| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Solid tumors, Pancreatic Cancer, Colorectal Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Solid tumors, Pancreatic Cancer, 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10049280 |
| E.1.2 | Term | Solid tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061451 |
| E.1.2 | Term | Colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10033604 |
| E.1.2 | Term | Pancreatic cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Phase Ib:
To define the maximum tolerated dose (MTD) and/or the RP2R of
ribociclib and trametinib in patients with solid tumors
Phase II:
To assess overall response rate (ORR) with the combination of ribociclib and trametinib in patients with:
● Advanced or metastatic pancreatic adenocarcinoma who have failed at least one prior systemic treatment (Arm 1)
● Advanced or metastatic KRAS-mutant CRC who have failed at least two prior lines of treatment (Arm 2) |
|
| E.2.2 | Secondary objectives of the trial |
Phase Ib and II:
● To evaluate the safety and tolerability of ribociclib in combination with trametinib
● To characterize the pharmacokinetics (PK) of ribociclib (and metabolite LEQ803) and trametinib when administered in combination
Phase Ib:
● To assess the preliminary anti-tumor activity of ribociclib in combination with trametinib
Phase II:
● To evaluate duration of response (DOR), disease control rate (DCR), time to response (TTR), overall survival (OS), progression-free survival (PFS) and clinical benefit rate (CBR) of ribociclib in combination with trametinib |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria (All):
•Written informed consent must be obtained prior to any study specific
screening procedures
•Patient has histologically and/or cytologically confirmed malignancies:
Phase I:
• Patients with advanced or metastatic solid tumors who have failed at
least one prior line of systemic antineoplastic therapy in the advanced
setting without a standard of care treatment option available;
Phase II:
•Advanced or metastatic pancreatic adenocarcinoma who have failed at
least one prior systemic antineoplastic therapies in the advanced setting
•Advanced or metastatic KRAS-mutant CRC who have failed at least two
prior systemic antineoplastic therapies in the advanced setting without a
standard of care treatment option available. Testing for KRAS mutation
in patients with CRC using locally approved diagnostic kit will be used for
eligibility.
•Phase II only: patient must have measurable disease
•Patient has an ECOG performance status 0 or 1.
•Patient has adequate bone marrow and organ function
•Patient must have specified laboratory values within normal limits or
corrected to within normal limits with supplements before the first dose
of study medication on Cycle 1 Day 1:
•Standard 12-lead ECG values defined
Other protocol-defined inclusion/exclusion criteria may apply |
|
| E.4 | Principal exclusion criteria |
Phase II only:
• Patient has received prior treatment with a MEK inhibitor or a CDK4/6
inhibitor.
Phase I and Phase II:
•Patient with a known hypersensitivity to the study drugs or any of the
excipients of ribociclib or trametinib.
•Patient is concurrently using other anti-cancer therapy.
•Patient has received radiotherapy ≤ 4 weeks or limited field radiation
for palliation ≤ 2 weeks prior to Cycle 1 Day 1
•Patient has received local therapy to liver ≤ 3 months of C1D1
•History of liver disease as follow:
•Cirrhosis
•Autoimmune hepatitis
•Portal hypertension
•Drug induced liver steatosis
•Prior systemic anti-cancer treatment within 28 days prior to Cycle 1
Day 1
•Prior therapy with anthracyclines at cumulative doses of 450 mg/ m2
or more for doxorubicin or 900 mg/m2 or more for epirubicin.
•Patient is currently receiving warfarin or other coumadin derived anticoagulant
•Patient has a history of deep venin thrombosis or pulmonary embolism
within 6 months of screening.
•Patient has a concurrent malignancy or malignancy within 3 years prior
to Cycle 1 Day 1, with the exception of adequately treated basal or
squamous cell carcinoma or curatively resected cervical cancer.
•Patients with central nervous system (CNS) involvement
•Patient has impairment of GI function or GI disease that may
significantly alter the absorption of the study drugs
•History of interstitial lung disease or pneumonitis.
•Clinically significant, uncontrolled heart disease and/or cardiac
repolarization abnormality
•Patient is currently receiving any strong inducers or inhibitors of
CYP3A4/5 and/or Substances that have a narrow therapeutic window
and are predominantly metabolized through CYP3A4/5 and cannot be
discontinued 7 days prior to Cycle 1 Day 1:
•Patient is currently receiving or has received systemic corticosteroids ≤
2 weeks prior to starting study drug, or who have not fully recovered
from side effects of such treatment.
•History of retinal vein occlusion (RVO)
Other protocol-defined inclusion/exclusion criteria may apply |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase Ib
● Frequency of dose limiting toxicities (DLTs) at each dose level associated with administration of ribociclib and trametinib in a 28 day cycle
Phase II
● Overall response rate (ORR) defined as the proportion of patients with a best overall confirmed response of complete response (CR) or partial response (PR) as assessed per response evaluation criteria in solid tumors (RECIST) 1.1 by investigator assessment
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase Ib
Safety will be monitored by the assessments described below as well as collecting of the adverse events at every visit (see Table 7-1 of the protocol).
Phase II
Imaging assessments will be performed at screening within 28 days prior to Cycle 1 Day 1 and subsequently every 6 weeks during the first 12 months and every 12 weeks thereafter.
|
|
| E.5.2 | Secondary end point(s) |
Phase Ib and II
● Adverse Events (AEs), serious AEs (SAEs), changes in hematology and chemistry values, vital signs, electrocardiograms (ECGs), dose interruptions, reductions and dose intensity.
● PK parameters such as but not limited to Cmax, Tmax, and AUC and Cmin for ribociclib (and metabolite LEQ803) and trametinib
Phase Ib
● Progression disease rate defined as the proportion of patients with a progression disease as assessed per RECIST 1.1 by investigator assessment
● PFS, defined as time from first dose of study drug to progression or death due to any cause
Phase II
● Duration of response (DOR), calculated as the time from the date of the first documented CR or PR to the first documented progression or death due to any cause
● Disease control rate (DCR), time to response (TTR) calculated as the time from first dose to first documented response (CR+PR)
● Progression free survival (PFS)
● Overall survival (OS), defined as time from first dose of study drug to death due to any cause
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase Ib and II
Safety will be monitored by the assessments described below as well as collecting of the adverse events at every visit (see Table 7-1 of the protocol).
Phase Ib
Imaging assessments will be performed at screening within 28 days prior to Cycle 1 Day 1 and subsequently every 8 weeks during the first 12 months and every 12 weeks thereafter.
Phase II
Imaging assessments will be performed at screening within 28 days prior to Cycle 1 Day 1 and subsequently every 6 weeks during the first 12 months and every 12 weeks thereafter.
|
|
| 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 | Yes |
| 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 |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| Phase Ib open label, dose escalation part followed by open-label two-arm non-randomized Phase II |
|
| 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 | 2 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 9 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Germany |
| Hong Kong |
| Netherlands |
| Russian Federation |
| Spain |
| Taiwan |
| Turkey |
| United States |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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