Durvalumab for MSI-H or POLE Mutated Metastatic Colorectal Cancer
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|ClinicalTrials.gov Identifier: NCT03435107|
Recruitment Status : Active, not recruiting
First Posted : February 15, 2018
Last Update Posted : August 28, 2020
The POLE mutations represent high somatic mutation loads in patients with colorectal cancer, especially in those with MMR proficient or MSS, therefore, tumors harbouring POLE mutations might be susceptible to immune checkpoint blockade.
Based on these reasons, the investigators planned a phase II study of durvalumab monotherapy in patients with previously treated, metastatic, MMR deficient (MSI-H) or POLE mutated colorectal cancer.
|Condition or disease||Intervention/treatment||Phase|
|Metastatic Colorectal Cancer||Drug: Durvalumab||Phase 2|
Later-line therapies after failure of standard treatments for metastatic colorectal cancer patients are limited; regorafenib and TAS-102 have shown clinical activity for these patients, however, efficacy outcomes seemed not to be sufficient although there have been rather higher frequencies of adverse events.
Mismatch repair (MMR) deficiency or microsatellite instability-high (MSI-H) played a role of negative predictive factor for adjuvant fluorouracil-based chemotherapy in patients with resected colorectal cancer. In the metastatic setting, deficient MMR or MSI-H represented poor prognosis; however, their predictive role has been documented after the pembrolizumab trial was reported. The results of the pembrolizumab trial demonstrated that the PD-1 blockade with pembrolizumab monotherapy showed 40% of confirmed immune-related objective response rates in patients with MMR deficient metastatic colorectal cancers; hence there was no objective response in those with MMR proficient tumors. The progression-free rates at 20 weeks were 78% versus 11%, respectively, also favouring those with MMR deficient tumors. However, the MMR deficiency of MSI-H is found in only about 5% in patients with metastatic colorectal cancer, which is too small to expand potential candidate of immunotherapy.
One of the proposed mechanism of promising efficacy from pembrolizumab for MMR deficient colorectal cancer is that MMR deficient or MSI-H colorectal cancers harbour higher somatic mutation loads than MMR proficient colorectal cancer (a mean of 1782 somatic mutations per tumor in the MMR deficient tumors versus 73 in the MMR proficient tumors in the results of pembrolizumab trial); somatic mutations have the potential to encode non-self immunogenic antigens; therefore, immunotherapy enhancing immune surveillance produced promising treatment efficacy in the MMR deficient tumors.
The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, and it involves DNA repair and chromosomal replication. The POLE mutations are located in the exonuclease domain, and their presence has already been reported in the various cancers including colorectal and endometrial cancer.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||33 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||A Phase II Study of Durvalumab in Patients With Mismatch Repair Deficient or POLE Mutated Metastatic Colorectal Cancer|
|Actual Study Start Date :||April 12, 2018|
|Estimated Primary Completion Date :||March 31, 2022|
|Estimated Study Completion Date :||May 31, 2022|
The mismatch repair deficient or microsatellite instable, or POLE mutated metastatic colorectal cancer patients who were refractory to fluoropyrimidines, irinotecan and oxaliplatin with or without targeted agents will be accrued.
After checking the eligibility for the study entry, patients will be entered into the study treatment with durvalumab monotherapy.
Study treatment consists of durvalumab 1500 mg Q4W for patients > 30 kg, and will be repeated every 4 weeks. For patients ≤ 30 kg, weight based dosing of 20 mg/kg durvalumab Q4W will be used.
Response evaluation will be performed every 8 weeks (± 1-week window period). Treatment will be continued until disease progression, unacceptable adverse events or the patient's refusal.
Treatment through progression is at the investigator's discretion, and the investigator should ensure that patients do not have any significant, unacceptable, or irreversible toxicity that indicate that continuing treatment will not further benefit the patient. The Investigator should ensure that patients still meet all of the inclusion criteria and none of the exclusion criteria for this study.
- Objective response rates (RECIST 1.1) [ Time Frame: First measurement should be at 8weeks from first administration.After first measurement, it should be followed up at every 8weeks until date of progression disease or date of death from any cause, whichever came first, assessed up to 46months.. ]CT (or MRI) scans of evaluable/measurable lesions by RECIST 1.1.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03435107
|Korea, Republic of|
|Asan Medical Center|
|Seoul, Korea, Republic of, 05505|
|Principal Investigator:||Tae Won Kim, Professor||Asan Medical Center|