Avelumab for DNA Mutated Metastatic Colorectal Cancer

Not Applicable

Completed

Conditions: Neoplasms

Registration Number: KCT0003561

Lead Sponsor: Asan Medical Center

Brief Summary: In this open-label, multicenter, phase II study, avelumab showed promising antitumor activity and manageable toxicity in patients with mCRC harboring dMMR/MSI-H or POLE mutation. The ORR and median PFS were 24.2% and 3.9 months, respectively, and six of eight responders were continuing avelumab treatment with durable response at the end of the analysis. Of note, the ORR and median PFS were 28.6% and 8.1 months, respectively, in patients with MSI-H by PCR or NGS, which were thought to be more reliable methods of determining the MSI status than IHC. Although no patients with POLE mutations had response to avelumab, the limitations of small sample size and variation in mutation sites need to be taken into account. TRAEs of any grade and TRAEs of grade 3 or 4 were observed in 72.7% and 18.2% of patients, respectively, which was consistent with previous studies [17]. There were two discontinuations of treatment, one because of a TRAE and the other because of a serious adverse event, probably related to treatment. There were no treatment-related deaths. The efficacy of avelumab (an anti–PD-L1 inhibitor) for mCRC with dMMR/MSI-H, specifically in patients with MSI-H by PCR or NGS, is comparable to that of pembro- lizumab and nivolumab (anti–PD-1 inhibitors) in this setting. In the KEYNOTE-016 trial, only patients with MSI-H CRC had the objective response to pembrolizumab (ORR 40%), whereas none of those with MSS CRC had the objective response [4]. A subsequent multicenter trial of pembrolizu-mab for dMMR/MSI-H CRC, the KEYNOTE-164 phase II study, resulted in an ORR of 33% and a median PFS of 4.1 months; the 12-month PFS and OS rates were 34% to 41% and 72% to 76%, respectively, according to prior line of treatment [6,7]. Nivolumab also showed promising antitumor activity in terms of ORR (31.1%) in dMMR/MSI-H CRC, and the 12-month PFS and OS rates were 50% and 73%, respectively [5]. All these favorable results in dMMR/MSI-H CRC contrast sharply with those of later-line conventional chemotherapy for overall mCRC with treatments such as regorafenib or TAS-102, which resulted in ORR of only 1% and median PFS of around 2 months [2,3]. Several phase I results from the JAVELIN Solid Tumor Trials have shown promising ORRs and disease stabilization with avelumab in various types of advanced tumors. Specifically, among 53 patients with metastatic or locally advanced previously treated solid tumors, four (8%) achieved respon-ses and 30 (57%) had SD [18]. The ORR with avelumab ranged from 6.7% to 18.2%, depending on tumor type such as metastatic or unresectable previously treated renal cell carcinoma [12], urothelial carcinoma [13], non-small cell lung cancer [15], and ovarian cancer [14]. In a phase II study of 88 patients with chemotherapy-refractory metastatic Merkel cell carcinoma [11], the ORR with avelumab was 33%, including a CR rate of 11.4%. To date, avelumab has been approved for treatment of previously treated metastatic Merkel cell carcinoma, urothelial carcinoma, and renal cell carcinoma in combination with axitinib. Several explorations to expand

Detailed Description: Not available

Recruitment & Eligibility

Status: Completed

Sex: All

Target Recruitment: 33

Inclusion Criteria

1. Organizational / Cell Proven Leader's Sun-Ram
2. If there is a DNA repair gene deficiency or hydroformia or POLE gene mutation.
3. If a patient has performed at least primary therapy for the treatment of metastatic colon cancer
4. RECIST 1.1. The presence of measurable lesions according to the criteria
5. If no surgical treatment is possible
6. Age over 20 years old
7. ECOG activity also 0-1
8. Suitable long-term features.
A. Bone marrow function : Metabolism (Hb) = 9.0g, Forge (ANC) = 1500mm 3, Platelet (PLT) = 1000mm / mm 3
B. Liver function : bilirubin = 1.5 times the normal upper limit and AST / ALT = 2.5 times the normal upper limit (5 times the normal upper limit if there is a liver)
C.New function : serum creatine = 1.5 times the normal upper limit or calculated CCr (Cockroft) = 30ml / min
9. Patients willing to comply with and comply with research plans during the study
10. A patient who understands that he or she can sign a consent form, voluntarily participate in research, and withdraw participation at any time.
11. No chance of pregnancy if the subject is a female (at least 60 years of age and no menstruation has occurred for more than one year, or if a hysterectomy or both is performed)
12. For both sexes during pregnancy, patients who are able to comply with the proper contraception method during the duration of the antifectivity medication and up to at least eight weeks after the stay is stopped.

Exclusion Criteria

1. If you have used a PD-1 or PD- L inhibitor before.
2. If 28 days have passed since the last chemotherapy was implemented
3. Use of immunosuppressant within 28 days ; however, it is acceptable in other cases ;
If you have a history of other primary cancers within three years, you will be able to exclude the cancer of the cervical cancer that has been cured of hypertherotomy, the skin cancer that is caused by parenchema, and the cancer of 4 types. In the case of thyroid gland cancer, under the judgment of the researcher, if it does not affect the course and outcome of treatment of metastatic colon cancer, the patient is responsible for participating in the total
5. Unadjusted central nervous system transition
6. Previous history of radiation therapy is allowed. However, there must be an appraisible lesion that is not within the radiation field.
7. In principle, radiotherapy is not allowed during research therapy. However, if it is found that the radiolysis is essential, and radiation therapy is not due to the progression of disease, then the general manager is responsible for the study.
8. Clinical significant cardiovascular disease ; within six months of this study registration, stroke / myocardial infarction and instability, and congestive heart failure in the New York Heart Association (NYC) class 2 or higher, or therapy required.
9. Active autoimmune diseases within two years, but not under the following conditions ; Type 1 diabetes, vitiligo, psoriasis or hypothyroidism that do not require immunosuppressant
10. Inflammatory disease history
11. A history of immunodeficiency
12. A transplant patient, including a homogeneous stem cell transplant.
13. NCI CTCAE V4.03 Overacterpose to Avelumab or Avelumab Components Including Overach
14. A history of active tuberculosis
15. .Avelumab Allow for first doses of antivirus within four weeks or within a period that is prohibited by clinical testing
16. HIV infection
17. Active HBV / HCV infection (HBV surface antigen and HCV RNA positive) during screening phase
18. Major surgeries or severe trauma within 28 days of the start of the study.
19. Unrepaired window, ulcer, or fracture
20. If the gastrointestinal bleeding persists or if there is a suspicion of intestinal obstruction
21. If you are currently involved in other clinical studies
22. Pregnant or breast-feeding patients. Fertility women should be tested for pregnancy within seven days of participating in the study and confirmed to be negative
23. A drug user who is deemed to be likely to interfere with research participation and interpretation of research results. A medicallegialsocial disorder
24. Active infection requiring mental therapy
25. Residual toxicity associated with previous therapy (Evaluation of abnormalities higher than grade 1 according to NCI CTCAE v.4.03) ; Neurological disease not considered a safety risk to patients based on the judgment of testers ; 2
26. A recent (within the past year) severe case of chronic pneumonia, in which clinical trial drug administration and participation could increase the risk, or even disrupt the interpretation of test results.