Single Cell Characterization of Persistent Cells Upon Treatment With Durvalumab (MEDI4736) With or Without Tremelimumab in MSS and MSI Colorectal and Endometrial Tumors: the SERPENTINE Clinical Trial
Overview
- Phase
- Phase 2
- Status
- Recruiting
- Sponsor
- Vall d'Hebron Institute of Oncology
- Enrollment
- 60
- Locations
- 1
- Primary Endpoint
- Evaluation of Objective Response Rate (ORR)
Overview
Brief Summary
The SERPENTINE trial (ESR 21-21165) is a phase II clinical study aiming to evaluate the efficacy of durvalumab and tremelimumab, alone or in combination, in patients with colorectal or endometrial cancer. The trial targets patients with microsatellite instability-high (MSI-H) tumors and those with microsatellite stable (MSS) tumors.
Colorectal and endometrial cancers present significant challenges due to their heterogeneity and variable responses to treatment. Immunotherapy, particularly checkpoint inhibitors like durvalumab and tremelimumab, has shown promise in some patients, but predicting response remains elusive. The SERPENTINE trial aims to address this gap by investigating the effectiveness of these immunotherapies in a carefully selected patient population.
Detailed Description
The trial is a single-center, open-label study with two cohorts: one for patients with MSI-H tumors and another for those with MSS tumors. Patients will be randomized to receive either durvalumab alone or in combination with tremelimumab. Tumor assessments will be conducted every 8 weeks using RECIST v1.1 criteria. Statistical analysis will employ descriptive statistics, and safety and efficacy data will be analyzed based on intention-to-treat principles.
Study Design
- Study Type
- Interventional
- Allocation
- Non Randomized
- Intervention Model
- Parallel
- Primary Purpose
- Treatment
- Masking
- None
Eligibility Criteria
- Ages
- 18 Years to — (Adult, Older Adult)
- Sex
- All
- Accepts Healthy Volunteers
- No
Inclusion Criteria
- •Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Written informed consent and any locally required authorization (e.g., Health Insurance Portability and Accountability Act in the US, European Union \[EU\] Data Privacy Directive in the EU) obtained from the patient/legal representative prior to performing any protocol-related procedures, including screening evaluations.
- •Age \> 18 years at time of study entry.
- •Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Cohort 1: histologically confirmed recurrent or metastatic CRC or endometrial cancer irrespective of prior treatment history with chemotherapy and/or targeted agents, not amenable to surgery and known tumor MSI-H or dMMR status per local standard of practice.
- •Cohort 2: histologically confirmed recurrent or metastatic CRC not amenable to surgery and known tumor MSS or pMMR status per local standard of practice, that have progressed during or after, at least 2 lines of fluoropyrimidine, irinotecan and/or oxaliplatin containing therapy with or without bevacizumab according to institutional practice or have not tolerated therapy for advanced/metastatic disease; if epidermal growth factor receptor (EGFR) positive/RAS wild type, prior anti-EGFR treatment is required. Or histologically confirmed recurrent or metastatic endometrial cancer that have progressed during or after a platinum and taxane-based regimen, not amenable to surgery and known tumor MSS or pMMR status per local standard of practice.
- •Life expectancy of \> 12 weeks.
- •Body weight \>30 kg.
- •Adequate normal organ and marrow function as defined below:
- •Hemoglobin ≥9.0 g/dL
- •Absolute neutrophil count (ANC) 1.5 (or 1.0) x 109/L (\> 1500 per mm3)
Exclusion Criteria
- •Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.
- •Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 14 days prior to the first dose of trial treatment. The following are exceptions to this criterion:
- •Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- •Systemic corticosteroids at physiologic doses not to exceed \<\<10 mg/day\>\> of prednisone or its equivalent
- •Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication).
- •Has had a prior anti-cancer mAb within 4 weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from AEs due to mAbs administered more than 4 weeks earlier.
- •Has had prior chemotherapy, targeted small molecule therapy, hormonal therapy or radiation therapy for cancer therapy within 2 weeks prior to study Day
- •Concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.
- •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.
Arms & Interventions
Control arm
Patients in this arm receive Durvalumab alone. Durvalumab is administered intravenously (IV) at a dose of 1500 mg every 4 weeks. This arm is designed to evaluate the efficacy and safety of Durvalumab monotherapy in patients with colorectal or endometrial cancer.
Intervention: Durvalumab (Drug)
MSI arm
Patients in this arm receive a combination of Durvalumab and Tremelimumab. They initially receive Tremelimumab as a single dose of 300 mg IV, followed by Durvalumab administered at a dose of 1500 mg IV every 4 weeks. This arm aims to assess the efficacy and safety of combining Durvalumab with Tremelimumab in patients with colorectal or endometrial cancer.
Intervention: Durvalumab (Drug)
MSI arm
Patients in this arm receive a combination of Durvalumab and Tremelimumab. They initially receive Tremelimumab as a single dose of 300 mg IV, followed by Durvalumab administered at a dose of 1500 mg IV every 4 weeks. This arm aims to assess the efficacy and safety of combining Durvalumab with Tremelimumab in patients with colorectal or endometrial cancer.
Intervention: Tremelimumab (Drug)
MSS arm
Patients in this arm also receive a combination of Durvalumab and Tremelimumab. Similar to Cohorte 1B, they receive Tremelimumab as a single dose of 300 mg IV, followed by Durvalumab administered at a dose of 1500 mg IV every 4 weeks. However, patients in this arm have tumors with microsatellite stability (MSS), unlike Cohorte 1B where patients have tumors with microsatellite instability (MSI). This arm aims to evaluate the efficacy and safety of the Durvalumab and Tremelimumab combination in patients with MSS tumors.
Intervention: Durvalumab (Drug)
MSS arm
Patients in this arm also receive a combination of Durvalumab and Tremelimumab. Similar to Cohorte 1B, they receive Tremelimumab as a single dose of 300 mg IV, followed by Durvalumab administered at a dose of 1500 mg IV every 4 weeks. However, patients in this arm have tumors with microsatellite stability (MSS), unlike Cohorte 1B where patients have tumors with microsatellite instability (MSI). This arm aims to evaluate the efficacy and safety of the Durvalumab and Tremelimumab combination in patients with MSS tumors.
Intervention: Tremelimumab (Drug)
Outcomes
Primary Outcomes
Evaluation of Objective Response Rate (ORR)
Time Frame: From treatment initiation until objective response confirmation or progression of disease (24 months).
Assess the objective response rate (ORR) of Durvalumab or Tremelimumab 300 mg single dose followed by Durvalumab in patients with microsatellite instable (MSI) colorectal cancer (CRC) or endometrial cancer (EC) and Tremelimumab 300 mg single dose followed by Durvalumab in refractory microsatellite stable (MSS) CRC and EC according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
Secondary Outcomes
- Antitumor Activity Assessment (PFS)(Throughout the study duration (24 months).)
- Antitumor Activity Assessment (OS)(Throughout the study duration (24 months).)
- Antitumor Activity Assessment (DoR)(Throughout the study duration (24 months).)
- Antitumor Activity Assessment (TTMR)(Throughout the study duration (24 months).)
- Antitumor Activity Assessment (irRR)(Throughout the study duration (24 months).)
- Antitumor Activity Assessment (biomarkers)(Throughout the study duration (24 months).)
- Single-Cell Characterization of Persistent Cells(At baseline, at the time of maximal response, and at progression (48 months).)
- Correlation of Antitumor Activity with Biomarkers(Throughout the study duration (24 months).)
- Exploration of Immunotoxicity Biomarkers(Throughout the study duration (24 months).)