MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01)
- Registration Number
- NCT04495621
- Lead Sponsor
- Menarini Group
- Brief Summary
Open-label, dose-confirmation and cohort expansion, multicenter, Phase Ib/II study to assess the anti-tumor activity and safety of MEN1611 in combination with cetuximab for the treatment of participants with phosphatidylinositol 3-kinase, catalytic, alpha polypeptide gene (PIK3CA)-mutated metastatic colorectal cancer.
- Detailed Description
This Phase Ib/II study investigated the anti-tumor activity and safety of daily oral doses MEN1611 in combination with cetuximab in female and male participants affected by PIK3CA-mutated, neuroblastoma-Kristen-rat sarcoma virus (N-K-RAS) wild-type, and BRAF wild-type metastatic colorectal cancer.
MEN1611 is a potent, selective class I phosphoinositide 3-kinase (PI3K) inhibitor. The maximum tolerated dose of MEN1611 given as single agent was assessed in a Phase I trial in participants with advanced solid tumors.
This Phase Ib/II started with a dose confirmation part (Step 1) to identify the recommended phase 2 dose of MEN1611 given in combination with cetuximab.
The study continued with a cohort expansion (Step 2) to explore the anti-tumor activity of the selected MEN1611 dose level combined with cetuximab with further assessment of safety and tolerability.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 29
- Histological documentation of adenocarcinoma of the colon or rectum.
- Progression or recurrence following prior irinotecan, oxaliplatin, 5-fluorouracil (5-FU) and anti-epidermal growth factor receptor (EGFR) containing regimens for metastatic disease.
- Best response according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria to the last anti-EGFR containing regimen of partial response or stable disease for at least 4 months.
- Measurable disease according to RECIST criteria.
- N-K-RAS (exons 2, 3 and 4) and BRAF wild-type and PIK3CA mutated.
- Eastern Cooperative Oncology Group performance status of 0 or 1.
Main
- Previous treatment with PI3K inhibitor.
- Brain metastases, unless treated >4 weeks before screening visit and only if clinically stable and not receiving corticosteroids.
- National Cancer Institute Common Terminology Criteria for Adverse Events v5.0 Grade ≥2 diarrhea.
- History of significant, uncontrolled or active cardiovascular disease.
- Known active or uncontrolled pulmonary dysfunction.
- Uncontrolled diabetes mellitus (glycated hemoglobin >7%) and fasting plasma glucose >126 milligrams/deciliter.
- Known history of human immunodeficiency virus infection or active infection with hepatitis C virus or hepatitis B virus.
- Concurrent chronic immunosuppressive treatment either with steroids or other immunosuppressive agents.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description MEN1611 MEN1611 MEN1611 + Cetuximab MEN1611 Cetuximab MEN1611 + Cetuximab
- Primary Outcome Measures
Name Time Method Phase 1b: Recommended Phase 2 Dose (RP2D) of MEN1611 in Combination With Cetuximab Day 1 through Day 28 of Cycle 1 (28 days/cycle) RP2D was defined as the highest dose level in milligrams (mg) at which no more than 1 participant during the dose confirmation phase (Phase 1b) experienced a dose-limiting toxicity (DLT) during the DLT assessment window (28 days), or the maximum dose judged to be tolerable by the data safety committee.
Best Overall Response Rate (ORR) of MEN1611 in Combination With Cetuximab Up to 37 Months The best ORR was defined as percentage of participants who had a best overall response to therapy of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) and was defined according to Response Evaluation Criteria in Solid Tumors version 1.1 assessment locally performed using computed tomography scans or magnetic resonance imaging of the chest and abdomen (including pelvis and adrenal glands).
Phase 1b: Number of Participants With DLTs for MEN1611 Day 1 through Day 28 of Cycle 1 (28 days/cycle) A DLT was defined as any of the following adverse drug reactions (ADRs) related to the combination regimens or to MEN1611 alone and unrelated to the participants' underlying disease or concomitant medication occurring during Cycle 1 over the DLT assessment window of 28 days: any Grade 3 (lasting \>7 days) or Grade 4 increase in aspartate aminotransferase, alanine aminotransferase, or alkaline phosphatase; any Grade ≥3 cardiac disorder or new segmental wall-motion abnormalities; any Grade ≥3 non-hematologic toxicity with the following exceptions: nausea, vomiting, diarrhea, skin rash, hyperglycemia. An ADR was defined as any adverse event suspected by the investigator and/or the sponsor to be related to MEN1611, cetuximab, or both given in combination.
- Secondary Outcome Measures
Name Time Method Plasma Concentration of MEN1611 in Combination With Cetuximab Day 22 (1.5 hours postdose) of Cycle 1 (28 days/cycle) Blood samples were taken for the analyses of MEN1611 in plasma at designated time points. Results are reported as nanograms/millilitre (ng/mL).
Disease Control Rate (DCR) of MEN1611 in Combination With Cetuximab Up to 37 Months DCR was defined as percentage of participants whose disease shrank or remained stable over a certain time period and was calculated based on the sum of the CR, PR, and SD rates according to local assessment.
Duration of Response (DOR) of MEN1611 in Combination With Cetuximab Up to 37 months DOR was defined as the time from confirmation of a PR, CR or SD as locally assessed, until the disease had been shown to progress following treatment. Participants with a previous response who did not show a relapse or died without recording a relapse were censored at their last available relapse-free tumor assessment date. Participants with only one tumor assessment after baseline showing a PD were not included in the calculation.
Progression-free Survival (PFS) of MEN1611 in Combination With Cetuximab Up to 37 months PFS was defined as the number of days between the first study treatment administration to the date of first documented disease progression as per local assessment, relapse or death from any cause. Responding participants and participants who were lost to follow-up were censored at their last tumor assessment date.
Overall Survival (OS) of MEN1611 in Combination With Cetuximab Up to 37 months OS was defined as the number of days between the first study treatment administration and death from any cause. Participants still alive that had withdrawn from the study were censored using the latest among end of study and follow-up dates. Drop-out participants were considered censored and the last available date in which the participant was known to be alive was considered.
Trial Locations
- Locations (28)
Amsterdam University Medical Center
🇳🇱Amsterdam, Netherlands
Klinikum rechts der Isar der TU
🇩🇪Munich, Germany
ICO - Site Paul Papin
🇫🇷Angers, France
ICO - Site René Gauducheau
🇫🇷Saint-Herblain, France
Istituto Clinico Humanitas
🇮🇹Rozzano, Italy
Klinikum der Universitaet Muenchen Campus Grosshadern
🇩🇪Munich, Germany
Universitaetsklinikum Tuebingen
🇩🇪Tuebingen, Germany
Azienda Ospedaliero Universitaria San Martino
🇮🇹Genoa, Italy
Istituto Europeo di Oncologia (IEO)
🇮🇹Milan, Italy
Azienda Socio Sanitaria Territoriale Niguarda
🇮🇹Milan, Italy
Azienda Ospedaliero Universitaria Pisana
🇮🇹Pisa, Italy
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
Radboud Nijmegen
🇳🇱Nijmegen, Netherlands
Erasmus Medisch Centrum
🇳🇱Rotterdam, Netherlands
Examen sp. z o.o.
🇵🇱Skórzewo, Poland
Centrum Onkologii-Instytut im.M.Sklodowskiej Curie
🇵🇱Warsaw, Poland
Hospital Universitari Vall d'Hebron
🇪🇸Barcelona, Spain
Hospital Universitario Ramon y Cajal
🇪🇸Madrid, Spain
Fundacion Jimenez Diaz
🇪🇸Madrid, Spain
Centro Integral Oncologico Clara Campal
🇪🇸Madrid, Spain
Hospital Clinico Universitario de Valencia
🇪🇸Valencia, Spain
Asklepios Klinik Altona
🇩🇪Hamburg, Germany
Mayo Clinic Arizona
🇺🇸Phoenix, Arizona, United States
The Oncology Institute of Hope and Innovation
🇺🇸Anaheim, California, United States
MultiCare Health System Institute for Research and Innovation
🇺🇸Tacoma, Washington, United States
Centre Georges François Leclerc
🇫🇷Dijon, France
Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin
🇩🇪Berlin, Germany
Universitaetsklinikum Carl Gustav Carus TU Dresden
🇩🇪Dresden, Germany