Metastatic Colorectal CancerPhase 2NCT03150706
Avelumab for MSI-H or POLE Mutated Metastatic Colorectal Cancer
A Phase 2 study testing Avelumab 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?
- Avelumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 33 participants
- Where
- 1 siteSouth Korea
- Study dates
- 22 May 2017to 31 Dec 2021
- Phase
- Phase 2
- Are there results?
- None posted in the registry
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 4. ≥ 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, D5S345, D17S250)
- Progressed after at least first-line systemic chemotherapy for metastatic setting.
- ≥ 1 measurable lesion(s) by RECIST 1.1.
- Unresectable advanced or metastatic disease.
- Age over 20 years old.
Show all 12Show fewer
- ECOG 0-1, but final decision by clinical.
- 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 (Cockroft) ≥ 30 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 highly efficient contraception since signing of the IC form until at least 8 weeks after the last study drug administration.
Who cannot join
- Any prior treatment with PD-1 or PD-L1 inhibitor.
- Receipt of the last dose of chemotherapy ≤ 28 days prior to the first dose of study drugs.
- Current or prior use of immunosuppressive medication within 28 days before the first dose of avelumab, with the exceptions for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
- 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.
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- 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.
- Clinically significant (i.e., active) cardiovascular disease: cerebral vascular accident/stroke (< 6 months prior to enrollment), myocardial infarction (< 6 months prior to enrollment), unstable angina, congestive heart failure (≥ New York Heart Association Classification Class II), or serious cardiac arrhythmia requiring medication.
- Active or prior documented autoimmune disease within the past 2 years; subjects with diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring immunosuppressive treatment are eligible.
- Active or prior documented inflammatory bowel disease.
- History of prior immunodeficiency.
- History of allogeneic organ transplantation.
- Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03 Grade ≥ 3)
- History of previous clinical diagnosis of active tuberculosis.
- Vaccination within 4 weeks of the first dose of avelumab and while on trials is prohibited except for administration of inactivated vaccines
- 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.
- Active infection requiring systemic therapy.
- 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.
- Other severe acute or chronic medical conditions including immune colitis, inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase II Study of Avelumab 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, Investigator planned a phase II study of avelumab 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.
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, Investigator planned a phase II study of avelumab monotherapy in patients with previously treated, metastatic, MMR deficient (MSI-H) or POLE mutated colorectal cancer.
- Conditions
- Metastatic Colorectal Cancer
- Being tested
- Avelumab
- Keywords
- POLE mutation, mismatch repair deficient, Avelumab
- Medical subject headings
- Colorectal Neoplasms, Turcot syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
AvelumabDrug
Also called MSB0010718C
Patients will receive 10 mg/kg of avelumab via intravenous infusion every 2 weeks.
Response evaluation will be performed every 6 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 |
|---|---|---|
| Avelumab | Experimental | The mismatch repair deficient or microsatellite instable, or POLE mutated metastatic colorectal cancer patients who were progressed after at least one prior systemic treatment for metastatic setting.
After checking the eligibility for the study entry, patients will be entered into the study treatment with avelumab monotherapy. Receives: Drug: Avelumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Serum CEA, TSH, T3, free T4, EKG,CT (or MRI) scans of evaluable/measurable lesions by RECIST 1.1.
During the CRT
Measured: 6 weeks(maximum 7 weeks)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 May 2017
- Study start22 May 2017
- Primary completion31 Jul 2021 (estimated)
- Study completion31 Dec 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- 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
- Collaborators
- Merck KGaA, Darmstadt, Germany
- 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
- NCT03150706
- Sponsor's protocol ID
- mCRC avelumab
- Status last verified
- Apr 2020
- First submitted
- 9 May 2017
- Last updated
- 3 Apr 2020
- Results posted
- No
- 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 3 Apr 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase II Study of Avelumab in Patients With Mismatch Repair Deficient or POLE Mutated Metastatic Colorectal Cancer
- ClinicalTrials.gov ID
- NCT03150706
- Acronym / sponsor ID
- mCRC avelumab
- Conditions
- Metastatic Colorectal Cancer
- Keywords
- POLE mutation, mismatch repair deficient, Avelumab
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 33 participants (actual)
- Lead sponsor
- Asan Medical CenterUniversity, hospital or other
- Collaborators
- Merck KGaA, Darmstadt, Germany
- Study start
- 22 May 2017 (actual)
- Primary completion
- 31 Jul 2021 (estimated)
- Study completion
- 31 Dec 2021 (estimated)
- First posted
- 12 May 2017 (actual)
- Results
- Not posted in the source record
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, Investigator planned a phase II study of avelumab 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.
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, Investigator planned a phase II study of avelumab monotherapy in patients with previously treated, metastatic, MMR deficient (MSI-H) or POLE mutated colorectal cancer.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Avelumab | Experimental | Drug: AvelumabThe mismatch repair deficient or microsatellite instable, or POLE mutated metastatic colorectal cancer patients who were progressed after at least one prior systemic treatment for metastatic setting. After checking the eligibility for the study entry, patients will be entered into the study treatment with avelumab 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 4. ≥ 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, D5S345, D17S250)
- Progressed after at least first-line systemic chemotherapy for metastatic setting.
- ≥ 1 measurable lesion(s) by RECIST 1.1.
- Unresectable advanced or metastatic disease.
Key exclusion criteria (26 listed)
- Any prior treatment with PD-1 or PD-L1 inhibitor.
- Receipt of the last dose of chemotherapy ≤ 28 days prior to the first dose of study drugs.
- Current or prior use of immunosuppressive medication within 28 days before the first dose of avelumab, with the exceptions for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (e.g., intra-articular injection); b. Systemic corticosteroids at physiologic doses ≤ 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
- 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.
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 |
|---|---|---|
| AvelumabAlso: MSB0010718CPatients will receive 10 mg/kg of avelumab via intravenous infusion every 2 weeks. Response evaluation will be performed every 6 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 | Avelumab |
Primary outcome
Serum CEA, TSH, T3, free T4, EKG,CT (or MRI) scans of evaluable/measurable lesions by RECIST 1.1.
Time frame: 6 weeks(maximum 7 weeks)
During the CRT
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 3 Apr 2020.
- 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 Avelumab 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 26 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: status not confirmed, as of the sponsor's last update on 3 Apr 2020. 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?
Results are not available in the source record.
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?
Serum CEA, TSH, T3, free T4, EKG,CT (or MRI) scans of evaluable/measurable lesions by RECIST 1.1. (time frame: 6 weeks(maximum 7 weeks)). 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 3 Apr 2020.