Metastatic Colorectal Neoplasms, Microsatellite Stable / Proficient Mismatch Repair Colorectal Cancer
Conditions
Keywords
Colorectal Neoplasms, Metastatic Colorectal Cancer, Microsatellite Stability, DNA Mismatch Repair, Receptors, CCR8, CCR8 Antagonists, Fruquintinib, Pembrolizumab, Antibodies, Monoclonal, Immune Checkpoint Inhibitors, VEGFR Inhibitors, Combination Drug Therapy, Phase Ib Clinical Trial, Phase II Clinical Trial
Brief summary
This study aims to evaluate the efficacy and safety of the concurrent combination therapy of S 531011 + fruquintinib or S 531011 + fruquintinib + pembrolizumab in patients with MSS/pMMR colorectal cancer.
Detailed description
This study aims to evaluate the efficacy and safety of the concurrent combination therapy of S-531011 plus fruquintinib, or S-531011 plus fruquintinib plus pembrolizumab, in patients with MSS/pMMR colorectal cancer. Eligible participants include patients with metastatic colon or rectal cancer who are 18 years of age or older, have an ECOG Performance Status of 0-1, and have MSS or pMMR tumor status. After written explanation and the provision of written informed consent, participants will be enrolled. The study consists of a Phase Ib part and a Phase II part. In the Phase Ib part (N = 6-12/Arm), participants will be assigned to Arm A or Arm B. Enrollment into Arm B will begin only after enrollment into Arm A has been completed in both phases. Arm A consists of S-531011 (intravenous, once every 3 weeks) plus fruquintinib (5 mg orally once daily on Days 1-21 of a 28-day cycle). Arm B consists of S-531011 (intravenous, once every 3 weeks), fruquintinib (5 mg orally once daily on Days 1-21 of a 28-day cycle), and pembrolizumab (200 mg, intravenous, once every 3 weeks). In the Phase II part (N = 22/Arm), the recommended dose determined in the Phase Ib part will be used.
Interventions
DRUGFruquintinib
Fruquintinib will be administered orally once daily on Days 1-21 of each 28-day cycle. In the Phase Ib part, fruquintinib will be started at 5 mg (Dose Level 0). A reduced dose of 4 mg may be used in Dose Level -1 according to the predefined dose-finding scheme by evaluating DLT profile. In the Phase II part, fruquintinib will be administered at the recommended dose determined in the Phase Ib part.
BIOLOGICALPembrolizumab
Pembrolizumab will be administered intravenously at a dose of 200 mg once every 3 weeks (q3w).
BIOLOGICALS-531011
S-531011 will be administered intravenously once every 3 weeks (q3w). In the Phase Ib part, A reduced dose of S-531011 may be used in Dose Level -1 according to the predefined dose-finding scheme by evaluating DLT profile. In the Phase II part, S-531011 will be administered at the recommended dose determined in the Phase Ib part.
Sponsors
National Cancer Center Hospital East
Shionogi
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This study uses a parallel assignment model with two experimental arms (Arm A and Arm B). Enrollment into Arm B will begin only after enrollment into Arm A has been completed. Participants will receive the assigned intervention throughout the study without crossover between arms.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients with histologically confirmed unresectable adenocarcinoma of the colon or rectum. 2. Confirmed microsatellite stable (MSS) or proficient mismatch repair (pMMR) status. 3. Prior treatment with standard systemic chemotherapy and refractory or intolerant\* to such therapies. Standard chemotherapy must include all of the following: \- Fluoropyrimidine, irinotecan, and oxaliplatin (with or without anti-VEGF antibody therapy) \- For patients with RAS and BRAF wild-type tumors: prior treatment with anti-EGFR monoclonal antibody (cetuximab or panitumumab) \- For patients with BRAF V600E mutation: prior treatment with a BRAF inhibitor (encorafenib) \*For patients who relapse during adjuvant chemotherapy or within 6 months after the last dose of postoperative adjuvant chemotherapy, that adjuvant therapy counts as prior systemic therapy. 4. Presence of measurable disease according to RECIST version 1.1. 5. Age ≥ 18 years at the time of informed consent. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Laboratory values within 14 days prior to enrollment meeting all of the following (tests performed on the same weekday 2 weeks before the enrollment date are acceptable): <!-- --> 1. Absolute neutrophil count ≥ 1,500/mm³ 2. Hemoglobin ≥ 9.0 g/dL 3. Platelet count ≥ 75,000/mm³ 4. Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) 5. AST (GOT) ≤ 2.5 × ULN; ≤ 5 × ULN if liver metastases are present 6. ALT (GPT) ≤ 2.5 × ULN; ≤ 5 × ULN if liver metastases are present 7. Creatinine ≤ 1.5 mg/dL 8. Proteinuria ≤ 1+ or \< 1.0 g/24 h (urine protein-to-creatinine ratio \< 1 may be used; if 24-hour urine is collected, the measured value takes precedence) 8. No blood transfusion within 7 days prior to enrollment (a transfusion given on the same weekday 1 week earlier is considered ineligible). 9\. Women of childbearing potential must have a negative pregnancy test within 14 days prior to enrollment. Both male and female participants must agree to use appropriate contraception during the study and for 4 months after the last dose of study treatment. Female participants must also agree not to breastfeed during the study and for 4 months after the last dose. (Tests performed on the same weekday 2 weeks before the enrollment date are acceptable.) 10. Able to take oral medication. 11. Written informed consent obtained from the participant.
Exclusion criteria
1. Prior treatment with fruquintinib for metastatic colorectal cancer. 2. Prior treatment with any anti-CCR8 antibody, regardless of indication. 3. Receipt of chemotherapy, radiotherapy, immunotherapy, or any antitumor therapy, or investigational agents within 14 days prior to enrollment, or persistence of CTCAE Grade ≥ 2 toxicities from prior therapies (excluding alopecia, hyperpigmentation, and peripheral sensory neuropathy). 4. History of acute coronary syndrome (including myocardial infarction or unstable angina), coronary angioplasty, or stent placement within 6 months prior to enrollment. 5. History or current findings of congestive heart failure of NYHA Class III or higher. 6. Uncontrolled hypertension. 7. Known central nervous system metastases. (If CNS metastasis is clinically suspected, brain CT or MRI must be performed during screening.) 8. Active double primary malignancy (simultaneous or metachronous with disease-free interval \< 2 years), except for carcinoma in situ or intramucosal carcinoma lesions considered curable by local therapy. 9. Serious comorbidities requiring inpatient treatment (e.g., paralytic ileus, bowel obstruction, pulmonary fibrosis, uncontrolled diabetes, heart failure, myocardial infarction, angina, renal failure, hepatic failure, psychiatric disorders, cerebrovascular disorders, or transfusion-requiring ulcers). 10. Active infections, including: \- HBs antigen positive * Patients may be eligible if receiving nucleoside analog antiviral therapy and HBV-DNA \< 20 IU/mL (1.3 log IU/mL). \- HBs antibody positive or HBc antibody positive AND HBV-DNA positive * If HBV-DNA \< 20 IU/mL, the patient may be eligible. - HCV antibody positive * Patients may be eligible if HCV-RNA is below the detection limit. - HIV positive * Patients may be eligible if HIV infection is ruled out by confirmatory testing. * Other active infections requiring treatment. 11. History of autoimmune disease or chronic/recurrent autoimmune disease (patients with type 1 diabetes, hypothyroidism manageable with hormone replacement, or localized skin diseases such as vitiligo, psoriasis, or alopecia not requiring systemic therapy are eligible). 12. Requirement for systemic corticosteroids or immunosuppressive agents, or receipt of such therapy within 2 weeks prior to enrollment (treatment given on the same weekday 2 weeks earlier renders the patient ineligible), except for temporary administration for testing, allergic reactions, or edema associated with radiotherapy. 13. Lack of willingness or inability to comply with study procedures. 14. Considered unsuitable for the study by the principal investigator or sub-investigator. Pregnancy and Contraception: A woman of childbearing potential includes any female who has experienced menarche, has not undergone permanent sterilization (e.g., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), and is not postmenopausal. Postmenopause is defined as at least 12 consecutive months of amenorrhea without another medical cause. Women using oral contraceptives, intrauterine devices, or mechanical barrier methods are considered capable of becoming pregnant. If a female participant is determined to be not capable of becoming pregnant, this must be documented in source records. Women must use effective contraception for at least 1 month prior to first study treatment, from the time of consent, and for at least 4 months after the last dose. Men must use effective contraception during study treatment and for at least 4 months after the last dose. Acceptable contraception includes vasectomy or condom use for male participants or male partners, and tubal ligation, contraceptive pessary, intrauterine devices, or oral contraceptives for female participants or female partners.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-Limiting Toxicity (DLT) Rate [Phase Ib Part] | Up to 29 days after first dose | Percentage of participants experiencing dose-limiting toxicities (DLTs). |
| Objective Response Rate (ORR) [Phase II Part] | From baseline to objective disease progression or death, assessed up to 24 months. | Objective response rate assessed by the principal investigator or sub-investigator.Participants treated at the recommended dose in Phase Ib are included. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Serum Concentration of S-531011 (Cmax) | From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration | Maximum observed concentration of S-531011 in serum. |
| Time to Maximum Observed Serum Concentration of S-531011 (Tmax) | From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration | Time to reach the maximum observed serum concentration of S-531011. |
| Area Under the Serum Concentration-Time Curve of S-531011 (AUC) | From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration | Area under the serum concentration-time curve of S-531011. |
| Terminal Elimination Half-Life of S-531011 (t1/2) | From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration | Terminal elimination half-life of S-531011 estimated from serum concentration-time data. |
| Anti-S-531011 Antibody (ADA) Titer | From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration | Titer of anti-S-531011 antibodies measured to assess immunogenicity. |
| Incidence of Anti-S-531011 Antibody (ADA) Positivity | From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration | Proportion of participants with detectable anti-S-531011 antibodies. |
| Neutralizing Anti-S-531011 Antibody (NAb) Titer | From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration | Titer of neutralizing anti-S-531011 antibodies in participants who test positive for anti-S-531011 antibodies. |
| Incidence of Neutralizing Anti-S-531011 Antibody (NAb) Positivity | From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration | Proportion of participants with detectable neutralizing anti-S-531011 antibodies. |
| Duration of Response (DoR) [Phase Ib/II Part] | From first documented response until disease progression or death from any cause, whichever occurs first, assessed up to 12 months after the last subject is enrolled | Duration of confirmed objective response. |
| Disease Control Rate (DCR) [Phase Ib/II Part] | Up to 12 months after the last subject is enrolled | Percentage of participants achieving CR, PR, or SD. |
| Progression-Free Survival (PFS) [Phase Ib/II Part] | From enrollment until disease progression or death from any cause, whichever occurs first, assessed up to 12 months after the last subject is enrolled | Time from enrollment to radiological progression or death. |
| Overall Survival (OS) [Phase Ib/II Part] | From enrollment until death from any cause, assessed up to 12 months after the last subject is enrolled | Time from enrollment to death. |
| Incidence of Adverse Events [Phase Ib/II Part] | From first dose until 30 days after last dose for all adverse events, and thereafter for related adverse events up to 12 months after the last subject is enrolled | Percentage of participants experiencing adverse events. |
Contacts
CONTACTAkihito Kawazoe, MD
CONTACTKazumasa Yamamoto, MD
Outcome results
None listed