A Study of Abemaciclib (LY2835219) in Combination With Another Anti-cancer Drug in Participants With Lung Cancer (NSCLC)

Study Description

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Brief Summary:

The main purpose of this study is to evaluate the safety and tolerability of abemaciclib in combination with another anti-cancer drug in participants with NSCLC that is advanced or has spread to other parts of the body (stage IV). The study will also investigate how the body processes the combination treatment and how the study drug affects the body. The study will also collect disease-related symptoms and participant-reported pain related to NSCLC.

Condition or disease	Intervention/treatment	Phase
Carcinoma, Non-small Cell Lung	Drug: Abemaciclib; Drug: Pemetrexed; Drug: Gemcitabine; Drug: Ramucirumab; Drug: LY3023414; Drug: Pembrolizumab	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	150 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase 1b Study of LY2835219 in Combination With Multiple Single Agent Options for Patients With Stage IV NSCLC
Study Start Date :	March 2014
Estimated Primary Completion Date :	May 2018
Estimated Study Completion Date :	November 2018

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Abemaciclib + Pemetrexed; Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 500 milligrams/square meter (mg/m^2) pemetrexed given intravenously (IV) over approximately 10 minutes on Day 1 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Drug: Abemaciclib; Administered orally; Other Name: LY2835219 Drug: Pemetrexed; Administered IV; Other Name: Alimta
Experimental: Abemaciclib + Gemcitabine; Abemacicilib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 1250 milligram/square meter (mg/m^2) gemcitabine given intravenously over approximately 30 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Drug: Abemaciclib; Administered orally; Other Name: LY2835219 Drug: Gemcitabine; Administered IV; Other Name: Gemzar
Experimental: Abemaciclib + Ramucirumab; Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Day 1 or 8 to 10 milligram/kilogram (mg/kg) ramucirumab given intravenously over approximately 60 minutes on Days 1 and 8 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Drug: Abemaciclib; Administered orally; Other Name: LY2835219 Drug: Ramucirumab; Administered IV; Other Name: Cyramza
Experimental: Abemaciclib + LY3023414; Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100, 150, or 200mg LY3023414 given orally every 12 hours on Days 1 through 21 of a 21-day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Drug: Abemaciclib; Administered orally; Other Name: LY2835219 Drug: LY3023414; Administered orally
Experimental: Abemaciclib + Pembrolizumab; Abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 200 mg pembrolizumab given intravenously over approximately 30 minutes on day 1 of a 21 day cycle. Participants may continue to receive treatment until discontinuation criteria are met.	Drug: Abemaciclib; Administered orally; Other Name: LY2835219 Drug: Pembrolizumab; Administered IV

Outcome Measures

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Primary Outcome Measures :

1. Number of Participants with One or More Drug Related Adverse Events [ Time Frame: Baseline through study completion (15 months) ]

Secondary Outcome Measures :

1. Pharmacokinetics: Maximum Concentration (Cmax) of Abemaciclib, Pemetrexed, Gemcitabine, Ramucirumab, and LY3023414 [ Time Frame: Baseline through study completion (15 months) ]
2. Number of Participants with a Complete or Partial Tumor Response (Overall Response Rate) [ Time Frame: Baseline through study completion (15 months) ]
3. Progression Free Survival Time [ Time Frame: Date of first dose until first documented progression or death (15 months) ]
4. Change from Baseline in MD Anderson Symptom Inventory Scale-Lung Cancer (MDASI-LC) [ Time Frame: Baseline, through study completion (15 months) ]
5. Pharmacokinetics: Area Under the Concentration Curve (AUC) of Abemaciclib, Pemetrexed, Gemcitabine, Ramucirumab, and LY3023414 [ Time Frame: Baseline through study completion (15 months) ]

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• For all Parts: The participant must have stage IV non-small cell lung cancer (NSCLC).
• For Part A (abemaciclib + pemetrexed): Non-squamous subtypes only. The participant must have received at least one but no more than three prior therapies for advanced/metastatic NSCLC.
• For Part B (abemaciclib + gemcitabine): Any subtype. The participant must have received at least one but not more than three prior therapies for advanced/metastatic NSCLC.
• For Part C (abemaciclib + ramucirumab): Any subtype. The participant must have received at least two but not more than three prior therapies for advanced/metastatic NSCLC.
• For Part D (abemaciclib + LY3023414): Any subtype. The participant must have received at least two, but not more than three prior therapies for advanced/metastatic NSCLC. The participant must not have received prior treatment with any phosphoinositide 3-kinase (PI3K) or mammalian target of rapamycin (mTOR) inhibitor.
• For Part E (abemaciclib + pembrolizumab): Any subtype. The participant must have received at least one but no more than three prior therapies for advanced/metastatic NSCLC.
• Have either measureable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

• Have adequate organ function including:

  • Hematologic: Absolute neutrophil count (ANC) 1.5 x 109/liter (L), platelets 100 x 109/L, and hemoglobin 8 gram/deciliter (g/dL).
  • Hepatic: Bilirubin 1.5 times upper limits of normal (ULN), alanine aminotransferase (ALT) and aspartate transaminase (AST) 3.0 times ULN. For participants with tumor involvement of the liver, AST and ALT equaling ≤5.0 times ULN are acceptable. Alkaline phosphatase ≤5.0 times ULN for participants with tumor involvement of the bone is acceptable.
  • Renal: Serum creatinine 1.5 times ULN.
• Have a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale.
• Have discontinued all previous therapies for cancer (including chemotherapy, radiotherapy, immunotherapy, and investigational therapy) for at least 21 days for myelosuppressive agents or 14 days for nonmyelosuppressive agents prior to receiving study drug, and recovered from the acute effects of therapy (treatment related toxicity resolved to baseline) except for residual alopecia.
• Male and female participants of reproductive potential must agree to use medically approved contraceptive precautions during the trial and 3 to 4 months (as appropriate) following last dose of study drug.
• Have an estimated life expectancy of ≥12 weeks.
• Are able to swallow oral medications.

Exclusion Criteria:

• Have a personal history of any of the following conditions: presyncope or syncope of either unexplained or cardiovascular etiology, ventricular arrhythmia (including but not limited to ventricular tachycardia and ventricular fibrillation), or sudden cardiac arrest. Exception: Participants with controlled atrial fibrillation for >30 days prior to study treatment are eligible.
• Parts A, B, D and E: Have central nervous system (CNS) metastasis with development of associated neurological changes 14 days prior to receiving study drug.
• Have a history of any other cancer (except non-melanoma skin cancer or carcinoma in-situ of the cervix or breast), unless in complete remission with no therapy for a minimum of 3 years.
• Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 3 to 4 months after the last dose of trial treatment (as appropriate).
• Have active bacterial, fungal, and/or known viral infection (for example, human immunodeficiency virus [HIV] antibodies, hepatitis B surface antigen [HBSAg], or hepatitis C antibodies). Screening is not required for enrollment.
• Parts A, B, C, and E: Have QTc interval of > 470 millisecond (msec) on screening electrocardiogram (ECG). Part D participants have QTc interval of >450msec on screening ECG.

Additional Exclusion Criteria For Part C

• History or evidence of cardiovascular risk including any of the following:

  • History of acute coronary syndromes (including myocardial infarction and angina), coronary angioplasty, or stenting within 6 months prior to enrollment.
  • History or evidence of current ≥Class II congestive heart failure as defined by New York Heart Association.
  • Treatment refractory hypertension defined as a blood pressure of systolic >140 millimeter of mercury (mmHg) and/or diastolic >90 mmHg which cannot be controlled by antihypertensive therapy.
  • Participants with intracardiac defibrillators.
• History or evidence of CNS disease. Radiographic screening of all participants without history of CNS metastasis is required.
• Radiographically documented evidence of major vessel invasion or encasement by cancer.
• Uncontrolled thromboembolic or hemorrhagic disorders.
• Participants receiving daily treatment with aspirin >325mg/day or other known inhibitors of platelet function.
• History of gross hemoptysis within 2 months of study entry.
• Evidence of nonhealing wounds, ulcers, or bone fractures within 28 days prior to study entry.
• Undergone major surgery within 28 days prior to first dose of study drug or have subcutaneous venous access device placement within 7 days prior to first dose.

Additional Exclusion Criteria For Part D

• Have insulin-dependent diabetes mellitus or a history of gestational diabetes mellitus.
• Participants with a type 2 diabetes mellitus are eligible if adequate control of blood glucose level is obtained by oral anti-diabetic agents as documented by hemoglobin A1c (HbA1c) <7%.
• History or evidence of cardiovascular risk including any of the following -- History of acute coronary syndromes (including myocardial infarction and angina), coronary angioplasty, or stenting within 6 months prior to enrollment.

Additional Exclusion Criteria for Part E

• Received prior monoclonal antibody (mAb) within 4 weeks prior to study.
• Has active autoimmune disease that has required treatment in the past 2 years.
• Has history of interstitial lung disease or pneumonitis.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Locations

United States, Arkansas
Highlands Oncology Group
Fayetteville, Arkansas, United States, 72703
United States, California
UCLA Department of Medicine-Hematology/Oncology
Los Angeles, California, United States, 90095
University of California, Davis - Health Systems
Sacramento, California, United States, 95817
United States, Indiana
Indiana Cancer Pavilion
Indianapolis, Indiana, United States, 46202
United States, New Jersey
Hackensack University Medical Center
Hackensack, New Jersey, United States, 07601
United States, New Mexico
University of New Mexico Cancer Center
Albuquerque, New Mexico, United States, 87102
United States, North Carolina
Carolinas Medical Center
Charlotte, North Carolina, United States, 28204
United States, Tennessee
The West Clinic
Germantown, Tennessee, United States, 38138
Spain
Hospital Universitario Ramon y Cajal
Madrid, Spain, 28034
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
Majadahonda, Spain, 28222
For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
Sevilla, Spain, 41013

Sponsors and Collaborators

Eli Lilly and Company

Merck Sharp & Dohme Corp.

Investigators

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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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Additional Information:

Click here for more information about this study: A Study of Abemaciclib (LY2835219) in Combination With Another Anti-cancer Drug in Participants With Stage IV Non-small Cell Lung Cancer (NSCLC) 

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

Gelbert LM, Cai S, Lin X, Sanchez-Martinez C, Del Prado M, Lallena MJ, Torres R, Ajamie RT, Wishart GN, Flack RS, Neubauer BL, Young J, Chan EM, Iversen P, Cronier D, Kreklau E, de Dios A. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs. 2014 Oct;32(5):825-37. doi: 10.1007/s10637-014-0120-7. Epub 2014 Jun 13.

Responsible Party:	Eli Lilly and Company
ClinicalTrials.gov Identifier:	NCT02079636 History of Changes
Other Study ID Numbers:	15266; I3Y-MC-JPBJ ( Other Identifier: Eli Lilly and Company ); 2013-004648-41 ( EudraCT Number ); KEYNOTE-238 ( Other Identifier: Merck )
First Posted:	March 6, 2014
Last Update Posted:	March 29, 2018
Last Verified:	March 2018

Additional relevant MeSH terms:

Carcinoma, Non-Small-Cell Lung; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Gemcitabine; Pemetrexed; Pembrolizumab	Ramucirumab; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors