Clinical Trials

Inclusion Criteria:

• Able to give written informed consent before any study related procedure.
• Male and female patients aged ≥ 18 years.
• Histological documentation of adenocarcinoma of the colon or rectum with radiological evidence of progressive disease after last treatment received.
• Progression or recurrence following prior irinotecan, oxaliplatin, 5-FU and anti-EGFR containing regimens for metastatic disease. Patients who have a history of intolerance of irinotecan-based therapy or ineligibility 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 ineligibility 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 at least stable disease (SD) for 4 months.
• Measurable disease according to RECIST criteria, version 1.1.
• N-K-RAS (exons 2, 3 and 4) and BRAF wild-type and PIK3CA mutations detected in ctDNA assay during [pre]- screening period centrally analysed 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  ≥ .5x 10^9/L, platelet count of ≥ 100.0x 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 ≤ 1.5 x ULN.*
• Adequate electrolytes (serum potassium and magnesium levels within institutional normal limits). Replacement treatment to achieve adequate electrolytes is allowed.
• Not pregnant, not breastfeeding, or 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 drug, and agrees to refrain from donating sperm during the entire study treatment period and for 6 months after the last administration of study drug.

* Inclusion criteria will be re-evaluated prior to the start of any study treatment (Day 1 of Cycle 1, as applicable).

Exclusion Criteria:

• Previous treatment with PI3K inhibitor.
• Previous treatment with an anti-EGFR containing regimen for metastatic disease within 6 months prior to inclusion into the study.
• Hypersensitivity and/or contraindication to MEN1611, cetuximab or to any component of the formulations.
• Inability to swallow oral medications.
• Untreated brain metastases, with the exception of patients with previously treated brain metastases (including with previously treated brain metastases (including radiation and/or surgery) > 4 weeks earlier 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 any study treatment (Day 1 of Cycle 1, as applicable).
• 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, as applicable);
  • 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, as applicable);
  • 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, as applicable).
• 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 30 days of the first administration of any study treatment.
• 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 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.