MEN1611 With Cetuximab in Metastatic Colorectal Cancer (C-PRECISE-01) (C-PRECISE-01)

Open-label, Multicentre, Phase Ib/II Study of MEN1611, a PI3K Inhibitor, and Cetuximab in Patients With PIK3CA Mutated Metastatic Colorectal Cancer Failing Irinotecan, Oxaliplatin, 5-FU and Anti-EGFR Containing Regimens

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.

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: MEN1611; Drug: Cetuximab

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.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• France
  • Angers, France, 49055
    • ICO - Site Paul Papin
  • Dijon, France, 21000
    • Centre Georges François Leclerc
  • Saint-Herblain, France, 44800
    • ICO - Site René Gauducheau
• Germany
  • Berlin, Germany, 12203
    • Charite Universitaetsmedizin Berlin - Campus Benjamin Franklin
  • Dresden, Germany, 01307
    • Universitaetsklinikum Carl Gustav Carus TU Dresden
  • Hamburg, Germany, 22763
    • Asklepios Klinik Altona
  • Munich, Germany, 81377
    • Klinikum der Universitaet Muenchen Campus Grosshadern
  • Munich, Germany, 81675
    • Klinikum rechts der Isar der TU
  • Tuebingen, Germany, 72076
    • Universitaetsklinikum Tuebingen
• Italy
  • Genoa, Italy, 16132
    • Azienda Ospedaliero Universitaria San Martino
  • Milan, Italy, 20141
    • Istituto Europeo di Oncologia (IEO)
  • Milan, Italy, 20162
    • Azienda Socio Sanitaria Territoriale Niguarda
  • Pisa, Italy, 56126
    • Azienda Ospedaliero Universitaria Pisana
  • Rozzano, Italy, 20089
    • Istituto Clinico Humanitas
• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam University Medical Center
  • Maastricht, Netherlands, 6229 HX
    • Maastricht University Medical Center
  • Nijmegen, Netherlands, 6525 GA
    • Radboud Nijmegen
  • Rotterdam, Netherlands, 3015 GD
    • Erasmus Medisch Centrum
• Poland
  • Skórzewo, Poland, 60-185
    • Examen sp. z o.o.
  • Warsaw, Poland, 00-001
    • Centrum Onkologii-Instytut im.M.Sklodowskiej Curie
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28040
    • Fundacion Jimenez Diaz
  • Madrid, Spain, 28034
    • Hospital Universitario Ramon y Cajal
  • Madrid, Spain, 28050
    • Centro Integral Oncologico Clara Campal
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
• United States
  • Arizona
    • Phoenix, Arizona, United States, 85054
      • Mayo Clinic Arizona
  • California
    • Anaheim, California, United States, 92801
      • The Oncology Institute of Hope and Innovation
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Health System Institute for Research and Innovation

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Main Inclusion Criteria:

• 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 Exclusion Criteria:

• 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 Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: MEN1611; MEN1611 + Cetuximab	Drug: MEN1611; MEN1611 oral dose administered twice daily for a continuous 28-day cycle.; Drug: Cetuximab; Cetuximab solution for infusion administered weekly via intravenous infusion.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1b: Recommended Phase 2 Dose (RP2D) of MEN1611 in Combination With Cetuximab	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.	Day 1 through Day 28 of Cycle 1 (28 days/cycle)
Best Overall Response Rate (ORR) of MEN1611 in Combination With Cetuximab	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).	Up to 37 Months
Phase 1b: Number of Participants With DLTs for MEN1611	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.	Day 1 through Day 28 of Cycle 1 (28 days/cycle)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Plasma Concentration of MEN1611 in Combination With Cetuximab	Blood samples were taken for the analyses of MEN1611 in plasma at designated time points. Results are reported as nanograms/millilitre (ng/mL).	Day 22 (1.5 hours postdose) of Cycle 1 (28 days/cycle)
Disease Control Rate (DCR) of MEN1611 in Combination With Cetuximab	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.	Up to 37 Months
Duration of Response (DOR) of MEN1611 in Combination With Cetuximab	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.	Up to 37 months
Progression-free Survival (PFS) of MEN1611 in Combination With Cetuximab	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.	Up to 37 months
Overall Survival (OS) of MEN1611 in Combination With Cetuximab	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.	Up to 37 months

Collaborators and Investigators

• Sponsor: Menarini Group
• Investigators: Study Chair: Josep Tabernero, MD, PhD, Vall d' Hebron Institute of Oncology (VHIO), Barcelona, Spain

Study record dates

Study Major Dates

• Study Start (Actual): July 20, 2020
• Primary Completion (Actual): January 12, 2024
• Study Completion (Actual): February 27, 2024

Study Registration Dates

• First Submitted: June 30, 2020
• First Submitted That Met QC Criteria: July 28, 2020
• First Posted (Actual): August 3, 2020

Study Record Updates

• Last Update Posted (Actual): May 1, 2025
• Last Update Submitted That Met QC Criteria: April 29, 2025
• Last Verified: April 1, 2025

More Information

Terms related to this study

• Keywords: Cetuximab; Metastatic Colorectal Cancer; mCRC; PI3K Inhibitor; anti-EGFR; PIK3CA mutated; MEN1611
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Intestinal Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colonic Diseases; Colorectal Neoplasms; Antineoplastic Agents, Immunological; Antineoplastic Agents; Cetuximab
• Other Study ID Numbers: MEN1611-02; 2019-003727-38 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No