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Avelumab and Cetuximab in Combination With FOLFOX in Patients With Previously Untreated Metastatic Colorectal Cancer - The Phase II AVETUX-CRC Trial. (AVETUX)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03174405
Recruitment Status : Active, not recruiting
First Posted : June 2, 2017
Last Update Posted : October 5, 2020
Sponsor:
Information provided by (Responsible Party):
AIO-Studien-gGmbH

Tracking Information
First Submitted Date  ICMJE May 31, 2017
First Posted Date  ICMJE June 2, 2017
Last Update Posted Date October 5, 2020
Actual Study Start Date  ICMJE July 17, 2017
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: June 1, 2017)
Progression Free Survival Rate (PFS) @ 12 months [ Time Frame: during 12 months of treatment ]
PFS according to RECIST 1.1 at 12months of treatment
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: June 1, 2017)
  • Safety [ Time Frame: 21 months ]
    Safety and tolerability (acc. to NCI CTC AE v4.03 and to the obtained data on vital signs, clinical parameters (oxygen saturation) and feasibility of the regimen)
  • Response Rate (RR) [ Time Frame: 4 years ]
    Response Rate (RR) according to RECIST v1.1 and modified RECIST (mRECIST)
  • Progression Free Survival (PFS) [ Time Frame: 4 years ]
    Progression Free Survival (PFS) according to RECIST v1.1 and mRECIST
  • Overall survival (OS) [ Time Frame: 4 years ]
    Overall survival (OS)
  • Translational research [ Time Frame: 48 months ]
    Translational research (correlation of clonal dynamics (RAS/EGFR subclones) with immune response signature to determine control of mutant subclones by the combination of anti-EGFR with anti-PD-L1, and PD-L1 (and MSI) status with efficacy
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Avelumab and Cetuximab in Combination With FOLFOX in Patients With Previously Untreated Metastatic Colorectal Cancer - The Phase II AVETUX-CRC Trial.
Official Title  ICMJE Avelumab and Cetuximab in Combination With FOLFOX in Patients With Previously Untreated Metastatic Colorectal Cancer - The Phase II AVETUX- Colorectal Cancer (CRC) Trial.
Brief Summary AVETUX is a single arm multicentric phase II investigator initiated trial conducted by the Arbeitsgemeinschaft Internistische Onkologie (AIO) in 11 German sites in patients with previously untreated RAS/BRAF wildtype mCRC independent of MSI status.
Detailed Description

The primary clinical objective is to determine the efficacy of a standard 1st line regimen (FOLFOX and cetuximab) in patients with RAS/v-Raf murine sarcoma viral oncogene homolog B (BRAF) wildtype, Microsatellite Instability (MSI) or icrosatellite Stability (MSS) MCRC with avelumab in terms of progression free survival rate after 12 months (acc. to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1).

The main secondary objective is to determine safety and tolerability, according to NCI Common Terminology Criteria for Adverse Events (CTCAE v4.03) and to the obtained data on vital signs, clinical parameters (oxygen saturation) and feasibility of the regimen. Further secondary objectives are to determine the efficacy of the experimental regimen in terms of objective response rate (acc. to RECIST v1.1 and irRECIST), and overall survival, to correlate clonal dynamics (RAS/EGFR subclones) with immune response signature to determine control of mutant subclones by the combination of anti-Epidermal growth factor receptor (EGFR) with anti-PD-L1and PD-L1 staining (and MSI status) with efficacy.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Metastatic Colorectal Cancer
Intervention  ICMJE Drug: Avelumab

All eligible patients will receive cetuximab and mFOLFOX6 combined avelumab from the second cycle onwards.

Cetuximab at a dose of 250 mg/m2 IV over 60 to 90 min (day 1 and 8) (first dose 400mg/m2) mFOLFOX6 (administration according to local standard) Oxaliplatin at a dose of 85 mg/m2 IV (day 1) 5-FU 400 mg/m2 IV bolus (day 1) LV at a dose of 400 mg/m2 iv (day 1) 5-FU at a dose of 2400 mg/m2 IV (day 1-3) Avelumab at a dose of 10mg/kg IV over 60 to 90 min (day 1 from cycle 2 onwards)

Study Arms  ICMJE Experimental: AVELUMAB
Intervention: Drug: Avelumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: June 1, 2017)
43
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE August 2021
Estimated Primary Completion Date July 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Patients with histologically confirmed, previously untreated RAS and BRAF wildtype, MSI or MSS metastatic colorectal cancer (primary tumor may be present)
  2. Patients with at least one measurable lesion acc. to RECIST v1.1
  3. ECOG Performance status ≤ 1
  4. Life expectancy > 3 months
  5. Age ≥ 18 years.
  6. Haematologic function as follows: ANC ≥ 1.5 x 10^9/L, platelets ≥ 100 x10^9/L, hemoglobin ≥ 9 g/dL or 5.59 mmol/L
  7. Adequate liver function as measured by serum transaminases (AST & ALT) ≤ 2.5 x ULN (in case of liver metastases < 5 x ULN) and total bilirubin ≤ 1.5 x ULN. Patients with known Gilbert disease who have serum bilirubin level ≤ 3 × ULN may be enrolled.
  8. Adequate renal function: serum creatinine ≤ 1.5 x ULN
  9. Negative serum pregnancy test at screening for women of childbearing potential. 10. Highly effective contraception for both male and female subjects if the risk of conception exists. (Note: The effects of the trial drug on the developing human fetus are unknown; thus, women of childbearing potential and men able to father a child must agree to use 2 highly effective contraception, defined as methods with a failure rate of less than 1 % per year. Highly effective contraception is required at least 28 days prior, throughout and for at least 90 days after avelumab treatment and 6 month after standard chemotherapy.

11. At least 6 months after completion of adjuvant chemotherapy. 12. Written informed consent 13. Ability to comply with the protocol for the duration of the study, including hospital/office visits for treatment and scheduled follow-up visits and examinations

Exclusion Criteria:

  1. Malignancies other than disease under study within 5 years prior to inclusion, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS > 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
  2. All subjects with known brain metastases, except those meeting the following criteria:

    1. Brain metastases that have been treated locally and are clinically stable for at least 2 weeks prior to enrolment
    2. No ongoing neurological symptoms that are related to the brain localization of the disease (sequelae that are a consequence of the treatment of the brain metastases are acceptable)
    3. Subjects must be either off steroids or on a stable or decreasing dose of <10mg daily prednisone (or equivalent)
  3. Prior organ transplantation, including allogeneic stem-cell transplantation
  4. Significant acute or chronic infections including, among others:

    1. Known history of testing positive test for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
    2. Positive test for HBV surface antigen and / or confirmatory HCV RNA (if anti-HCV antibody tested positive)
  5. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent (Subjects with diabetes type I, vitiligo, psoriasis, hypo- or hyperthyroid disease not requiring immunosuppressive treatment are eligible)
  6. Concomitant treatment with corticosteroids or other immunosuppressants, besides treatment of brain metastases as mentioned in criteria 2 or:

    1. Subjects requiring hormone replacement with corticosteroids are eligible if the steroids are administered only for the purpose of hormonal replacement and at doses ≤ 10 mg or 10 mg equivalent prednisone per day
    2. Administration of steroids through a route known to result in a minimal systemic exposure (topical, intranasal, intro-ocular, or inhalation) are acceptable
  7. Known severe hypersensitivity reactions to monoclonal antibodies (Grade ≥ 3 NCI-CTCAE v 4.03), any history of anaphylaxis, or uncontrolled asthma (that is, 3 or more features of partially controlled asthma)
  8. Pregnancy or lactation
  9. Known alcohol or drug abuse 10. Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrolment), myocardial infarction (< 6 months prior to enrolment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.

11. Persisting toxicity related to prior therapy (NCI CTCAE v. 4.03 Grade > 1); however, alopecia, sensory neuropathy Grade ≤ 2, or other Grade ≤ 2 not constituting a safety risk based on investigator's judgment are acceptable.

12. All other significant diseases (for example, inflammatory bowel disease, uncontrolled asthma, colitis and pneumonitis), which, in the opinion of the Investigator, might impair the subject's tolerance of trial treatment 13. Any psychiatric condition that would prohibit the understanding or rendering of informed consent 14. Vaccination within 4 weeks of the first dose of avelumab and while on trial is prohibited except for administration of inactivated vaccines 15. Any approved anticancer therapy, including chemotherapy, hormonal therapy or radiotherapy, within 4 weeks prior to initiation of study treatment 16. Major surgical procedure within 28 days prior to treatment or anticipation of need for a major surgical procedure during the course of the study

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03174405
Other Study ID Numbers  ICMJE AIO-KRK-0216
2016-004434-26 ( EudraCT Number )
MS100070_0065 ( Other Grant/Funding Number: Merck )
Has Data Monitoring Committee Yes
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  ICMJE
Plan to Share IPD: No
Responsible Party AIO-Studien-gGmbH
Study Sponsor  ICMJE AIO-Studien-gGmbH
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Alexander Stein, PD Dr. Universitätsklinikum Hamburg-Eppendorf
PRS Account AIO-Studien-gGmbH
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP