PIK3CA mutated colorectal cancer MedDRA version: 21.0 Level: LLT Classification code 10052362 Term: Metastatic colorectal cancer System Organ Class: 100000004864
Conditions
Sponsors
Menarini Ricerche S.p.A.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Patients meeting all the following criteria will be eligible for entry into the pre-screening: 1. Able to give written informed consent. 2. Metastatic colorectal cancer (mCRC). 3. Progression or recurrence following prior anti-EGFR containing regimen and at least in second line of treatment for mCRC. 4. Known N-K-RAS (exons 2, 3 and 4) wild-type status. 5. Known BRAF wild-type or unknown BRAF status. 6. Male and female aged = 18 years. Patients meeting all the following criteria at Screening Visit will be eligible for entry into the study: 1. Able to give written informed consent before any study related procedure. 2. Histological documentation of adenocarcinoma of the colon or rectum with radiological evidence of progressive disease after last treatment received. 3. Progression or recurrence following prior 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. 4. 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. 5. Measurable disease according to RECIST criteria, version 1.1. 6. Having a tumour N-K-RAS (exons 2, 3 and 4) and BRAF wild-type and PIK3CA mutation, as per centrally-analysed ctDNA during the[pre]-screening period using a validated test. 7. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1. 8. Life expectancy = 12 weeks. 9. Adequate cardiac function as defined by left ventricular ejection fraction of = 50% measured by a multigated acquisition (MUGA) scan or echocardiography (ECHO). 10. Adequate bone marrow function as defined by absolute neutrophil count (ANC) of = 1.5x 10^9/L, platelet count of = 100.0x 10^9/L and haemoglobin of = 9 g/dL. 11. Adequate liver function, as determined by total bilirubin within upper limit of normal (ULN) (= 1.5x ULN if documented liver involvement; = 3x ULN with direct bilirubin = 1.5x ULN in case of patients with coexisting known Gilbert’s disease) and/or AST and alanine aminotransferase (ALT) = 2.5x ULN (= 5x ULN if liver metastases). 12. Adequate renal function assessed by creatinine clearance = 50 mL/min. 13. Adequate electrolytes (serum potassium and magnesium levels within institutional normal limits). Replacement treatment to achieve adequate electrolytes levels is allowed. 14. Not pregnant, not breastfeeding, and at least 1 of the following conditions applies: a) Not a woman of childbearing potential (WOCBP). OR b) 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. 15. 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 fema
Exclusion criteria
Exclusion criteria: Patients will not be eligible for entry into the pre-screening if they meet ANY of the following exclusion criteria: 1. Patients with a known PIK3CA WT status Note: this exclusion criterion does not apply if PIK3CA WT status was assessed before the last anti-EGFR containing regimen. 2. Previous treatment with PI3K inhibitor. 3. Hypersensitivity and/or contraindication to MEN1611, cetuximab or to any component of the formulations. 4. 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 Cycle 1: 1. Previous treatment with PI3K inhibitor. 2. Hypersensitivity and/or contraindication to MEN1611, cetuximab or to any component of the formulations. 3. Inability to swallow oral medications. 4. 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. 5. NCI CTCAE v5.0 Grade = 2 diarrhoea, which is not resolved in the week prior to the start of the study treatment (Day 1 of Cycle 1, as applicable). 6. History of significant, uncontrolled or active cardiovascular disease, specifically including, but not restricted to: a) Myocardial infarction within 6 months prior to the first dose of any study treatment (Day 1 of Cycle 1, as applicable). b) 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). c) Congestive heart failure (CHF) New York Heart Association Class III-IV. d) Clinically significant atrial arrhythmia (including clinically significant bradyarrhythmia), as determined by the Investigator. e) Long QT syndrome or other risk factors for “Torsades de Pointes” or increased QTc interval according to Fridericia formula (QTcF > 450 msec for males and QTcF > 460 msec for females). f) Ventricular arrhythmia. 7. 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). 8. Uncontrolled hypertension (defined as persistent BP of = 150/90 mmHg despite treatment, measured on at least 2 separate occasions). 9. Known active or uncontrolled pulmonary dysfunction. 10. Any serious and/or unstable pre-existing psychiatric or neurologic illness or other conditions that could interfere with patient’s safety. 11. Uncontrolled diabetes mellitus (HbA1c > 7%) and FPG > 126 mg/dL. 12. Known history of human immunodeficiency virus (HIV) infection or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). 13. Patients diagnosed with another primary malignancy, except for: adequately treated nonmelanoma 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. 14. Concurrent chronic immunosuppressive treatment either with steroids or other immunosuppressive agents. 15. 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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Step 1: To determine the RP2D of MEN1611 when administered orally in combination with cetuximab to patients with PIK3CA mutated colorectal cancer failing irinotecan, oxaliplatin, 5-FU and anti-EGFR containing regimens. Step 2: To assess the anti-tumour activity of MEN1611 in combination with cetuximab in patients with PIK3CA mutated metastatic colorectal cancer failing irinotecan, oxaliplatin, 5-FU and anti-EGFR containing regimens.;Secondary Objective: - To assess the safety and tolerability of MEN1611 in combination with cetuximab. - To assess the PK profile of MEN1611 when given in combination with cetuximab.;Primary end point(s): Step 1 (Identification of Dose for Cohort Expansion): 1. Identification of the dose for the Cohort Expansion, defined as the highest dose level (maximum dose tested 48 mg BID, minimal dose tested 32 mg BID) at which no more than 1 of 6 patients experiences a DLT during the DLT assessment window (28 days) or the maximum dose judged to be tolerable by the DSC. The DSC will review and evaluate all the available safety data, any DLTs and PK data collected during Step 1, in order to confirm the RP2D to be tested in Step 2. Step 2 (Cohort Expansion Phase): 1.Best ORR defined according to RECIST v1.1 assessment locally performed using CT scan or MRI of the chest and abdomen (including pelvis and adrenal glands). Any other areas of disease involvement should be additionally investigated based on signs and symptoms of the individual patient.;Timepoint(s) of evaluation of this end point: Step 1 (Dose-confirmation Phase): Cycle 1 (28 days) Step 2 (Cohort-expansion Phase): throughout the study duration | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary Endpoints 1. Safety and tolerability: -Incidence, severity as per CTCAE version 5.0 grading, seriousness and treatment-causality of treatment emergent adverse events (TEAEs). -Frequency of clinically significant abnormalities in physical examination, safety laboratory tests, urinalysis, vital signs and 12-lead ECG. 2. PK profile: MEN1611 plasma concentration-time data will be analysed using a population PK approach. A nonlinear mixed effects model will be used to determine population PK parameters and their associated variabilities (e.g. apparent systemic clearance [CL/F], [V/F], [Ka]). Individual PK parameters (e.g. area under the concentration time curve [AUC], maximum observed plasma concentration [Cmax]) will be estimated using a post hoc analysis. 3. Disease Control Rate (DCR) defined as percentage of patients whose disease shrinks or remains stable over a certain time period. DCR is the sum of the complete, partial and stable disease rates according to local assessment. 4. Duration of response defined as time from confirmation of a PR, CR or SD as locally assessed, until the disease has been shown to progress following treatment. 5.PFS: 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 patients and patients who are lost to follow-up are censored at their last tumour assessment date. 6. OS: Defined as the number of days between the first study treatment administration and death from any cause. For the baseline assessment, CT scan or MRI should be performed no more than 4 weeks before the start of study treatment. Follow-up assessment will be performed every 2 cycles during study treatment starting from Day 1 Cycle 3 (within a window of 7 days before the visit date) until objective disease progression as defined by RECIST v1.1 or at the End of Study Visit. Any other site at which a | — |
Countries
France, Germany, Italy, Netherlands, Poland, Spain, United States
Contacts
Public ContactAgostino Lazzaro
IQVIA
Outcome results
None listed