,&#xD;
             amiodarone) and BCRP inhibitors (e.g. rosuvastatin, sulfasalazine). The required&#xD;
             washout period prior to starting afatinib is at least five half-lifes.&#xD;
&#xD;
         25. Concomitant use of P-gp-inducers (e.g. rifampicin, carbamazepine, phenytoin,&#xD;
             phenobarbital, St. John's wort) The required washout period prior to starting afatinib&#xD;
             is at least five half-lifes (e.g. 5 weeks for phenobarbital).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christoph Heining, Dr.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Center of Tumor Diseases (NCT) Dresden</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>NCT Dresden</name>
      <address>
        <city>Dresden</city>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NCT Heidelberg</name>
      <address>
        <city>Heidelberg</city>
        <zip>69120</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>May 15, 2020</study_first_submitted>
  <study_first_submitted_qc>May 29, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 1, 2020</study_first_posted>
  <last_update_submitted>June 15, 2023</last_update_submitted>
  <last_update_submitted_qc>June 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Afatinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04410653
org study id: NCT/DKTK PMO-1604
nct id: NCT04410653
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Whole-genome and transcriptome sequencing of patients with advanced solid tumors enrolled in
      the NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research) program
      revealed recurrent NRG1 fusions in a substantial proportion of patients with KRAS wild-type
      (KRASwt) pancreatic adenocarcinoma (PDAC) and a case of signet-ring cell carcinoma of the
      appendix. NRG1 rearrangements drive tumor development through ERBB receptor-mediated
      signaling, as evidenced by objective response to ERBB inhibition in two cases of
      NRG1-rearranged PDAC in the MASTER cohort. Recently, NRG1 fusions have also been identified
      as a therapeutic target in a substantial number of the invasive mucinous subtype of lung
      adenocarcinoma (IMA) as well as in cholangiocellular carcinoma and, at low incidence, other
      tumor entities, suggesting oncogenic properties across a broader spectrum of malignancies.

      Within this phase II clinical trial, the investigators aim to investigate the efficacy of the
      pan-ERBB inhibitor afatinib in advanced-stage NRG1-rearranged malignancies across all tumor
      entities following progression on standard therapy. Due to the enrichment of
      NRG1-rearrangements observed in KRASwt PDAC and IMA, two separate study arms will focus on
      these tumor entities while a third arm will allow inclusion of patients with any other NRG1
      rearranged malignancy. Recruitment of adequate patient numbers in this well-defined molecular
      subgroup will be achieved by a multicenter approach including all DKTK partner sites and
      on-site pre-screening of PDAC for KRAS mutational status. Eligible patients will be
      identified by in-depth molecular characterization of tumors within the NCT/DKTK MASTER
      program or identification of a NRG1-rearranged tumor by another method for fusion detection
      (e.g. gene fusion panel).

      Patients with NRG1-rearranged tumors fulfilling eligibility criteria will be offered to
      participate in the trial and receive afatinib monotherapy until tumor progression or
      discontinuation for other reasons. To assess mechanisms of secondary resistance and to
      investigate the clinical impact of liquid biopsies in this setting, blood samples for exome
      sequencing will be taken prior to initiation of the study treatment as well as at the time of
      progression.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Disease Control Rate
time frame: 6 months
description: Primary objective of the study is to assess clinical activity of afatinib in adult patients with (locally) advanced or recurrent solid tumors harboring NRG1-rearrangments. Clinical efficacy is determined by disease control rate (DCR) including CR, PR, and SD according to RECIST v1.1 criteria.
measure: Progression-free Survival
time frame: through study completion, an average of 1 year
description: To assess progression-free survival (PFS) of afatinib in adult patients with advanced solid tumors harboring NRG1-rearrangments.
measure: Overall survival
time frame: through study completion, an average of 1 year
description: To assess OS (overall survival) of afatinib in adult patients with advanced solid tumors harboring NRG1-rearrangments.
measure: Safety and Tolerability: Toxic effects are graded according to the National Cancer Institute Common Toxicity Criteria (CTCAE) version 5.0
time frame: 6 months
description: This endpoint includes all AEs, their severity, SAEs, the relation of AEs to the study treatment, dose modifications for toxicity and discontinuation of study treatment during the trial phase. Toxic effects are graded according to the National Cancer Institute Common Toxicity Criteria (CTCAE) version 5.0.
measure: Patient reported Outcomes
time frame: 6 months
description: Patient Reported Outcomes including quality of life (QLQ) of patients treated with afatinib.
Patient-Reported Outcomes (PROs) including health-related quality of life (QoL) are calculated as the new European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 Summary Score recommended by the EORTC Quality of Life Group. In addition, the EORTC QLQ function and symptom scores will be calculated according to the actual EORTC Scoring Manual.
arm group label: Arm 1 (KRASwt PDAC)
arm group type: Experimental
arm group label: Arm 2 (IMA)
arm group type: Experimental
arm group label: Arm 3 (other)
arm group type: Experimental
intervention type: Drug
intervention name: Afatinib 40 MG
description: single oral dose of afatinib each day starting at a dose of 40 mg on day 1, continuously, until the development of progressive disease or unacceptable adverse events
arm group label: Arm 1 (KRASwt PDAC)
arm group label: Arm 2 (IMA)
arm group label: Arm 3 (other)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Christoph Heining, Dr.
role: Principal Investigator
affiliation: National Center of Tumor Diseases (NCT) Dresden
facility: 
facility: 
country: Germany
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Afatinib
sharing ipd: Yes