A Multicenter, Phase Ib/II Clinical Trial to Evaluate the Efficacy and Safety of Concurrent Combination Therapy of S-531011 Plus Fruquintinib or S-531011 Plus Fruquintinib Plus Pembrolizumab in Patients With MSS/pMMR Colorectal Cancer

Обзор

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.

Подробное описание

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.

Вмешательства

• Биопрепарат S-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.
• Препарат Fruquintinib
  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.
• Биопрепарат Pembrolizumab
  Pembrolizumab will be administered intravenously at a dose of 200 mg once every 3 weeks (q3w).

Первичные конечные точки

• Dose-Limiting Toxicity (DLT) Rate [Phase Ib Part] [Срок оценки: Up to 29 days after first dose]
• Objective Response Rate (ORR) [Phase II Part] [Срок оценки: From baseline to objective disease progression or death, assessed up to 24 months.]

Вторичные конечные точки (12)

• Maximum Observed Serum Concentration of S-531011 (Cmax) [Срок оценки: 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 Maximum Observed Serum Concentration of S-531011 (Tmax) [Срок оценки: 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 (AUC) [Срок оценки: 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 (t1/2) [Срок оценки: From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration]
• Anti-S-531011 Antibody (ADA) Titer [Срок оценки: From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration]
• Incidence of Anti-S-531011 Antibody (ADA) Positivity [Срок оценки: From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration]
• Neutralizing Anti-S-531011 Antibody (NAb) Titer [Срок оценки: From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration]
• Incidence of Neutralizing Anti-S-531011 Antibody (NAb) Positivity [Срок оценки: From the first through the ninth administration of S-531011 (each cycle is 21 days) and at 30 days after the final administration]
• Duration of Response (DoR) [Phase Ib/II Part] [Срок оценки: 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]
• Disease Control Rate (DCR) [Phase Ib/II Part] [Срок оценки: Up to 12 months after the last subject is enrolled]
• Progression-Free Survival (PFS) [Phase Ib/II Part] [Срок оценки: From enrollment until disease progression or death from any cause, whichever occurs first, assessed up to 12 months after the last subject is enrolled]
• Overall Survival (OS) [Phase Ib/II Part] [Срок оценки: From enrollment until death from any cause, assessed up to 12 months after the last subject is enrolled]

Критерии участия

Критерии включения

• Patients with histologically confirmed unresectable adenocarcinoma of the colon or rectum.
• Confirmed microsatellite stable (MSS) or proficient mismatch repair (pMMR) status.
• 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.

• Presence of measurable disease according to RECIST version 1.1.
• Age ≥ 18 years at the time of informed consent.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
• 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):

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• Absolute neutrophil count ≥ 1,500/mm³
• Hemoglobin ≥ 9.0 g/dL
• Platelet count ≥ 75,000/mm³
• Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN)
• AST (GOT) ≤ 2.5 × ULN; ≤ 5 × ULN if liver metastases are present
• ALT (GPT) ≤ 2.5 × ULN; ≤ 5 × ULN if liver metastases are present
• Creatinine ≤ 1.5 mg/dL
• 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.

Критерии исключения

• Prior treatment with fruquintinib for metastatic colorectal cancer.
• Prior treatment with any anti-CCR8 antibody, regardless of indication.
• 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).
• History of acute coronary syndrome (including myocardial infarction or unstable angina), coronary angioplasty, or stent placement within 6 months prior to enrollment.
• History or current findings of congestive heart failure of NYHA Class III or higher.
• Uncontrolled hypertension.
• Known central nervous system metastases. (If CNS metastasis is clinically suspected, brain CT or MRI must be performed during screening.)
• 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.
• 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).
• 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.
• 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).
• 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.
• Lack of willingness or inability to comply with study procedures.
• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07591597 · EPOC2501 · jRCT2031260047

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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