Study of Safety and Efficacy of Ribociclib and Trametinib in Patients With Metastatic or Advanced Solid Tumors

Study Overview
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Brief Summary
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Phase Ib dose escalation in advanced solid tumors to identify dose for Phase II dose expansion in advanced or metastatic pancreatic cancer and KRAS-mutant colorectal cancer. Open-label, nonrandomized.

Detailed Description
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Upon careful review of all available efficacy and safety data from the study phase Ib part, Novartis decided to not start the study phase II part. This decision was in no means triggered by an unfavorable safety profile of the combination. The observed safety profile of the combination represents contributions of the individual safety profile of trametinib and ribociclib. No new safety signals were observed. The study was closed early in line with protocol Section 4.4.

Official Title
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A Phase I/II Study of Safety and Efficacy of Ribociclib (LEE011) in Combination With Trametinib (TMT212) in Patients With Metastatic or Advanced Solid Tumors

Conditions
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Solid Tumors for Phase Ib, Pancreatic Cancer for Phase II, Colorectal Cancer for Phase II

Intervention / Treatment
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* Drug: ribociclib
* Drug: Trametinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria (All): Written informed consent must 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 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 Active viral 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 anti-coagulant 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: single group for phase 1b parallel group for phase 2
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Advanced or metastatic solid tumors<br>Patients in the Phase I portion of the study who have advanced or metastatic solid tumors | Drug: ribociclib<br>* Combination treatment with LEE and TMT<br>* Other names: LEE011;Drug: Trametinib<br>* Combination treatment with LEE and TMT<br>* Other names: TMT212;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose limiting toxicities (DLTs) | Phase Ib part: The primary variable is the incidence of DLTs during the first 21 days of therapy. Estimation of the MTD of the combination treatment will be based upon the estimation of the probability of DLT during the first 21 days of therapy for patients in the DDS. | 21-day cycle one of treatment | 
| Objective Response Rate (ORR) | Phase II part: The primary variable used to evaluate the efficacy of the ribociclib and trametinib combination is the ORR, defined as the proportion of patients with a best overall confirmed CR or PR, as assessed per RECIST 1.1 by investigator assessment. | Until progression of disease up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Duration of response (DOR) | Phase II part: Among patients with a confirmed response (PR or CR) per RECIST 1.1, DOR is defined as the time from first documented response (PR or CR) to the date of first documented disease progression or death due to any cause. The distribution function of DOR will be estimated using the Kaplan-Meier method. The median DOR along with 95% CI will be presented by treatment arm. | Until progression of disease up to 1 year | 
| Time to response | Phase II part: Time to overall response of CR or PR (TTR) is defined as the time from start of study drug to first documented response (CR or PR, which must be confirmed subsequently) for patients with a confirmed CR or PR. TTR will be summarized by treatment arm, using descriptive statistics. | Until progression of disease up to 1 year | 
| Disease control rate | Phase II part: Disease control rate (DCR) is defined as the proportion of patients with best overall response of CR, PR, or SD per RECIST 1.1. DCR will be estimated and the binomial exact 95% CI will be provided by arm. | Until progression of disease up to 1 year | 
| Progression disease rate | Phase Ib part: Progression disease rate defined as the proportion of patients with a progression disease as assessed per RECIST 1.1 by investigator assessment. | Until progression of disease up to 1 year | 
| Progression free survival | Phase Ib and phase II parts: Progression-free survival (PFS) is defined as the time from the date of the first dose of study drug to the date of first documented disease progression per RECIST 1.1 or death due to any cause. | Until progression of disease up to 1 year | 
| overall survival | Phase Ib and phase II parts: Overall survival (OS) is defined as the time from the date of first dose of study drug to the date of death due to any cause. | Until death up to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Trametinib, Ribociclib, LEE011, TMT212, advanced solid tumors, pancreatic cancer, KRAS-mutant colorectal cancer, colorectal cancer, advanced pancreatic cancer, metastatic pancreatic cancer