Clinical trial NCT02703571: Study of Safety and Efficacy of Ribociclib and Trametinib in Patients With Metastatic or Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
Conditions: Solid Tumors for Phase Ib
Pancreatic Cancer for Phase II
Colorectal Cancer for Phase II
Keywords: Trametinib
Ribociclib
LEE011
TMT212
advanced solid tumors
pancreatic cancer
KRAS-mutant colorectal cancer
colorectal cancer
advanced pancreatic cancer
metastatic pancreatic cancer
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-03-09
Enrollment: 95
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: single group for phase 1b parallel group for phase 2
Primary purpose: TREATMENT

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.

Eligibility criteria: 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.

Primary outcomes:
measure: Incidence of dose limiting toxicities (DLTs)
timeFrame: 21-day cycle one of treatment
measure: Objective Response Rate (ORR)
timeFrame: Until progression of disease up to 1 year
Secondary outcomes:
measure: Duration of response (DOR)
timeFrame: Until progression of disease up to 1 year
measure: Time to response
timeFrame: Until progression of disease up to 1 year
measure: Disease control rate
timeFrame: Until progression of disease up to 1 year
measure: Progression disease rate
timeFrame: Until progression of disease up to 1 year
measure: Progression free survival
timeFrame: Until progression of disease up to 1 year
measure: overall survival
timeFrame: Until death up to 1 year
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Duarte
country: United States
facility: City of Hope National Medical Center
state: California
city: New Haven
country: United States
facility: Yale University School of Medicine
state: Connecticut
city: Miami
country: United States
facility: University of Miami Sylvester Comp Cancer Ctr
state: Florida
city: Boston
country: United States
facility: Dana Farber Cancer Center
state: Massachusetts
city: Houston
country: United States
facility: UT MD Anderson Cancer Center
state: Texas
city: Melbourne
country: Australia
facility: Novartis Investigative Site
state: Victoria
city: Leuven
country: Belgium
facility: Novartis Investigative Site
city: Edmonton
country: Canada
facility: Novartis Investigative Site
state: Alberta
city: Vancouver
country: Canada
facility: Novartis Investigative Site
state: British Columbia
city: Koeln
country: Germany
facility: Novartis Investigative Site
city: Ulm
country: Germany
facility: Novartis Investigative Site
city: Amsterdam
country: Netherlands
facility: Novartis Investigative Site
city: Utrecht
country: Netherlands
facility: Novartis Investigative Site
city: Barcelona
country: Spain
facility: Novartis Investigative Site
state: Catalunya
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: