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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02857270
Recruitment Status : Recruiting
First Posted : August 5, 2016
Last Update Posted : September 17, 2019
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 Metastatic Pancreatic Ductal Adenocarcinoma 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 : 272 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 : December 15, 2021
Estimated Study Completion Date : December 15, 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 (dose timing will be determined) 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 Monotherapy
LY3214996 given orally (dose timing will be determined) 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
Experimental: Japan Part 3
LY3214996 given orally, nab-paclitaxel given IV and gemcitabine IV.
 Drug: LY3214996
Administered orally

Drug: Nab-paclitaxel
Administered IV

Drug: Gemcitabine
Administered IV


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 Cetuximanb [ 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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Information from the National Library of Medicine

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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: 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 an NRAS mutation, 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, and colorectal cancer with a RAS mutation and advanced or metastatic cancer with an activating mitogen activated protein kinase pathway alteration (dose expansion).
    • Part D: Have metastatic pancreatic ductal adenocarcinoma (dose escalation and dose expansion).
    • Part E: Metastatic BRAF V600E colorectal cancer (dose escalation and dose expansion).
  • 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.
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 Recruiting
Washington, District of Columbia, United States, 20007
Contact    202-444-2223      
Principal Investigator: Stephen V Liu         
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    412-864-7859      
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 Recruiting
Houston, Texas, United States, 77030
Contact    713-745-6601      
Principal Investigator: Shubham Pant         
Australia, New South Wales
St Vincent's Hospital Recruiting
Sydney, New South Wales, Australia, 2010
Contact    61293555655      
Principal Investigator: Anthony Joshua         
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 Recruiting
Sunto-Gun, Shizuoka, Japan, 411-8777
Contact    81120360605      
Principal Investigator: Tomoya Yokota         
National Cancer Center Hospital Recruiting
Chuo-Ku, Tokyo, Japan, 104-0045
Contact    81120360605      
Principal Investigator: Toshio Shimizu         
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:
Click here for more information about this study: A Study of LY3214996 Administered Alone or in Combination With Other Agents in Participants With Advanced/Metastatic Cancer  This link exits the ClinicalTrials.gov site

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: September 17, 2019
Last Verified: September 1, 2019
Keywords provided by Eli Lilly and Company:
MAPK
RAS
BRAF
Additional relevant MeSH terms:
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Adenocarcinoma
Neoplasms
Neoplasms by Histologic Type
Carcinoma
Neoplasms, Glandular and Epithelial
Gemcitabine
Paclitaxel
Albumin-Bound Paclitaxel
Cetuximab
Midazolam
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
 Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antimetabolites
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Adjuvants, Anesthesia
Hypnotics and Sedatives
Central Nervous System Depressants
Anti-Anxiety Agents
Tranquilizing Agents