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

• ClinicalTrials.gov Identifier: NCT02079636
• Recruitment Status: Completed
• First Posted: March 6, 2014
• Results First Posted: September 11, 2020
• Last Update Posted: September 11, 2020
• Sponsor: Eli Lilly and Company
• Collaborator: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

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

Expanded Access : An investigational treatment associated with this study is available outside the clinical trial.   More info ...

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 142 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
• Actual Study Start Date: March 28, 2014
• Actual Primary Completion Date: May 2, 2018
• Actual Study Completion Date: August 29, 2019

Arms and Interventions

Arm	Intervention/treatment
Experimental: Abemaciclib + Pemetrexed; 150 milligram (mg) or 200 mg 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; 150 mg or 200 mg abemaciclib 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; 150 mg or 200 mg 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; 100 mg or 150 mg or 200 mg abemaciclib given orally every 12 hours on Days 1 through 21 of a 21-day cycle in combination with 100, 150, or 200 mg 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; 100 mg or 150 mg 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; Other Name: Keytruda

Outcome Measures

Primary Outcome Measures :

1. Number of Participants With Dose-Limiting Toxicities (DLT) or DLT-equivalent in Part A, B, C, D and E [ Time Frame: Baseline through study completion (Up To 15 Months) ]
   A DLT defined as adverse event(AE) occurring between Day 1 and Day 21 of Cycle 1 that was considered at least possibly related to either abemaciclib or the combination therapy and fulfilled a criteria selected (using the National Cancer Institute Common Terminology Criteria for Adverse Events,version 4.0 [NCI-CTCAE v 4.0] [NCI 2009]):Grade(Gr)≥3 nonhematological toxicity,Gr4 thrombocytopenia lasting at least 5 days and/or complicated with bleeding,Gr≥3 febrile neutropenia(ntr) and for Part D participants (pts): Gr3 hyperglycemia (fasting) of <5 days, Gr3 hypertriglyceridemia or hyperlipidemia without optimal treatment.A DLT-equivalent defined as AE that would have met the criteria for DLT if it had occurred during Cycle 1 for pts enrolled in dose-escalation phase,but that occurs between 1)Day 1 and Day 21 of Cycle 2 and beyond for a participant enrolled in dose-escalation phase 2) at any time for a participant in dose-expansion phase.

Secondary Outcome Measures :

1. Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) in Part A, B, C, D and E [ Time Frame: Baseline through study completion (Up To 15 Months) ]
   ORR is the best response of CR or PR as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is a disappearance of all target and non-target lesions and normalization of tumor marker level. PR is an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of not-target lesions or appearance of new lesions. Overall response rate is calculated as a total number of participants with CR or PR divided by the total number of participants with at least 1 measurable lesion, multiplied by 100.
2. Progression Free Survival Time in Part A, B, C, D and E [ Time Frame: Date of first dose until first documented progression or death (Up To 15 Months) ]
   Progression free survival (PFS) defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. PFS time was summarized using Kaplan-Meier estimates.
3. Change From Baseline in MD Anderson Symptom Inventory Scale-Lung Cancer (MDASI-LC) in Part A, B, C, D and E [ Time Frame: Baseline, through study completion (Up To 15 Months) ]
   The MDASI-LC is a self-reported lung cancer instrument included 22 items covered by one of the following dimensions: Mean core symptom severity (Core items 1-13: pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, remembering things, lack of appetite, drowsy, dry mouth, sad, vomiting, numbness/tingling), Lung cancer symptoms (3 items: coughing, constipation, sore throat), Mean symptom severity (13 core items plus 3 lung items) and Interference with mood or functional status (6 items: general activity, mood, work, relations with other people, walking, enjoyment of life). The mean of all symptom subscale items was calculated where 0 equals "not present" and 10 equals "as bad as you can imagine." A change from baseline with negative values indicate improvement, positive values indicate worsening.
4. Pharmacokinetics (PK): Maximum Concentration (Cmax) of Abemaciclib on Day 1 and at Steady State (Cycle 2 Day 1) in Part A , B, C, D and E [ Time Frame: Cycle 1 Day 1 (C1D1) pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; Cycle 2 Day 1 (C2D1) pre-dose and 1, 2, 4, 6, 8, 10 h post-dose ]
   Cmax of Abemaciclib on day 1 and at steady State (Cycle 2 Day 1) Part A , B, C, D and E was evaluated.
5. Pharmacokinetics: Maximum Concentration (Cmax) of Pemetrexed at Steady State in Part A [ Time Frame: C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose ]
   Cmax of pemetrexed at steady state in Part A was evaluated.
6. PK: Dose-normalized Maximum Concentration (Cmax) of Active Gemcitabine Metabolite: 2',2'-Difluorodeoxyuridine (dFdU) on Day 1 and at Steady State (Cycle 2 Day 1) in Part B [ Time Frame: C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose ]
   Cmax of active gemcitabine metabolite (dFdU) on day 1 and at steady state (Cycle 2 Day 1) dose-normalized to 1250 mg/m^2 in Part B was evaluated.
7. PK: Maximum Concentration (Cmax) of Ramucirumab at 1 Hour Post-End-of-Infusion in Part C [ Time Frame: C1D1 and C2D1: 1 hour post-end-of-infusion ]
   Cmax of ramucirumab at 1 hour post-end-of-Infusion in Part C was evaluated.
8. PK: Maximum Concentration (Cmax) of LY3023414 in Part D [ Time Frame: C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose ]
   Cmax of LY3023414 in Part D was evaluated.
9. PK: Area Under the Concentration Curve (AUC) of Abemaciclib in Part A, B, C, D and E [ Time Frame: C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose ]
   Area under the concentration time curve from zero to 8 hours AUC(0-8h) of abemaciclib in Part A, B, C, D and E was evaluated.
10. PK: Area Under the Concentration Curve (AUC) of Pemetrexed at Steady State in Part A [ Time Frame: C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose ]
    Area under the plasma concentration versus time curve from time zero to infinity (AUC[0-∞]) of Pemetrexed in Part A was evaluated.
11. PK: Area Under the Concentration Curve (AUC) of Active Gemcitabine Metabolite: 2',2'-Difluorodeoxyuridine (dFdU) on Day 1 and at Steady State (Cycle 2 Day 1) in Part B [ Time Frame: C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose ]
    Area under the plasma concentration time curve from time zero to 12 hours (AUC[0-12h]) of active gemcitabine metabolite (dFdU) in Part B was evaluated
12. PK: Area Under the Concentration Curve (AUC) of LY3023414 in Part D [ Time Frame: C1D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose; C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose ]
    Area under the plasma concentration versus time curve from time zero to infinity (AUC) of LY3023414 in Part D was evaluated. For Day 1, AUC is defined as AUC from time zero to infinity (AUC[0-∞]), for steady state, AUC is defined as AUC from time zero to the end of the dosing interval, tau (AUC[0-tau ])

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• 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

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

  Study Documents (Full-Text)

Documents provided by Eli Lilly and Company:

Statistical Analysis Plan  [PDF] April 22, 2016

Study Protocol  [PDF] February 8, 2019

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):

Kim ES, Kelly K, Paz-Ares LG, Garrido P, Jalal S, Mahadevan D, Gutierrez M, Provencio M, Schaefer E, Shaheen M, Johnston EL, Turner PK, Kambhampati SRP, Beckmann R, Hossain A, John WJ, Goldman JW. Abemaciclib in Combination with Single-Agent Options in Patients with Stage IV Non-Small Cell Lung Cancer: A Phase Ib Study. Clin Cancer Res. 2018 Nov 15;24(22):5543-5551. doi: 10.1158/1078-0432.CCR-18-0651. Epub 2018 Aug 6.

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
• 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
• Results First Posted: September 11, 2020
• Last Update Posted: September 11, 2020
• Last Verified: November 15, 2019

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; Pembrolizumab; Pemetrexed; 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; Antineoplastic Agents, Immunological; Folic Acid Antagonists; Nucleic Acid Synthesis Inhibitors