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

Study Description

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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.

Condition or disease	Intervention/treatment	Phase
Solid Tumors; Pancreatic Cancer; Colorectal Cancer	Drug: ribociclib; Drug: Trametinib	Phase 1; Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	150 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
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
Actual Study Start Date :	June 29, 2016
Estimated Primary Completion Date :	September 16, 2019
Estimated Study Completion Date :	March 16, 2021

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Advanced or metastatic pancreatic cancer; Patients in the Phase II portion of the study who have advanced or metastatic pancreatic cancer	Drug: ribociclib; Other Name: LEE011; Drug: Trametinib; Other Name: TMT212
Experimental: KRAS-mutant colorectal cancer; Patients in the Phase II portion of the study who have KRAS-mutant colorectal cancer	Drug: ribociclib; Other Name: LEE011; Drug: Trametinib; Other Name: TMT212

Outcome Measures

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Primary Outcome Measures :

1. Incidence of dose limiting toxicities (DLTs) [ Time Frame: 21-day cycle one of treatment ]

   Phase I 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.

2. Objective Response Rate (ORR) [ Time Frame: 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 Outcome Measures :

1. Duration of response (DOR) [ Time Frame: Until progression of disease up to 1 year ]
   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.
2. Time to response [ Time Frame: Until progression of disease up to 1 year ]
   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.
3. Disease control rate [ Time Frame: Until progression of disease up to 1 year ]
   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.
4. Progression disease rate [ Time Frame: Until progression of disease up to 1 year ]
   Progression disease rate defined as the proportion of patients with a progression disease as assessed per RECIST 1.1 by investigator assessment.
5. Progression free survival [ Time Frame: Until progression of disease up to 1 year ]
   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.
6. overall survival [ Time Frame: Until death up to 1 year ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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.

Contacts and Locations

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Contacts

Contact: Novartis Pharmaceuticals	1-888-669-6682	novartis.email@novartis.com
Contact: Novartis Pharmaceuticals	+41613241111	novartis.email@novartis.com

Locations

United States, Arkansas
Highlands Oncology Group	Recruiting
Fayetteville, Arkansas, United States, 72703
Contact: Gayla Riggins 479-587-1700 griggins@hogonc.com
Principal Investigator: J. Thaddeus Beck
United States, California
City of Hope National Medical Center	Recruiting
Duarte, California, United States, 91010
Contact: Loran Lord 626-256-4673 ext 85013 llord@coh.org
Principal Investigator: Marwan G. Fakih
United States, Connecticut
Yale University School of Medicine	Recruiting
New Haven, Connecticut, United States, 06520
Contact: Nicole Sinclair Nicole.Sinclair@yale.edu
Principal Investigator: Patricia M. LoRusso
United States, Florida
University of Miami Sylvester Comp Cancer Ctr	Recruiting
Miami, Florida, United States, 33136
Contact: Tamara Leon 305-243-0865 txl351@med.miami.edu
Principal Investigator: Jaime Merchan
United States, Massachusetts
Dana Farber Cancer Center	Recruiting
Boston, Massachusetts, United States, 02215
Contact: Brian Beardslee, MSN, RN 617-632-5638 brian_beardslee@dfci.harvard.edu
Principal Investigator: Geoffrey Shapiro
United States, Texas
UT MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
Contact: Vanda Stepanek 713-792-3238 vstepane@mdanderson.org
Principal Investigator: Filip Janku
Australia, Victoria
Novartis Investigative Site	Recruiting
Melbourne, Victoria, Australia, 3000
Belgium
Novartis Investigative Site	Recruiting
Leuven, Belgium, 3000
Canada, Alberta
Novartis Investigative Site	Recruiting
Edmonton, Alberta, Canada, T6G 1Z2
Canada, British Columbia
Novartis Investigative Site	Recruiting
Vancouver, British Columbia, Canada, V5Z 4E6
Germany
Novartis Investigative Site	Recruiting
Koeln, Germany, 50937
Novartis Investigative Site	Recruiting
Ulm, Germany, 89081
Netherlands
Novartis Investigative Site	Recruiting
Amsterdam, Netherlands, 1066 CX
Novartis Investigative Site	Recruiting
Utrecht, Netherlands, 3584 CX
Spain
Novartis Investigative Site	Recruiting
Barcelona, Catalunya, Spain, 08035

Sponsors and Collaborators

Novartis Pharmaceuticals

Investigators

Study Director:	Novartis Pharmaceuticals	Novartis Pharmaceuticals

More Information

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Responsible Party:	Novartis Pharmaceuticals
ClinicalTrials.gov Identifier:	NCT02703571 History of Changes
Other Study ID Numbers:	CTMT212X2106; 2015-005019-34 ( EudraCT Number )
First Posted:	March 9, 2016
Last Update Posted:	August 7, 2018
Last Verified:	August 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided
Plan Description:	Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations. This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Novartis ( Novartis Pharmaceuticals ):

Trametinib; Ribociclib; LEE011; TMT212; advanced solid tumors	pancreatic cancer; KRAS-mutant colorectal cancer; colorectal cancer; advanced pancreatic cancer; metastatic pancreatic cancer

Additional relevant MeSH terms:

Colorectal Neoplasms; Pancreatic Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases	Intestinal Diseases; Rectal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Trametinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action