Colorectal Cancer for Phase II, Pancreatic Cancer for Phase II, Solid Tumors for Phase Ib
Conditions
Keywords
Trametinib, Ribociclib, LEE011, TMT212, advanced solid tumors, pancreatic cancer, KRAS-mutant colorectal cancer, colorectal cancer, advanced pancreatic cancer, metastatic pancreatic cancer
Brief summary
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
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.
Interventions
DRUGribociclib
Combination treatment with LEE and TMT
DRUGTrametinib
Combination treatment with LEE and TMT
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
single group for phase 1b parallel group for phase 2
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of dose limiting toxicities (DLTs) | 21-day cycle one of treatment | 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. |
| Objective Response Rate (ORR) | Until progression of disease up to 1 year | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease control rate | Until progression of disease up to 1 year | 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. |
| Progression disease rate | Until progression of disease up to 1 year | 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. |
| Duration of response (DOR) | Until progression of disease up to 1 year | 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. |
| overall survival | Until death up to 1 year | 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. |
| Progression free survival | Until progression of disease up to 1 year | 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. |
| Time to response | Until progression of disease up to 1 year | 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. |
Countries
Australia, Belgium, Canada, Germany, Netherlands, Spain, United States
Outcome results
None listed