Clinical trial NCT02079636: A Study of Abemaciclib (LY2835219) in Combination With Another Anti-cancer Drug in Participants With Lung Cancer (NSCLC)
Official title: A Phase 1b Study of LY2835219 in Combination With Multiple Single Agent Options for Patients With Stage IV NSCLC
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Carcinoma, Non-small Cell Lung
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
Collaborators: name: Merck Sharp & Dohme LLC
First posted: 2014-03-06
Enrollment: 142
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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.

Primary outcomes:
measure: Number of Participants With Dose-Limiting Toxicities (DLT) or DLT-equivalent in Part A, B, C, D and E
timeFrame: Baseline through study completion (Up To 15 Months)
Secondary outcomes:
measure: Number of Participants Achieving Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) in Part A, B, C, D and E
timeFrame: Baseline through study completion (Up To 15 Months)
measure: Progression Free Survival Time in Part A, B, C, D and E
timeFrame: Date of first dose until first documented progression or death (Up To 15 Months)
measure: Change From Baseline in MD Anderson Symptom Inventory Scale-Lung Cancer (MDASI-LC) in Part A, B, C, D and E
timeFrame: Baseline, through study completion (Up To 15 Months)
measure: 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
timeFrame: 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
measure: Pharmacokinetics: Maximum Concentration (Cmax) of Pemetrexed at Steady State in Part A
timeFrame: C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose
measure: 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
timeFrame: 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
measure: PK: Maximum Concentration (Cmax) of Ramucirumab at 1 Hour Post-End-of-Infusion in Part C
timeFrame: C1D1 and C2D1: 1 hour post-end-of-infusion
measure: PK: Maximum Concentration (Cmax) of LY3023414 in Part D
timeFrame: 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
measure: PK: Area Under the Concentration Curve (AUC) of Abemaciclib in Part A, B, C, D and E
timeFrame: 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
measure: PK: Area Under the Concentration Curve (AUC) of Pemetrexed at Steady State in Part A
timeFrame: C2D1 pre-dose and 1, 2, 4, 6, 8, 10 h post-dose
measure: 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
timeFrame: 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
measure: PK: Area Under the Concentration Curve (AUC) of LY3023414 in Part D
timeFrame: 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
Other outcomes:
Locations:
city: Fayetteville
country: United States
facility: Highlands Oncology Group
state: Arkansas
city: Los Angeles
country: United States
facility: UCLA Department of Medicine-Hematology/Oncology
state: California
city: Sacramento
country: United States
facility: University of California, Davis - Health Systems
state: California
city: Indianapolis
country: United States
facility: Indiana Cancer Pavilion
state: Indiana
city: Hackensack
country: United States
facility: Hackensack University Medical Center
state: New Jersey
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Germantown
country: United States
facility: The West Clinic
state: Tennessee
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal
city: Majadahonda
country: Spain
facility: 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.
city: Sevilla
country: Spain
facility: 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.
Study officials:
affiliation: Eli Lilly and Company
name: 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)
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.