Metastatic Colorectal CancerPhase 2NCT03435107
Durvalumab for MSI-H or POLE Mutated Metastatic Colorectal Cancer
A Phase 2 study testing Durvalumab in people with Metastatic Colorectal Cancer, run by Asan Medical Center at 1 site in South Korea.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 20 years and older
- Conditions the study is for
- Metastatic Colorectal Cancer
- What is being tested?
- Durvalumab
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 33 participants
- Where
- 1 siteSouth Korea
- Study dates
- 12 Apr 2018to 26 Apr 2023
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 20 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum.
- Mismatch repair deficient or microsatellite instable (defined below), or POLE mutated tumors A. Mismatch repair deficient: loss of expression by immunohistochemical stains ≥ 1 out of 4 markers (MLH1, MSH2, MSH6, PMS2) B. Microsatellite instable: loss of stability ≥2 out of 5 gene panels (BAT-25, BAT-26, D2S123, D5S346, D17S250)
- Refractory to at least one agent of prior treatments(fluoropyrimidines, irinotecan or oxaliplatin) Progressed after at least first-line systemic chemotherapy for metastatic setting (progressed within 6 months after completion of adjuvant chemotherapy is also considered as first-line failure)
- ≥ 1 measurable lesion(s) by RECIST 1.1.
- Unresectable advanced or metastatic disease.
- Age over 20 years old.
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- ECOG performance status of 0-1 or lower.
- Adequate organ functions. A. Bone marrow function: Hemoglobin 9.0≥ g/dL, ANC≥ 1,500/mm3, platelet≥ 100,000/mm3 B. Hepatic functions: bilirubin ≤ 1.5 X ULN, AST/ALT ≤ 2.5 X ULN (≤ 5 X ULN in cases of liver metastasis) C. Renal functions: serum Cr ≤ 1.5 X ULN or calculated CCr (Cockcroft) > 40 ml/min
- Be willing and able to comply with the protocol for the duration of the study.
- Give written informed consent prior to study-specific screening procedures, with the understanding that the patient has the right to withdraw the study at any time, without prejudice.
- Female subjects must either be of non-reproductive potential (≥ 60 years old and no menses for ≥ 1 year without an alternative medical cause, or history of hysterectomy, or history of bilateral tubal ligation, or history of bilateral oophorectomy) or must have a negative serum pregnancy test upon study entry.
- Women of childbearing potential and men must agree to use adequate contraception since signing of the IC form until at least 90days after the last study drug administration.
Who cannot join
- Any prior treatment with PD-1 or PD-L1 inhibitor, including durvalumab.
- Involvement in the planning and/or conduct of the study.
- Receipt of the last dose of chemotherapy ≤ 28 days prior to the first dose of study drugs.
- Mean QT interval corrected for heart rate (QTc) ≥ 470 msec calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction.
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
- Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
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- Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be included only after consultation with the Study Physician.
- Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
- Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiologic doses, which are not to exceed 10 mg/day of prednisolone, or an equivalent corticosteroid.
- Concurrent or previous history of another primary cancer within 3 years prior to randomisation except for curatively treated cervical cancer in situ, non-melanomatous skin cancer, superficial bladder cancer (pTis and pT1) and curatively treated thyroid cancer of any stage. Concurrent, histologically confirmed, unresected thyroid cancer without distant metastasis could be allowed with the agreement of the chief principal investigator.
- Uncontrolled CNS metastases; permitted if asymptomatic or neurologically stable.
- Prior radiation therapy would be permitted, but non-radiated evaluable lesions should be present at study entry.
- Radiation therapy during study treatment is not permitted, but if the local investigator decides that radiation therapy should be given during study treatments, he should be convinced that there is no evidence of disease progression with agreement of the chief principal investigator.
- Congestive heart failure ≥ New York Heart Association (NYHA) class 2.
- Unstable angina, new-onset angina within 3 months, or history of myocardial infarction within 6 months before the study entry.
- Active or prior documented autoimmune disease within the past 2 years; subjects with vitiligo, Grave's disease, or psoriasis not requiring systemic treatment (within the past 2 years) are not excluded.
- Active or prior documented inflammatory bowel disease.
- History of prior immunodeficiency.
- History of allogeneic organ transplantation.
- History of hypersensitivity to durvalumab or any excipient.
- History of previous clinical diagnosis of active tuberculosis.
- Receipt of live attenuated vaccination within 30 days prior to study entry.
- Known history of testing positive for HIV
- Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive) Except, resolved HBV infection (as evidenced by detectable HBV surface antibody, detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface antigen) or Chronic HBV infection (as evidenced by detectable HBV surface antigen or HBV DNA). Subjects with chronic HBV infection must have HBV DNA < 100 IU/mL and must be on antiviral therapy.
- Major surgery or significant traumatic injury within 28 days prior to study treatment.
- Non-healing wound, ulcer, or bone fracture.
- Current evidence of significant gastrointestinal bleeding or (impending) obstruction.
- Concomitant participation in another clinical trial.
- Pregnant of breast-feeding subjects. Women of child-bearing potential must have pregnancy test within 7 days and a negative result must be documented before start of study treatment.
- Substance abuse, medical, psychological or social conditions that may interfere with the subject's participation in the study or evaluation of the study results.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase II Study of Durvalumab in Patients With Mismatch Repair Deficient or POLE Mutated Metastatic Colorectal Cancer
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.
Read the detailed description
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.
- Conditions
- Metastatic Colorectal Cancer
- Being tested
- Durvalumab
- Medical subject headings
- Colorectal Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
DurvalumabDrug
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.
| Study group | Role | What they receive |
|---|---|---|
| Durvalumab | Experimental | 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. Receives: Drug: Durvalumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Objective Response Rates (RECIST 1.1)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI:
Complete Response (CR): Disappearance of all target lesions Partial Response (PR):>=30% decrease in the sum of the longest diameter of target lesions Overall Response (OR) = CR + PR
Measured: 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..
Secondary outcomes (1)
Disease Control Rate (DCR)
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI:
Disease control rate (DCR); The percentage of patients with the best overall response of complete response (CR), partial response (PR), or stable disease (SD) sustained for at least 6 weeks.
Measured: Through study completion, an average of 2 years and 3months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Feb 2018
- Study start12 Apr 2018
- Primary completion26 Apr 2023
- Study completion26 Apr 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Other trials for Metastatic Colorectal CancerStudies of the same condition, open and under way.
- More trials run by Asan Medical CenterThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 33 participants (actual)
Sponsor and investigators
- Lead sponsor
- Asan Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Tae Won Kim, Asan Medical Center
- Investigators
- Tae Won Kim, Professor, Principal investigator, Asan Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03435107
- Sponsor's protocol ID
- 2017-1151
- Status last verified
- Oct 2024
- First submitted
- 7 Feb 2018
- Last updated
- 15 Oct 2024
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 15 Oct 2024. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study of Durvalumab in Patients With Mismatch Repair Deficient or POLE Mutated Metastatic Colorectal Cancer
- ClinicalTrials.gov ID
- NCT03435107
- Acronym / sponsor ID
- 2017-1151
- Conditions
- Metastatic Colorectal Cancer
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 33 participants (actual)
- Lead sponsor
- Asan Medical CenterUniversity, hospital or other
- Study start
- 12 Apr 2018 (actual)
- Primary completion
- 26 Apr 2023 (actual)
- Study completion
- 26 Apr 2023 (actual)
- First posted
- 15 Feb 2018 (actual)
- Results
- Posted 15 Oct 2024
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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 design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Durvalumab | Experimental | Drug: DurvalumabThe 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. |
Who may qualify
- Ages
- 20 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum.
- Mismatch repair deficient or microsatellite instable (defined below), or POLE mutated tumors A. Mismatch repair deficient: loss of expression by immunohistochemical stains ≥ 1 out of 4 markers (MLH1, MSH2, MSH6, PMS2) B. Microsatellite instable: loss of stability ≥2 out of 5 gene panels (BAT-25, BAT-26, D2S123, D5S346, D17S250)
- Refractory to at least one agent of prior treatments(fluoropyrimidines, irinotecan or oxaliplatin) Progressed after at least first-line systemic chemotherapy for metastatic setting (progressed within 6 months after completion of adjuvant chemotherapy is also considered as first-line failure)
- ≥ 1 measurable lesion(s) by RECIST 1.1.
- Unresectable advanced or metastatic disease.
Key exclusion criteria (30 listed)
- Any prior treatment with PD-1 or PD-L1 inhibitor, including durvalumab.
- Involvement in the planning and/or conduct of the study.
- Receipt of the last dose of chemotherapy ≤ 28 days prior to the first dose of study drugs.
- Mean QT interval corrected for heart rate (QTc) ≥ 470 msec calculated from 3 electrocardiograms (ECGs) using Frediricia's Correction.
- Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion criteria
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| DurvalumabStudy 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. | Drug | Durvalumab |
Primary outcome
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..
Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by CT or MRI: Complete Response (CR): Disappearance of all target lesions Partial Response (PR):>=30% decrease in the sum of the longest diameter of target lesions Overall Response (OR) = CR + PR
1 secondary outcome
Disease Control Rate (DCR)
Time frame: Through study completion, an average of 2 years and 3months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 15 Oct 2024.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tae Won Kim, Professor principal investigator
Asan Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Durvalumab in people with Metastatic Colorectal Cancer, run by Asan Medical Center at 1 site in South Korea.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 15 Oct 2024. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in South Korea. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 15 Oct 2024). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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..). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Oct 2024; AzTrials last refreshed its copy on 7 Nov 2026.