Inclusion Criteria - Pre-Screening:

• Able to give written informed consent.
• Metastatic colorectal cancer (mCRC).
• Progression or recurrence following prior anti-EGFR containing regimen and at least in second line of treatment for mCRC.
• Known N-K-RAS (exons 2, 3 and 4) wild-type status.
• Known BRAF wild-type or unknown BRAF status.
• Male and female aged ≥ 18 years.

Inclusion Criteria - Screening:

• Able to give written informed consent before any study related procedure.
• Histological documentation of adenocarcinoma of the colon or rectum with radiological evidence of progressive disease after last treatment received.
• Progression or recurrence following irinotecan, oxaliplatin, fluoropyrimidine containing regimen and anti-EGFR containing regimens for metastatic disease. Patients who have a history of intolerance of irinotecan-based therapy or who are ineligible to receive irinotecan are also eligible as long as they have received a prior oxaliplatin-based therapy. Patients who have a history of intolerance of oxaliplatin-based therapy or who are ineligible to receive oxaliplatin are also eligible as long as they have received a prior irinotecan-based therapy.
• Best response according to Response Evaluation Criteria in Solid Tumours (RECIST) criteria to the last anti-EGFR containing regimen of partial response (PR) or stable disease (SD) for at least 4 months.
• Measurable disease according to RECIST criteria, version 1.1.
• Having a tumour N-K-RAS (exons 2, 3 and 4) and BRAF wild-type harbouring a PIK3CA mutation, as per centrallyanalysed ctDNA during the [pre]-screening period using a validated test.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Life expectancy ≥ 12 weeks.
• Adequate cardiac function as defined by left ventricular ejection fraction of ≥ 50% measured by a multigated acquisition (MUGA) scan or echocardiography (ECHO).
• Adequate bone marrow function as defined by ANC of ≥ 1.5 x 10^9 /L, platelet count of ≥ 100.0 x 10^9 /L and haemoglobin of ≥ 9 g/dL.
• Adequate liver function, as determined by total bilirubin within ULN (≤ 1.5 x ULN if documented liver involvement; ≤ 3 x ULN with direct bilirubin ≤ 1.5 x ULN in case of patients with coexisting known Gilbert’s disease) and/or AST and ALT ≤ 2.5 x ULN (≤ 5 x ULN if liver metastases).
• Adequate renal function assessed by creatinine clearance ≥ 50 mL/min (calculated by Cockcroft-Gault formula).
• Adequate electrolytes (serum potassium and magnesium levels within institutional normal limits). Replacement treatment to achieve adequate electrolytes levels is allowed.
• Not pregnant, not breastfeeding, and at least 1 of the following conditions applies:
  • Not a woman of childbearing potential (WOCBP); OR
  • A WOCBP who agrees to use highly effective contraception 4 weeks before the first dose of the study treatment, during the treatment period and for 6 months following the last dose of the study treatment. Patients should not breastfeed during and at least for 6 months after the last dose of the study treatment.
• Male patient who is surgically sterile or male patient who is willing to agree and have his female partners (if WOCBP) agreeing with the true abstinence (refrain from heterosexual intercourse) or who agrees to use and to have his female partners (if WOCBP) using barrier contraceptive measures during the entire study treatment period and for 6 months after the last administration of study treatment, and agrees to refrain from donating sperm during the entire study treatment period and for 6 months after the last administration of study treatment.

Exclusion Criteria:

• Patients will not be eligible for entry into the pre-screening if they meet ANY of the following exclusion criteria:
  • Patients with a known PIK3CA wild-type status;
  • Note: this exclusion criterion does not apply if PIK3CA wild-type status was assessed before the last anti-EGFR containing regimen.
• Previous treatment with phosphatidylinositol 3-kinase (PI3K) inhibitor.
• Hypersensitivity and/or contraindication to MEN1611, cetuximab or to any component of the formulations.
• Inability or unwillingness to abide by the study protocol; legal incapacity or limited legal capacity.
• None of the following exclusion criteria shall be met at Screening Visit and will be re-checked at Day 1 of Cycle 1:
  • Previous treatment with a PI3K inhibitor;
  • Hypersensitivity and/or contraindication to MEN1611, cetuximab or to any component of the formulations;
  • Inability to swallow oral medications;
  • Brain metastases, with the exception of patients with previously treated brain metastases (including radiation and/or surgery) > 4 weeks before the Screening Visit and only if clinically stable (as determined by the Investigator), and not receiving corticosteroids;
  • NCI CTCAE v5.0 Grade ≥ 2 diarrhea, which is not resolved in the week prior to the start of the study treatment (Day 1 of Cycle 1).
• History of significant, uncontrolled or active cardiovascular disease, specifically including, but not restricted to:
  • Myocardial infarction within 6 months prior to the first dose of any study treatment (Day 1 of Cycle 1);
  • Acute coronary syndromes (including unstable angina, coronary artery bypass grafting [CABG], coronary angioplasty or stenting) within 6 months prior to first dose of any study treatment (Day 1 of Cycle 1);
  • Congestive heart failure (CHF) New York Heart Association Class III-IV;
  • Clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the Investigator;
  • Long QT syndrome or other risk factors for “Torsades de Pointes” or increased QT interval (QTc) according to Fridericia formula (QTcF > 450 msec for males and QTcF > 460 msec for females);
  • Ventricular arrhythmia.
• Symptomatic thromboembolic events or cerebrovascular accident including transient ischaemic attack within 6 months prior to the start of any study treatment (Day 1 of Cycle 1).
• Uncontrolled hypertension (defined as persistent blood pressure [BP] of ≥ 150/90 mmHg despite treatment, measured on at least 2 separate occasions).
• Known active or uncontrolled pulmonary dysfunction.
• Any serious and/or unstable pre-existing psychiatric or neurologic illness or other conditions that could interfere with patient’s safety.
• Uncontrolled diabetes mellitus (glycated haemoglobin [HbA1c] > 7%) and fasting plasma glucose (FPG) > 126 mg/dL.
• Known history of human immunodeficiency virus (HIV) infection or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).
• Patients diagnosed with another primary malignancy, except for: Adequately treated non-melanoma skin cancer or cervical cancer in situ; or patients with another primary malignancy who are definitively relapse-free for at least 3 years since the diagnosis of the other primary malignancy.
• Concurrent chronic immunosuppressive treatment either with steroids or other immunosuppressive agents.
• Any chemotherapy, radiotherapy, immunotherapy, major surgery, biologic therapy or any other investigational agent within 28 days of the first administration of the study treatment or within five times the half-life of the investigational agent, whichever is longer. 
  • Note: Patients may receive palliative radiotherapy for painful bone metastases, as long as ≤ 25% of the bone marrow was irradiated and does not affect target and nontarget lesions being assessed.
• Any other concurrent severe and/or uncontrolled concomitant medical conditions (e.g., active or uncontrolled infection) that could cause unacceptable safety risks or compromise compliance with the protocol.
• Patient receiving treatment with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A as well as strong inhibitors or inducers of CYP1A within 2 weeks of the first administration of MEN1611. Switching to a different medication is allowed.
• Pregnant or breastfeeding women.
• Inability or unwillingness to abide by the study protocol; legal incapacity or limited legal capacity.
• Warfarin sodium therapy or any other coumadin-derivative anticoagulant.

Eligibility last updated 9/22/21. Questions regarding updates should be directed to the study team contact.