<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/NCT03828799</url>
  </required_header>
  <id_info>
    <org_study_id>2018-003541-42</org_study_id>
    <nct_id>NCT03828799</nct_id>
  </id_info>
  <brief_title>Safety, Tolerability and Efficacy of Regorafenib in Combination With FOLFIRINOX in Patients With Colorectal Cancer</brief_title>
  <acronym>FOLFIRINOX-R</acronym>
  <official_title>Safety, Tolerability and Efficacy of Regorafenib in Combination With FOLFIRINOX in Patients With RAS-mutated Metastatic Colorectal Cancer: a Dose-escalation, Phase I/II Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institut du Cancer de Montpellier - Val d'Aurelle</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institut du Cancer de Montpellier - Val d'Aurelle</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>
      Safety, tolerability and efficacy of regorafenib in combination with FOLFIRINOX in patients&#xD;
      with RAS-mutated metastatic colorectal cancer: a dose-escalation, phase I/II trial&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Colorectal cancer (CRC) is a major cause of morbidity and mortality globally. More than 50%&#xD;
      of patients can be expected to develop metastatic disease, and most of these patients will&#xD;
      require palliative systemic therapy. The primary goal for patients who present with&#xD;
      technically resectable liver metastases is definitely cure, with R0 resection as the primary&#xD;
      goal. Consequently, any patient with limited liver and/or lung metastases should be&#xD;
      considered a candidate for potential secondary resection as there are no criteria that allow&#xD;
      physicians to distinguish between those patients for whom purely palliative treatment and&#xD;
      those or whom potentially curative treatment is appropriate. Although survival times are&#xD;
      slightly shorter for patients who undergo conversion therapy followed by surgery than for&#xD;
      patients with initially resectable metastatic disease, they are far better than if resection&#xD;
      is not carried out at all. First-line therapy commonly involves the doublet regimens of&#xD;
      5-fluorouracil, folinic acid, and either oxaliplatin or irinotecan. The addition of targeted&#xD;
      therapies, such as bevacizumab (a pure anti-angiogenic agent which binds circulating VEGF-A),&#xD;
      cetuximab, and panitumumab, to FOLFOX (5FU, oxaliplatin) or FOLFIRI (5FU, irinotecan) may be&#xD;
      helpful to some patients in improving tumor response and ultimately overall survival. The&#xD;
      cytotoxic triplet FOLFOXIRI (5FU, oxaliplatin, irinotecan) with or without bevacizumab may be&#xD;
      an option in selected fit and motivated patients when cytoreduction (tumour shrinkage) is&#xD;
      needed to undergo conversion therapy.&#xD;
&#xD;
      RAS mutations are found in about 50% of mCRC tumors. These mutations exclude affected&#xD;
      patients from epidermal growth factor receptor (EGFR)-directed therapy. Besides their&#xD;
      negative predictive value, RAS mutations may also carry distinct prognostic information.&#xD;
      Modest studied the prognosis by RAS status of a total of 1239 mCRC patients from five&#xD;
      randomized trials studying 2-CT. Actually, PFS and OS were significantly influenced by&#xD;
      molecular subgroups. Multivariate comparison of Progression-Free Survival (PFS) and Overall&#xD;
      Survival (OS) in patients with mutant tumors versus patients with non-mutated tumors revealed&#xD;
      a negative prognostic effect of RAS mutations. Interestingly, the negative prognostic role of&#xD;
      these mutations was consistently observed across different treatment regimens (subgroups of&#xD;
      irinotecan- and oxaliplatin-treated patients as well as in bevacizumab- and&#xD;
      non-bevacizumab-treated patients). Median PFS and OS were 10.3 vs. 9.5 months and 26.9 vs.&#xD;
      21.1 months in RAS-wildtype (and BRAF-wildtype) and RAS-mut patients, respectively. The TRIBE&#xD;
      consortium reported that a 3-CT (FOLFOXIRI) combined with bevacizumab provided a&#xD;
      significantly longer PFS (the primary end-point of the study) than did the 2-CT FOLFIRI plus&#xD;
      bevacizumab . In the subgroup of RAS- and BRAF-wild-type patients, those in the FOLFOXIRI&#xD;
      plus bevacizumab group reported a median PFS of 13.7 months (95% CI, 10.1-18.1) compared with&#xD;
      12.2 months (95%CI, 9.5-14.4) in the FOLFIRI plus bevacizumab group (HR 0.85, 95%CI&#xD;
      0.55-1.3).&#xD;
&#xD;
      Later on, the same group reported that FOLFOXIRI plus bevacizumab provided a significantly&#xD;
      longer overall survival than the FOLFIRI plus bevacizumab group (HR 0.80, 95%CI 0·65-0·98;&#xD;
      p=0·03) . Looking at survival by RAS status, Cremolini reported that median OS was 37.1&#xD;
      months (95%CI, 29.7-42.7) in the RAS- and BRAF-wild-type subgroup compared with 25.6 months&#xD;
      (95%CI, 22.4-28.6) in the RAS-mut subgroup (HR 1.49, 95%CI, 1.11-1·99). Interestingly, median&#xD;
      PFS was 13.7 months (95% CI 10.1-18.1) in the RAS-wild-type subgroup treated with FOLFOXIRI&#xD;
      plus bevacizumab, while PFS data were not given for the RAS-mut patients . However, for these&#xD;
      RAS-mut patients, it was possible to estimate the median PFS (i.e. 9.4 months) from the&#xD;
      Kaplan-Meier curve which was provided.&#xD;
&#xD;
      Regorafenib is a small-molecule inhibitor of multiple membrane-bound and intracellular&#xD;
      kinases. Beyond its well-known antiangiogenic properties, regorafenib has also less-known&#xD;
      anti-proliferative activities in human colon cancer cell lines. Interestingly, regorafenib&#xD;
      potently inhibits growth of patient-derived CRC xenografts alone and in combination with&#xD;
      irinotecan . Regorafenib is approved for refractory mCRC patients, for locally advanced,&#xD;
      unresectable or metastatic GIST patients and for HCC patients previously treated with&#xD;
      sorafenib. The recommended dose is 160 mg (40 mg × 4 tablets) orally, once daily for the&#xD;
      first 21 days of each 28-day cycle. Two phase III trials demonstrated a significant overall&#xD;
      survival benefit for regorafenib over placebo in patients with mCRC who progressed on&#xD;
      standard therapies . Two phase II trials studied the safety and efficacy profile of&#xD;
      regorafenib when combined to chemotherapy in patients with mCRC . In vitro data indicate that&#xD;
      both regorafenib and its metabolite M-2 inhibit glucuronidation mediated by UGT1A1 ( uridine&#xD;
      5'diphospho-glucuronosyl tranferase A1) and UGT1A9 (whereas M-5 only inhibits UGT1A1), hence&#xD;
      triggering potential pharmacokinetic interactions. The study from Schultheis was designed to&#xD;
      explore whether addition of regorafenib to FOLFOX or FOLFIRI could be feasible as a treatment&#xD;
      of mCRC, in terms of safety and pharmacokinetic interactions of the various drug components&#xD;
      of the regimen. Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m²&#xD;
      bolus then 2400 mg/m² over 46 h, folinic acid 400 mg/m², and either oxaliplatin 85 mg/m² or&#xD;
      irinotecan 180 mg/m².&#xD;
&#xD;
      On days 4-10, patients received regorafenib 160 mg orally once daily. Drug-related adverse&#xD;
      events resulted in dose modification, dose interruption, or permanent discontinuation of&#xD;
      study treatment in 31 (69%) patients overall (18 [72%] FOLFOX and 13 [65%] FOLFIRI).&#xD;
&#xD;
      Dose reduction or dose interruption of at least one of the chemotherapy components was&#xD;
      observed in 52% of patients treated with FOLFOX and 65% of patients receiving FOLFIRI. A dose&#xD;
      reduction of 5-fluorouracil due to AEs was necessary in 18% of administered cycles.&#xD;
      5-Fluorouracil administration was omitted in 8% of cycles. Oxaliplatin and irinotecan doses&#xD;
      were reduced in 11% and 12% and interrupted in 11% and 5% of administered cycles,&#xD;
      respectively. Actually, regorafenib had acceptable tolerability in combination with&#xD;
      chemotherapy. The most frequent grade 3-4 AEs were: neutropenia (45%), Hand-Foot Skin&#xD;
      Reaction (15%), diarrhea (10%), and hypophosphatemia (12%). Regarding pharmacokinetics, area&#xD;
      under the curve (AUC) of irinotecan was significantly higher in cycle 2 (following&#xD;
      regorafenib dosing) than in cycle 1 (before regorafenib dosing); the ratio of AUC values&#xD;
      (cycle 2:cycle 1) was 1.28 (90% confidence interval [CI] 1.06 -1.54). Cmax of irinotecan was&#xD;
      only slightly increased, and t½ (half-life) was unchanged. For SN-38 (metabolite of&#xD;
      irinotecan), AUC was significantly higher in cycle 2 than in cycle 1 (ratio 1.44, 90% CI&#xD;
      1.12-1.85), while Cmax was unchanged. In line with the known elimination pathways of platinum&#xD;
      and 5-fluorouracil, no pharmacokinetic interaction with regorafenib was seen . The study from&#xD;
      O'Neil was designed to show whether the addition of regorafenib to FOLFIRI improves PFS (over&#xD;
      a placebo-FOLFIRI arm) when given as second-line therapy for patients treated initially with&#xD;
      oxaliplatin and fluoropyrimidine-based therapy. The regorafenib/FOLFIRI schedule that was&#xD;
      used was the one proposed by Schultheis (i.e. standard FOLFIRI with irinotecan 180 mg/m² plus&#xD;
      regorafenib 160 mg daily from day 4 to 10). The study met its primary endpoint of&#xD;
      demonstrating that the addition of regorafenib to FOLFIRI prolongs PFS compared to FOLFIRI&#xD;
      alone with a HR (Hazard Ratio) of 0.72. When looking at tumor response, authors found that&#xD;
      regorafenib (combined to chemo) provided more partial responses than placebo plus chemo (35%&#xD;
      vs. 19%, p= 0.045). The combination was very tolerable, with little increase in toxicity&#xD;
      compared to the control chemotherapy regimen. Of note, regarding the top-3 reported severe&#xD;
      (gr. 3-4) AEs, neutropenia, diarrhea, and hypophosphatemia were reported in 41%, 15%, and 14%&#xD;
      of the patients, respectively (as compared to 30%, 5%, and 0% in the placebo group).&#xD;
&#xD;
      Actually, there is room to combine regorafenib with a chemo triplet such as FOLFIRINOX&#xD;
      (5-fluorouracil, irinotecan, oxaliplatin) on the following conditions: controlling patients&#xD;
      on UGT1A polymorphisms (at least UGT1A1), stepwise dose-escalation of irinotecan and&#xD;
      regorafenib, mandatory granulocyte growth-factor injections.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">May 17, 2019</start_date>
  <completion_date type="Anticipated">October 31, 2024</completion_date>
  <primary_completion_date type="Actual">December 1, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <primary_purpose>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v5.0</measure>
    <time_frame>At the end of cycle 1 to 3 (each cycle is 14 days)</time_frame>
    <description>During the first three cycles</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Aprroximately 24 months</time_frame>
    <description>From baseline of first patient until the datebase cut-off</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease control rate (DCR)</measure>
    <time_frame>Aprroximately 24 months</time_frame>
    <description>From baseline of first patient until the datebase cut-off</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR)</measure>
    <time_frame>Tumor is assessed at 8 weeks intervals</time_frame>
    <description>From baseline of first patient until the end of treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Deepness of response (DpR)</measure>
    <time_frame>Tumor is assessed at 8 weeks intervals</time_frame>
    <description>From baseline of first patient until the end of treatment lesions at the nadir, in the absence of new lesions or progression of non-target lesions, as compared to baseline</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to recurrence under maintenance</measure>
    <time_frame>Approximately 10 months</time_frame>
    <description>From baseline of first patient until the progression of disease</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Aprroximately 24 months</time_frame>
    <description>From baseline of first patient until the datebase cut-off</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resection (R) rates</measure>
    <time_frame>Approximately at 6 months</time_frame>
    <description>Through the treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination of circulating free DNA concentration</measure>
    <time_frame>Baseline, 8 weeks, 16 weeks etc. through the end of treatment</time_frame>
    <description>From baseline of first patient until the end of treatment</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Metastatic Colorectal Cancer</condition>
  <arm_group>
    <arm_group_label>Folfirinox-R</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Folfirinox + regorafenib</description>
  </arm_group>
  <intervention>
    <intervention_type>Combination Product</intervention_type>
    <intervention_name>Folfirinox + regorrafenib</intervention_name>
    <description>folfirinox : from day 1 to day 3 regorafenib : day 4 to day 10 a cycle during 14 days</description>
    <arm_group_label>Folfirinox-R</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Written informed consent for full study.&#xD;
&#xD;
          2. Documentation of tumor RAS mutation, wild-type homozygous, heterozygous status of&#xD;
             UGT1A1 gene. The status of UGT1A1 gene will be performed by the laboratory chosen by&#xD;
             the investigator&#xD;
&#xD;
          3. Serum uracile &lt; 16 ng/ml&#xD;
&#xD;
          4. Measurable disease, defined as at least one unidimensional measurable lesion on a CT&#xD;
             scan, according to RECIST version 1.1.&#xD;
&#xD;
          5. ECOG performance status ≤1.&#xD;
&#xD;
          6. Life expectancy of at least 3 months.&#xD;
&#xD;
          7. Adequate bone marrow, renal and liver functions as evidenced by the following&#xD;
             laboratory requirements within 7 days prior to study treatment initiation: Absolute&#xD;
             neutrophil count (ANC) ≥ 1,500/ mm3 without biologic response modifiers such as&#xD;
             granulocyte colony-stimulating factor (G-CSF), within 21 days before the start of&#xD;
             study treatment, Platelet count ≥ 100 000/mm3 , without platelet transfusion within 21&#xD;
             days before the start of study treatment ,Hemoglobin (Hb) ≥ 9 g/dL, without blood&#xD;
             transfusion or erythropoietin, within 21 days before the start of study treatment,&#xD;
             Serum creatinine ≤ 1.5 x upper limit of normal(ULN) Serum calcium ≥ LLN and ≤ 1.2 x&#xD;
             UNL ; Serum magnesium ≥ LLN and ≤ 1.2 x UNL ; Kalemia ≥ LLN, Glomerular filtration&#xD;
             rate as assessed by the estimated glomerular filtration rate (eGFR) ≥ 50 mL/min per&#xD;
             1.73 m2 calculated by the Modification of Diet in Renal Disease (MDRD) abbreviated&#xD;
             formula, Total bilirubin ≤ 1.5 x ULN, Alanine aminotransferase (ALT) and aspartate&#xD;
             aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement of&#xD;
             their cancer), Alkaline phosphatase (ALP) ≤ 2.5 x ULN (≤ 5.0 x ULN for patients with&#xD;
             liver involvement for their cancer and/or bone metastases).&#xD;
&#xD;
          8. Lipase ≤ 1.5 x ULN.&#xD;
&#xD;
          9. Adequate coagulation, as assessed by the following laboratory test results:&#xD;
&#xD;
             International normalized ratio (INR) ≤ 1.5 or prothrombin time (PT) ≤ 1.5 x ULN,&#xD;
             Partial thromboplastin time (PTT) or activated PTT (aPTT) ≤ 1.5 x ULN, Note: Patients&#xD;
             on stable dose (dose has not been changed in at least 28 days) of anticoagulation&#xD;
             therapy will be allowed to participate if they have no sign of bleeding or clotting&#xD;
             and INR / PT and PTT / aPTT test results are compatible with the acceptable&#xD;
             benefit-risk ratio at the investigator's discretion. In such case, limits as noted&#xD;
             would not apply.&#xD;
&#xD;
         10. For women of reproductive potential, negative serum beta human chorionic gonadotropin&#xD;
             (β-HCG) pregnancy test obtained within 7 days before the start of study treatment.&#xD;
             Women not of reproductive potential are female patients who are postmenopausal or&#xD;
             permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral salpingectomy).&#xD;
&#xD;
         11. For women of childbearing potential and men, agreement to use an adequate&#xD;
             contraception for the duration of study participation and up to 4 months following&#xD;
             completion of therapy for women and 6 months for male patients. Females of&#xD;
             childbearing potential who are sexually active with a non-sterilized male partner must&#xD;
             use 2 methods of effective contraception. The investigator or a designated associate&#xD;
             is requested to advise the patient on how to achieve an adequate birth control.&#xD;
&#xD;
             Adequate contraception is defined in the study as any medically recommended method (or&#xD;
             combination of methods) as per standard of care.&#xD;
&#xD;
         12. Willingness and ability to comply with scheduled visits, treatment plan, laboratory&#xD;
             tests and other study procedures.&#xD;
&#xD;
         13. Affiliation to the Social Security System.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Previous or concurrent cancer that is distinct in primary site or histology from&#xD;
             colorectal cancer within 5 years prior to study inclusion, except for curatively&#xD;
             treated cervical cancer in situ, non-melanoma skin cancer and superficial bladder&#xD;
             tumors [Ta (noninvasive tumor), Tis (carcinoma in situ) and T1 (lamina propria&#xD;
             invasion)].&#xD;
&#xD;
          2. Discovery of metastases within 6 months after the termination of adjuvant&#xD;
             chemotherapy.&#xD;
&#xD;
          3. Previous treatment for metastatic disease. Radiotherapy within 28 days prior to first&#xD;
             dose of treatment.&#xD;
&#xD;
          4. Active cardiac disease including any of the following:&#xD;
&#xD;
             Congestive heart failure New York Heart Association (NYHA) class 2, Unstable angina&#xD;
             (angina symptoms at rest), new-onset angina (begun within the last 3 months),&#xD;
             Myocardial infarction less than 6 months before first dose of treatment, Cardiac&#xD;
             arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are&#xD;
             permitted).&#xD;
&#xD;
          5. ECG with a QT/QTc interval higher than 450 ms for men and higher than 470 ms for women&#xD;
             Uncontrolled hypertension.&#xD;
&#xD;
          6. Uncontrolled hypertension. (Systolic blood pressure &gt; 140 mmHg or diastolic pressure &gt;&#xD;
             90 mmHg despite optimal medical management).&#xD;
&#xD;
          7. Arterial or venous thrombotic or embolic events such as cerebrovascular accident&#xD;
             (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism&#xD;
             within 6 months before start of treatment.&#xD;
&#xD;
        8;Persistent proteinuria of National Cancer Institute Common Terminology Criteria for&#xD;
        Adverse Events (NCI-CTCAE V5) grade 3 (i.e. urinary protein ≥ 3.5 g/24 hrs) 9;Peripheral&#xD;
        neuropathy &gt; grade1 (NCI-CTCAE v5). 10.Major surgical procedure, open biopsy, or&#xD;
        significant traumatic injury within 28 days prior to first dose of Treatment.&#xD;
&#xD;
        11.Ongoing infection &gt;grade 2 (NCI-CTCAE v5). 12.Known history of human immunodeficiency&#xD;
        virus (HIV) infection. 13.Chronic hepatitis B or C infection (if hepatitis status cannot be&#xD;
        obtained from medical records, re-testing is required).&#xD;
&#xD;
        14.Seizure disorder requiring medication. 15.Symptomatic metastatic brain or meningeal&#xD;
        tumors. 16.Evidence or history of any bleeding diathesis, irrespective of severity. Any&#xD;
        hemorrhage or bleeding event ≥ grade 3 (NCI-CTCAE v5) within 4 weeks prior to the start of&#xD;
        study medication.&#xD;
&#xD;
        17.History of organ allograft. 18.Non-healing wound, ulcer, or bone fracture.&#xD;
        19.Dehydration Grade 1 NCI-CTCAE v5). 20.Substance abuse, medical, psychological, or social&#xD;
        conditions that may interfere with the patient's participation in the study or evaluation&#xD;
        of the study results.&#xD;
&#xD;
        21.Known hypersensitivity to any of the study drugs, study drug classes, or any constituent&#xD;
        of the products.&#xD;
&#xD;
        22.Interstitial lung disease with ongoing signs and symptoms. 23.Concomitant intake of St.&#xD;
        John's wort. 24.Live attenuated vaccines are prohibited 10 days before the treatment,&#xD;
        during the treatment and 3 months after the termination of treatment 25.History of&#xD;
        gastrointestinal fistula or perforation 26.Inability to swallow oral medication. 27.Any&#xD;
        malabsorption condition. 28.Pregnant or breast-feeding subjects. 29.Any condition that, in&#xD;
        the opinion of the investigator, would interfere with the evaluation of study treatment or&#xD;
        interpretation of patient safety or study results.&#xD;
&#xD;
        30.Participation in another clinical study with an investigational product during the last&#xD;
        30 days before inclusion. 31.Patients who might be interconnected with or dependent on the&#xD;
        sponsor site or the investigator.&#xD;
&#xD;
        32.Legal incapacity or limited legal capacity.&#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>Antoine Adenis, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Institut régional du cancer de Montpellier</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centre Antoine Lacassagne</name>
      <address>
        <city>Nice</city>
        <state>Alpes-Maritimes</state>
        <zip>06189</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Georges-François Leclerc</name>
      <address>
        <city>Dijon</city>
        <state>Côte d'Or</state>
        <zip>21079</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Cario - HPCA</name>
      <address>
        <city>Plérin</city>
        <state>Finistère</state>
        <zip>22190</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut du Cancer de Montpellier - Val d'Aurelle</name>
      <address>
        <city>Montpellier</city>
        <zip>34298</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
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  <reference>
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  <reference>
    <citation>Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. doi: 10.1056/NEJMoa1403108.</citation>
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  <verification_date>July 2023</verification_date>
  <study_first_submitted>January 24, 2019</study_first_submitted>
  <study_first_submitted_qc>February 1, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 4, 2019</study_first_posted>
  <last_update_submitted>July 3, 2023</last_update_submitted>
  <last_update_submitted_qc>July 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Metastatic colorectal cancer</keyword>
  <keyword>Colorectal cancer</keyword>
  <keyword>Folfirinox</keyword>
  <keyword>Regorafenib</keyword>
  <keyword>RAS mutated</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Folfirinox</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03828799
org study id: 2018-003541-42
nct id: NCT03828799
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Safety, tolerability and efficacy of regorafenib in combination with FOLFIRINOX in patients
      with RAS-mutated metastatic colorectal cancer: a dose-escalation, phase I/II trial
Colorectal cancer (CRC) is a major cause of morbidity and mortality globally. More than 50%
      of patients can be expected to develop metastatic disease, and most of these patients will
      require palliative systemic therapy. The primary goal for patients who present with
      technically resectable liver metastases is definitely cure, with R0 resection as the primary
      goal. Consequently, any patient with limited liver and/or lung metastases should be
      considered a candidate for potential secondary resection as there are no criteria that allow
      physicians to distinguish between those patients for whom purely palliative treatment and
      those or whom potentially curative treatment is appropriate. Although survival times are
      slightly shorter for patients who undergo conversion therapy followed by surgery than for
      patients with initially resectable metastatic disease, they are far better than if resection
      is not carried out at all. First-line therapy commonly involves the doublet regimens of
      5-fluorouracil, folinic acid, and either oxaliplatin or irinotecan. The addition of targeted
      therapies, such as bevacizumab (a pure anti-angiogenic agent which binds circulating VEGF-A),
      cetuximab, and panitumumab, to FOLFOX (5FU, oxaliplatin) or FOLFIRI (5FU, irinotecan) may be
      helpful to some patients in improving tumor response and ultimately overall survival. The
      cytotoxic triplet FOLFOXIRI (5FU, oxaliplatin, irinotecan) with or without bevacizumab may be
      an option in selected fit and motivated patients when cytoreduction (tumour shrinkage) is
      needed to undergo conversion therapy.

      RAS mutations are found in about 50% of mCRC tumors. These mutations exclude affected
      patients from epidermal growth factor receptor (EGFR)-directed therapy. Besides their
      negative predictive value, RAS mutations may also carry distinct prognostic information.
      Modest studied the prognosis by RAS status of a total of 1239 mCRC patients from five
      randomized trials studying 2-CT. Actually, PFS and OS were significantly influenced by
      molecular subgroups. Multivariate comparison of Progression-Free Survival (PFS) and Overall
      Survival (OS) in patients with mutant tumors versus patients with non-mutated tumors revealed
      a negative prognostic effect of RAS mutations. Interestingly, the negative prognostic role of
      these mutations was consistently observed across different treatment regimens (subgroups of
      irinotecan- and oxaliplatin-treated patients as well as in bevacizumab- and
      non-bevacizumab-treated patients). Median PFS and OS were 10.3 vs. 9.5 months and 26.9 vs.
      21.1 months in RAS-wildtype (and BRAF-wildtype) and RAS-mut patients, respectively. The TRIBE
      consortium reported that a 3-CT (FOLFOXIRI) combined with bevacizumab provided a
      significantly longer PFS (the primary end-point of the study) than did the 2-CT FOLFIRI plus
      bevacizumab . In the subgroup of RAS- and BRAF-wild-type patients, those in the FOLFOXIRI
      plus bevacizumab group reported a median PFS of 13.7 months (95% CI, 10.1-18.1) compared with
      12.2 months (95%CI, 9.5-14.4) in the FOLFIRI plus bevacizumab group (HR 0.85, 95%CI
      0.55-1.3).

      Later on, the same group reported that FOLFOXIRI plus bevacizumab provided a significantly
      longer overall survival than the FOLFIRI plus bevacizumab group (HR 0.80, 95%CI 0·65-0·98;
      p=0·03) . Looking at survival by RAS status, Cremolini reported that median OS was 37.1
      months (95%CI, 29.7-42.7) in the RAS- and BRAF-wild-type subgroup compared with 25.6 months
      (95%CI, 22.4-28.6) in the RAS-mut subgroup (HR 1.49, 95%CI, 1.11-1·99). Interestingly, median
      PFS was 13.7 months (95% CI 10.1-18.1) in the RAS-wild-type subgroup treated with FOLFOXIRI
      plus bevacizumab, while PFS data were not given for the RAS-mut patients . However, for these
      RAS-mut patients, it was possible to estimate the median PFS (i.e. 9.4 months) from the
      Kaplan-Meier curve which was provided.

      Regorafenib is a small-molecule inhibitor of multiple membrane-bound and intracellular
      kinases. Beyond its well-known antiangiogenic properties, regorafenib has also less-known
      anti-proliferative activities in human colon cancer cell lines. Interestingly, regorafenib
      potently inhibits growth of patient-derived CRC xenografts alone and in combination with
      irinotecan . Regorafenib is approved for refractory mCRC patients, for locally advanced,
      unresectable or metastatic GIST patients and for HCC patients previously treated with
      sorafenib. The recommended dose is 160 mg (40 mg × 4 tablets) orally, once daily for the
      first 21 days of each 28-day cycle. Two phase III trials demonstrated a significant overall
      survival benefit for regorafenib over placebo in patients with mCRC who progressed on
      standard therapies . Two phase II trials studied the safety and efficacy profile of
      regorafenib when combined to chemotherapy in patients with mCRC . In vitro data indicate that
      both regorafenib and its metabolite M-2 inhibit glucuronidation mediated by UGT1A1 ( uridine
      5'diphospho-glucuronosyl tranferase A1) and UGT1A9 (whereas M-5 only inhibits UGT1A1), hence
      triggering potential pharmacokinetic interactions. The study from Schultheis was designed to
      explore whether addition of regorafenib to FOLFOX or FOLFIRI could be feasible as a treatment
      of mCRC, in terms of safety and pharmacokinetic interactions of the various drug components
      of the regimen. Forty-five patients were treated every 2 weeks with 5-fluorouracil 400 mg/m²
      bolus then 2400 mg/m² over 46 h, folinic acid 400 mg/m², and either oxaliplatin 85 mg/m² or
      irinotecan 180 mg/m².

      On days 4-10, patients received regorafenib 160 mg orally once daily. Drug-related adverse
      events resulted in dose modification, dose interruption, or permanent discontinuation of
      study treatment in 31 (69%) patients overall (18 [72%] FOLFOX and 13 [65%] FOLFIRI).

      Dose reduction or dose interruption of at least one of the chemotherapy components was
      observed in 52% of patients treated with FOLFOX and 65% of patients receiving FOLFIRI. A dose
      reduction of 5-fluorouracil due to AEs was necessary in 18% of administered cycles.
      5-Fluorouracil administration was omitted in 8% of cycles. Oxaliplatin and irinotecan doses
      were reduced in 11% and 12% and interrupted in 11% and 5% of administered cycles,
      respectively. Actually, regorafenib had acceptable tolerability in combination with
      chemotherapy. The most frequent grade 3-4 AEs were: neutropenia (45%), Hand-Foot Skin
      Reaction (15%), diarrhea (10%), and hypophosphatemia (12%). Regarding pharmacokinetics, area
      under the curve (AUC) of irinotecan was significantly higher in cycle 2 (following
      regorafenib dosing) than in cycle 1 (before regorafenib dosing); the ratio of AUC values
      (cycle 2:cycle 1) was 1.28 (90% confidence interval [CI] 1.06 -1.54). Cmax of irinotecan was
      only slightly increased, and t½ (half-life) was unchanged. For SN-38 (metabolite of
      irinotecan), AUC was significantly higher in cycle 2 than in cycle 1 (ratio 1.44, 90% CI
      1.12-1.85), while Cmax was unchanged. In line with the known elimination pathways of platinum
      and 5-fluorouracil, no pharmacokinetic interaction with regorafenib was seen . The study from
      O'Neil was designed to show whether the addition of regorafenib to FOLFIRI improves PFS (over
      a placebo-FOLFIRI arm) when given as second-line therapy for patients treated initially with
      oxaliplatin and fluoropyrimidine-based therapy. The regorafenib/FOLFIRI schedule that was
      used was the one proposed by Schultheis (i.e. standard FOLFIRI with irinotecan 180 mg/m² plus
      regorafenib 160 mg daily from day 4 to 10). The study met its primary endpoint of
      demonstrating that the addition of regorafenib to FOLFIRI prolongs PFS compared to FOLFIRI
      alone with a HR (Hazard Ratio) of 0.72. When looking at tumor response, authors found that
      regorafenib (combined to chemo) provided more partial responses than placebo plus chemo (35%
      vs. 19%, p= 0.045). The combination was very tolerable, with little increase in toxicity
      compared to the control chemotherapy regimen. Of note, regarding the top-3 reported severe
      (gr. 3-4) AEs, neutropenia, diarrhea, and hypophosphatemia were reported in 41%, 15%, and 14%
      of the patients, respectively (as compared to 30%, 5%, and 0% in the placebo group).

      Actually, there is room to combine regorafenib with a chemo triplet such as FOLFIRINOX
      (5-fluorouracil, irinotecan, oxaliplatin) on the following conditions: controlling patients
      on UGT1A polymorphisms (at least UGT1A1), stepwise dose-escalation of irinotecan and
      regorafenib, mandatory granulocyte growth-factor injections.
allocation: N/A
intervention model: Sequential Assignment
primary purpose: Other
masking: None (Open Label)
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
time frame: At the end of cycle 1 to 3 (each cycle is 14 days)
description: During the first three cycles
measure: Progression-free survival (PFS)
time frame: Aprroximately 24 months
description: From baseline of first patient until the datebase cut-off
measure: Disease control rate (DCR)
time frame: Aprroximately 24 months
description: From baseline of first patient until the datebase cut-off
measure: Objective response rate (ORR)
time frame: Tumor is assessed at 8 weeks intervals
description: From baseline of first patient until the end of treatment
measure: Deepness of response (DpR)
time frame: Tumor is assessed at 8 weeks intervals
description: From baseline of first patient until the end of treatment lesions at the nadir, in the absence of new lesions or progression of non-target lesions, as compared to baseline
measure: Time to recurrence under maintenance
time frame: Approximately 10 months
description: From baseline of first patient until the progression of disease
measure: Overall survival (OS)
time frame: Aprroximately 24 months
description: From baseline of first patient until the datebase cut-off
measure: Resection (R) rates
time frame: Approximately at 6 months
description: Through the treatment
measure: Determination of circulating free DNA concentration
time frame: Baseline, 8 weeks, 16 weeks etc. through the end of treatment
description: From baseline of first patient until the end of treatment
arm group label: Folfirinox-R
arm group type: Experimental
description: Folfirinox + regorafenib
intervention type: Combination Product
intervention name: Folfirinox + regorrafenib
description: folfirinox : from day 1 to day 3 regorafenib : day 4 to day 10 a cycle during 14 days
arm group label: Folfirinox-R
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Antoine Adenis, MD
role: Study Chair
affiliation: Institut régional du cancer de Montpellier
facility: 
facility: 
facility: 
facility: 
country: France
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citation: Loupakis F, Cremolini C, Masi G, Lonardi S, Zagonel V, Salvatore L, Cortesi E, Tomasello G, Ronzoni M, Spadi R, Zaniboni A, Tonini G, Buonadonna A, Amoroso D, Chiara S, Carlomagno C, Boni C, Allegrini G, Boni L, Falcone A. Initial therapy with FOLFOXIRI and bevacizumab for metastatic colorectal cancer. N Engl J Med. 2014 Oct 23;371(17):1609-18. doi: 10.1056/NEJMoa1403108.
PMID: 25337750
citation: Mross K, Frost A, Steinbild S, Hedbom S, Buchert M, Fasol U, Unger C, Kratzschmar J, Heinig R, Boix O, Christensen O. A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors. Clin Cancer Res. 2012 May 1;18(9):2658-67. doi: 10.1158/1078-0432.CCR-11-1900. Epub 2012 Mar 15.
PMID: 22421192
citation: Schmieder R, Hoffmann J, Becker M, Bhargava A, Muller T, Kahmann N, Ellinghaus P, Adams R, Rosenthal A, Thierauch KH, Scholz A, Wilhelm SM, Zopf D. Regorafenib (BAY 73-4506): antitumor and antimetastatic activities in preclinical models of colorectal cancer. Int J Cancer. 2014 Sep 15;135(6):1487-96. doi: 10.1002/ijc.28669. Epub 2014 Apr 17.
PMID: 24347491
citation: Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M, Humblet Y, Bouche O, Mineur L, Barone C, Adenis A, Tabernero J, Yoshino T, Lenz HJ, Goldberg RM, Sargent DJ, Cihon F, Cupit L, Wagner A, Laurent D; CORRECT Study Group. Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013 Jan 26;381(9863):303-12. doi: 10.1016/S0140-6736(12)61900-X. Epub 2012 Nov 22.
PMID: 23177514
citation: Li J, Qin S, Xu R, Yau TC, Ma B, Pan H, Xu J, Bai Y, Chi Y, Wang L, Yeh KH, Bi F, Cheng Y, Le AT, Lin JK, Liu T, Ma D, Kappeler C, Kalmus J, Kim TW; CONCUR Investigators. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015 Jun;16(6):619-29. doi: 10.1016/S1470-2045(15)70156-7. Epub 2015 May 13.
PMID: 25981818
citation: Schultheis B, Folprecht G, Kuhlmann J, Ehrenberg R, Hacker UT, Kohne CH, Kornacker M, Boix O, Lettieri J, Krauss J, Fischer R, Hamann S, Strumberg D, Mross KB. Regorafenib in combination with FOLFOX or FOLFIRI as first- or second-line treatment of colorectal cancer: results of a multicenter, phase Ib study. Ann Oncol. 2013 Jun;24(6):1560-7. doi: 10.1093/annonc/mdt056. Epub 2013 Mar 13.
PMID: 23493136
citation: Leitinger B. Discoidin domain receptor functions in physiological and pathological conditions. Int Rev Cell Mol Biol. 2014;310:39-87. doi: 10.1016/B978-0-12-800180-6.00002-5.
PMID: 24725424
citation: Rammal H, Saby C, Magnien K, Van-Gulick L, Garnotel R, Buache E, El Btaouri H, Jeannesson P, Morjani H. Corrigendum: Discoidin Domain Receptors: Potential Actors and Targets in Cancer. Front Pharmacol. 2016 Sep 30;7:346. doi: 10.3389/fphar.2016.00346. eCollection 2016.
PMID: 27703433
citation: Gao H, Chakraborty G, Zhang Z, Akalay I, Gadiya M, Gao Y, Sinha S, Hu J, Jiang C, Akram M, Brogi E, Leitinger B, Giancotti FG. Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling. Cell. 2016 Jun 30;166(1):47-62. doi: 10.1016/j.cell.2016.06.009.
PMID: 27368100
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responsible party type: Sponsor
mesh term: Colorectal Neoplasms
mesh term: Folfirinox
sharing ipd: No