Durvalumab for MSI-H or POLE Mutated Metastatic Colorectal Cancer

NCT03435107 | Completed Phase 2 Results

• 1 other identifier: 2017-1151
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief 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. 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.

Conditions

Metastatic Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• 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

  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)

  Through study completion, an average of 2 years and 3months

Study Arms (1)

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.

Drug: Durvalumab

Interventions

Durvalumab DRUG

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.

Durvalumab

Eligibility Criteria

• Age: 20 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.
• Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
• 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.

Sponsors & Collaborators

• Asan Medical Center: lead

Study Sites (1)

Asan Medical Center

Seoul, 05505, South Korea

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

durvalumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Limitations and Caveats

The limitations of the present study include a relatively small sample size, the absence of a control group and a short follow-up duration.

Results Point of Contact

• Title: Project manager
• Organization: Academic Research Office, Clinical Trial Center, Asan Medical Center

jiyun.an@amc.seoul.kr

82-2-3010-7187

Study Officials

• Tae Won Kim, Professor

  Asan Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Study Record Dates

• First Submitted: February 7, 2018
• First Posted: February 15, 2018
• Study Start: April 12, 2018
• Primary Completion: April 26, 2023
• Study Completion: April 26, 2023
• Last Updated: October 15, 2024
• Results First Posted: October 15, 2024

Record last verified: 2024-10

Data Sharing

• IPD Sharing: Will not share

Locations

KR (1)