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A Study of LY3214996 Administered Alone or in Combination With Other Agents in Participants With Advanced/Metastatic Cancer

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ClinicalTrials.gov Identifier: NCT02857270
Recruitment Status : Recruiting
First Posted : August 5, 2016
Last Update Posted : February 21, 2021
Sponsor:
Information provided by (Responsible Party):
Eli Lilly and Company

Study Description
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Brief Summary:
The purpose of this study is to determine the safety of an extracellular signal regulated kinase (ERK1/2) inhibitor LY3214996 administered alone or in combination with other agents in participants with advanced cancer.

Condition or disease Intervention/treatment Phase
Advanced Cancer Metastatic Melanoma Metastatic Non-small Cell Lung Cancer Colorectal Cancer Drug: LY3214996 Drug: Midazolam Drug: Abemaciclib Drug: Nab-paclitaxel Drug: Gemcitabine Drug: Encorafenib Drug: Cetuximab Phase 1

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 245 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of an ERK1/2 Inhibitor (LY3214996) Administered Alone or in Combination With Other Agents in Advanced Cancer
Actual Study Start Date : September 29, 2016
Estimated Primary Completion Date : February 10, 2021
Estimated Study Completion Date : September 10, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: LY3214996 Dose Escalation
LY3214996 given orally once a day (or twice a day) for 21 days.
 Drug: LY3214996
Administered orally
Experimental: LY3214996 + Midazolam

(Preliminary Drug-Drug Interactions [DDI])

LY3214996 given orally (once a day) and midazolam given orally on cycle 1 day 1 and cycle 1 day 16 (21 day cycles except cycle 1 only = 22 days).

 Drug: LY3214996
Administered orally

Drug: Midazolam
Administered orally
Experimental: LY3214996 Dose Expansion
LY3214996 given orally (once a day) during each 21 day cycle.
 Drug: LY3214996
Administered orally
Experimental: LY3214996 + Abemaciclib
Dose Escalation and Expansion- LY3214996 given orally (dose timing will be determined) and abemaciclib given orally (single dose given during lead in period) twice a day every 12 hours during 21 day cycle.
 Drug: LY3214996
Administered orally

Drug: Abemaciclib
Administered orally
Other Name: LY2835219
Experimental: LY3214996 + Nab-Paclitaxel + Gemcitabine
Dose Escalation and Expansion- LY3214996 given orally (dose timing will be determined) and nab-paclitaxel given intravenously (IV) on day 1, 8, and 15 and gemcitabine IV on day 1, 8, and 15 during each 28 day cycle.
 Drug: LY3214996
Administered orally

Drug: Nab-paclitaxel
Administered IV

Drug: Gemcitabine
Administered IV
Experimental: LY3214996 + Encorafenib + Cetuximab
Dose Escalation and Expansion- LY3214996 given orally, encorafenib given orally and cetuximab given IV.
 Drug: LY3214996
Administered orally

Drug: Encorafenib
Administered orally

Drug: Cetuximab
Administered IV
Experimental: Japan Part 1
LY3214996 given orally.
 Drug: LY3214996
Administered orally
Experimental: Japan Part 2
LY3214996 given orally and abemaciclib given orally.
 Drug: LY3214996
Administered orally

Drug: Abemaciclib
Administered orally
Other Name: LY2835219


Outcome Measures
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Primary Outcome Measures :
  1. Number of Participants with LY3214996 Dose Limiting Toxicities (DLTs) [ Time Frame: Cycle 1 (21 Days) ]

Secondary Outcome Measures :
  1. Pharmacokinetics (PK): Area Under the Concentration-Time Curve (AUC) of LY3214996 Administered as Monotherapy and when Administered in Combination with Nab-Paclitaxel Plus Gemcitabine, Abemaciclib and Encorafenib Plus Cetuximab [ Time Frame: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 28 Day Cycles) ]
  2. PK: AUC of Gemcitabine when Administered with LY3214996 [ Time Frame: Cycle 1 Day 1 through Cycle 1 Day 15 (28 Day Cycles) ]
  3. PK: AUC of Nab-Paclitaxel when Administered with LY3214996 [ Time Frame: Cycle 1 Day 1 through Cycle 1 Day 15 (28 Day Cycles) ]
  4. PK: AUC of Abemaciclib and its Metabolites when Administered with LY3214996 [ Time Frame: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles) ]
  5. PK: AUC of Encorafenib when Administered with LY3214996 [ Time Frame: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles) ]
  6. PK: AUC of Cetuximab when Administered with LY3214996 [ Time Frame: Cycle 1 Day 1 through Cycle 2 Day 1 (up to 22 Day Cycles) ]
  7. PK: AUC of Midazolam and its 1'-Hydroxymidazolam Metabolite when Administered Alone and in Combination with LY3214996 [ Time Frame: Cycle 1 Day 1 through Cycle 1 Day 16 (21 Day Cycles) ]
  8. Objective Response Rate (ORR): Percentage of Participants With a Complete (CR) or Partial Response (PR) [ Time Frame: Baseline to Measured Progressive Disease or Start of New Anti-Cancer Therapy (Estimated up to 6 Months) ]
  9. Duration of Response (DoR) [ Time Frame: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 12 Months) ]
  10. Time to First Response (TTR) [ Time Frame: Baseline to Date of CR or PR (Estimated up to 6 Months) ]
  11. Progression Free Survival (PFS) [ Time Frame: Baseline to Progressive Disease or Death of Any Cause (Estimated up to 12 Months) ]
  12. Disease Control Rate (DCR): Percentage of Participants who Exhibit Stable Disease (SD), CR or PR [ Time Frame: Baseline through Measured Progressive Disease (Estimated up to 6 Months) ]
  13. Overall Survival (OS) (Dose Expansion Arms Only) [ Time Frame: Baseline to Date of Death from Any Cause (Estimated up to 2 Years) ]

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:

  • Have advanced or metastatic cancer (solid tumors) and be an appropriate candidate for experimental therapy.

    • Part B (No Longer Enrolling Participants): Have advanced or metastatic cancer with an activating mitogen-activated protein kinase pathway alteration, BRAF mutant metastatic melanoma refractory to or relapsed after treatment with RAF and/or MEK inhibitors, metastatic melanoma with a NRAS mutation, or BRAF mutant NSCLC.
    • Part C: Advanced, unresectable cancer (dose escalation) and advanced, unresectable, or metastatic non-small cell lung cancer with a BRAF or RAS mutation, or NRAS mutant melanoma (dose expansion).
    • Part D (No Longer Enrolling Participants): Have metastatic pancreatic ductal adenocarcinoma (dose escalation and dose expansion).
    • Part E: Metastatic BRAF V600E colorectal cancer.
  • Have discontinued previous treatments for cancer and have resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy to Grade ≤1 by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0.
  • Have adequate organ function.
  • Have a performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) scale.

Exclusion Criteria:

  • Have serious preexisting medical conditions.
  • Have a known human immunodeficiency virus (HIV) infection or known activated/reactivated hepatitis A, B, or C.
  • Have symptomatic central nervous system malignancy or metastasis.
  • Have current hematologic malignancies, acute or chronic leukemia.
  • Have a second primary malignancy that in the judgment of the investigator or Lilly may affect the interpretation of results.
  • Have prior malignancies. Participants with carcinoma in situ of any origin and participants with prior malignancies who are in remission and whose likelihood of recurrence is very low, as judged by the Lilly clinical research physician, are eligible for this study.
  • Have a mean QT interval corrected for heart rate (QTc) of ≥470 milliseconds on screening electrocardiogram (ECG) as calculated using the Bazett's formula at several consecutive days of assessment.
  • Have participated, within the last 28 days in a clinical trial involving an investigational product or are currently enrolled in a clinical trial involving an investigational product or any other type of medical research judged not to be scientifically or medically compatible with this study.
  • Have previously completed or withdrawn from this study or any other study investigating an ERK1/2 inhibitor.
  • If female, is pregnant, breastfeeding, or planning to become pregnant.
  • Have history or findings of central or branch retinal artery or venous occlusion with significant vision loss or other retinal diseases that cause current visual impairment or would likely cause visual impairment over the time period of the study.
  • Currently using concomitant medications that are strong inhibitors or inducers of CYP3A4.
  • Part C: have serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the investigator, would preclude participation in this study, including interstitial lung disease (ILD) or severe dyspnea at rest or requiring oxygen therapy.
  • Part C4 NRAS Melanoma: have previously completed or withdrawn from a study investigating a MEK inhibitor.
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02857270


Contacts
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Contact: There may be multiple sites in this clinical trial. 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559

Locations
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United States, District of Columbia
Georgetown University Medical Center Completed
Washington, District of Columbia, United States, 20007
United States, Florida
Florida Cancer Specialists Recruiting
Sarasota, Florida, United States, 34232
Contact    9413779993      
Principal Investigator: Manish Rajni Patel         
United States, Massachusetts
Massachusetts General Hospital Recruiting
Boston, Massachusetts, United States, 02114
Contact    617-643-3614      
Principal Investigator: Ryan Sullivan         
United States, New Hampshire
Dartmouth Hitchcock Medical Center Recruiting
Lebanon, New Hampshire, United States, 03756-0001
Contact    603-650-8162      
Principal Investigator: Konstantin Dragnev         
United States, Pennsylvania
UPMC Hillman Cancer Center Recruiting
Pittsburgh, Pennsylvania, United States, 15232-1305
Contact    412-623-8963      
Principal Investigator: Timothy F Burns         
United States, Tennessee
Sarah Cannon Cancer Center Recruiting
Nashville, Tennessee, United States, 37203
Contact    615-329-7274      
Principal Investigator: SMO Sarah Cannon Research Inst.         
Tennessee Oncology PLLC Recruiting
Nashville, Tennessee, United States, 37203
Contact    6153297274      
Principal Investigator: Johanna Chock Bendell         
United States, Texas
University of Texas MD Anderson Cancer Center Completed
Houston, Texas, United States, 77030
Australia, New South Wales
St Vincent's Hospital Completed
Sydney, New South Wales, Australia, 2010
Australia, Western Australia
Linear Clinical Research Ltd Recruiting
Nedlands, Western Australia, Australia, 6009
Contact    61893463823      
Principal Investigator: Michael Millward         
France
Gustave Roussy Recruiting
Villejuif Cedex, France, 94805
Contact    33142114385      
Principal Investigator: Antoine Hollebecque         
Japan
Shizuoka Cancer Center Completed
Sunto-Gun, Shizuoka, Japan, 411-8777
National Cancer Center Hospital Active, not recruiting
Chuo-ku, Tokyo, Japan, 104-0045
Sponsors and Collaborators
Eli Lilly and Company
Investigators
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Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST) Eli Lilly and Company
More Information
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Additional Information:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: Eli Lilly and Company
ClinicalTrials.gov Identifier: NCT02857270    
Other Study ID Numbers: 16419
I8S-MC-JUAB ( Other Identifier: Eli Lilly and Company )
2016-001907-21 ( EudraCT Number )
First Posted: August 5, 2016    Key Record Dates
Last Update Posted: February 21, 2021
Last Verified: February 1, 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Eli Lilly and Company:
MAPK
RAS
BRAF
Additional relevant MeSH terms:
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Carcinoma, Non-Small-Cell Lung
Colorectal Neoplasms
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Digestive System Diseases
 Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Gemcitabine
Paclitaxel
Cetuximab
Midazolam
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic