| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| PIK3CA mutated colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| PIK3CA mutated colorectal cancer |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
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. |
|
| E.2.2 | Secondary objectives of the trial |
- 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. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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 treatment. |
|
| E.4 | Principal 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 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 non-target lesions being assessed. (Please see
section 8.4.8.)
16. 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.
17. 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 a period corresponding to five times the half-life of the
drug prior to the first administration of MEN1611. Switching to a different medication is allowed.
18. Pregnant or breastfeeding women.
19. Inability or unwillingness to abide by the study protocol; legal incapacity or limited legal capacity.
20. Warfarin sodium therapy or any other coumadin-derivative anticoagulant |
|
| E.5 End points |
| E.5.1 | 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. |
|
| E.5.1.1 | 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 |
|
| E.5.2 | 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 new disease is suspected should be appropriately imaged. If an unscheduled
assessment is performed and the disease has not progressed, subsequent assessments should be performed at their scheduled visits. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Throughout the study duration |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| This is an open-label, 3+3 dose-confirmation and cohort expansion, multicenre, Phase 1b/II study |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 29 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United States |
| France |
| Germany |
| Italy |
| Netherlands |
| Poland |
| Spain |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The study ends 6 months after first study treatment administration to the last patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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