| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non Small Cell Lung Cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10061873 |
| E.1.2 | Term | Non-small cell lung cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part A: to determine the dose-limiting toxicity (DLT) of abemaciclib at doses up to 200 mg when combined with necitumumab 800 mg, in patients with Stage IV NSCLC as measured by the number of patients with a DLT in Cycle 1.
Part B: to evaluate the efficacy of necitumumab in combination with abemaciclib in terms of PFS rate at 3 months in patients with Stage IV NSCLC.
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| E.2.2 | Secondary objectives of the trial |
Part A:
•to investigate the safety profile as assessed by clinical and laboratory significant events of necitumumab in combination with abemaciclib
•to determine the overall response rate (ORR)
•to determine pharmacokinetics (PK) of necitumumab and abemaciclib
•to determine the immunogenicity of necitumumab
Part B:
To demonstrate the safety, efficacy and feasibility of necitumumab in combination with abemaciclib at the recommended dose by
•to determine PFS
•to determine ORR and disease control rate (DCR)
•to estimate OS
•to investigate the safety profile as assessed by clinical and laboratory significant events
•to determine pharmacokinetics (PK) of necitumumab and abemaciclib
•to determine the immunogenicity of necitumumab
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients are eligible to be included in the study only if they meet all of the following criteria:
[1]Histologically or cytologically confirmed NSCLC
•Part A: NSCLC Stage IV (any type)
•Part B: NSCLC Stage IV (squamous and nonsquamous)
[2]Stage IV disease at the time of study entry (American Joint Committee on Cancer [AJCC] Staging Manual, 7th Edition [Edge et al. 2009])
[3]Measurable disease at the time of study entry as defined by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Eisenhauer et al. 2009)
[4]The patient must have progressed after platinum-based chemotherapy AND have received a maximum of 1 other prior chemotherapy for advanced and/or metastatic disease OR must be judged by the physician as ineligible for further standard second-line chemotherapy. Prior treatment with EGFR-TKI and ALK inhibitors is mandatory in patients whose tumor has EGFR-activating mutations or ALK translocations. Prior targeting agents and neoadjuvant/adjuvant therapies are permitted with the exception of CDK4/6-targeting agents or necitumumab.
[5]The patient has tumor tissue available for biomarker analyses. The sample can be either 12 serially paraffin-embedded unstained tissue slides or a paraffin embedded tissue block.
[6]The patient has given written informed consent prior to any study specific procedures. Written consent may also be provided by a legal representative.
[7]The patient is 18 years or older if required by local law or regulations.
[8]The patient has resolution to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0, of all clinically significant toxic effects of prior chemotherapy, surgery, or radiotherapy (with the exception of alopecia).
[9]The patient has an Eastern Cooperative Oncology Group performance status score of 0-1.
[10]Have the following laboratory values:
•hematologic: absolute neutrophil count 1.5 × 109/L, platelets 100 × 109/L, and hemoglobin 9 g/dL. T ransfusion of blood products (including platelets or red blood cells) or administration of colony stimulating factors (including G-CSF, GM-CSF or recombinant erythropoietin) within 4 weeks prior to Cycle 1 Day 1 are not allowed.
•Serum albumin ≥25 g/L
•hepatic: bilirubin 1.5 × the upper limit of normal (ULN), alkaline phosphatase (ALP), alanine aminotransferase (ALT) and aspartate transaminase (AST) 3.0 times ULN. For patients with hepatic metastases, ALT and AST equaling ≤5.0 times ULN are acceptable.
•renal: serum creatinine 1.2 x ULN or calculated creatinine clearance >50 mL/min (per the Cockcroft-Gault formula as defined in Attachment 5) for patients with creatinine >1.2 x ULN.
[11]are men who are sterile (including vasectomy confirmed by post-vasectomy semen analysis) or who agree to use a reliable method of birth control and to not donate sperm during the study (and for at least 12 weeks following the last dose of necitumumab and abemaciclib or country requirements, whichever is longer) OR
[12]are women who are either: (a) not of child-bearing potential due to surgical sterilization (at least 6 weeks following surgical bilateral oophorectomy with or without hysterectomy or tubal ligation) confirmed by medical history or menopause; or (b) of child-bearing potential who have a negative serum pregnancy test within 14 days prior to study enrollment and agree to use a highly effective method of birth control during the study and for 6 months after the last dose of study drug(s) (oral hormonal contraception alone is not considered highly effective and must be used in combination with a barrier method).
[13]Are able to swallow oral medications.
[14]Have an estimated life expectancy of at least 12 weeks.
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| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[15]The patient is currently enrolled in a clinical trial involving an investigational product or non-approved use of a drug or device (other than the study treatment used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Prior treatment with CDK4/6-targeting agents or necitumumab is not permitted.
[16]The patient has undergone major surgery or received any investigational therapy in the 30-days prior to study enrollment.
[17]The patient has undergone chest irradiation within 4 weeks prior to receiving study treatment (except focal palliative irradiation, which is allowed up to 2 weeks prior to receiving study treatment).
[18]The patient has brain metastases that are symptomatic. (Patients who have completed radiotherapy for brain metastases at least 2 weeks prior to receiving study treatment, who are now non symptomatic or on stable dose of steroids or anticonvulsants during the 2 weeks prior to receiving study treatment, are eligible). Patients with asymptomatic brain metastases without need for treatment with steroids and who have not been treated with radiotherapy are eligible. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.
[19]History of arterial or venous thromboembolism within 3 months prior to study enrollment. Patients with a history of venous thromboembolism beyond 3 months prior to study enrollment can be enrolled if they are appropriately treated with low molecular weight heparin.
[20]History or evidence of current clinically relevant coronary artery disease ≥ Grade III by the Canadian Cardiovascular Society Angina Grading Scale or uncontrolled congestive heart failure of current > Class III as defined by the New York Heart Association.
[21]The patient has experienced myocardial infarction within 6 months prior to study enrollment.
[22]The patient has active infection requiring systemic therapy, including active tuberculosis or known history of infection with the human immunodeficiency virus (HIV 1/2 antibodies), or hepatitis B (e.g., HBsAg reactive) and/or C virus (e.g., HCV RNA qualitative is detected).
[23]The patient has a history of significant neurological or psychiatric disorders, including dementia, seizures, or bipolar disorder, potentially precluding protocol compliance.
[24]The patient has 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.
[25]The patient has any other serious uncontrolled medical disorders or psychological conditions that would, in the opinion of the investigator, limit the patient’s ability to complete the study or sign an informed consent document.
[26]The patient has a known allergy / history of hypersensitivity reaction to any of the treatment components, including any ingredient used in the formulation of necitumumab or abemaciclib, or any other contraindication to one of the administered treatments.
[27]The patient is pregnant or breastfeeding.
[28]The patient has a known history of drug abuse, that in the opinion of the investigator, may have an impact on the safety of the patient and/or limit the patient’s ability to complete the study or adhere to any protocol procedure.
[29]The patient has a concurrent active malignancy. Previous history of malignancy is permitted, provided that the patient has been free of disease for ≥3 years, with the exception of adequately treated basal or squamous cell carcinoma of the skin, preinvasive carcinoma of the cervix, or any cancers that in the judgment of the investigator and sponsor may not affect the interpretation of results (for example, prostate, bladder).
[30]The patient is receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, chemo-embolization, targeted therapy, or an investigational agent.
[31]History of interstitial lung disease
[32]Recent (within 30 days before enrollment) or concurrent yellow fever vaccination
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| E.5 End points |
| E.5.1 | Primary end point(s) |
PART A: dose-limiting toxicity (DLT) of abemaciclib when combined with necitumumab 800 mg, as measured by the number of patients with a DLT in Cycle 1
PART B: The primary endpoint is Progression Free Survival Rate at 3 months as defined by RECIST 1.1 (Eisenhauer et al. 2009).
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
PART A: cycle 1 of each cohort
PART B: approximately 5 month after enrollment completion
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| E.5.2 | Secondary end point(s) |
PART A and Part B
Objective Response Rate (ORR): The objective response rate is the percentage of patients with a best response of CR or PR.
Immunogenicity: Incidence of anti-necitumumab antibodies will be tabulated.
Pharmacokinetics: Pharmacokinetic parameters of abemaciclib and necitumumab in Part A will be calculated using noncompartmental analysis (NCA) methodology. Summary level data for Part B will be presented as graphics and table listings.
Safety: Safety analyses will be performed for all patients enrolled in the study who receive any amount of study drug (necitumumab or abemaciclib).
PART B only
Progression Free Survival Rate (PFS): The time from the date of enrollment to the date of objective progression or the date of death due to any cause, whichever is earlier as defined by RECIST 1.1 (Eisenhauer et al. 2009)
Overall Survival (OS): OS duration is measured from the date of enrollment to the date of death from any cause.
Disease Control Rate (DCR): The proportion of patients in the analysis population who exhibit a SD or confirmed CR or PR relative to baseline during the study. Response is defined by RECIST 1.1 (Eisenhauer et al. 2009).
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Safety:An interim safety analysis will be performed after the first 15 evaluable patients in the Part B portion of the trial have completed 2 cycles of study treatment (or otherwise discontinued study treatment). Patients with squamous and nonsquamous NSCLC who received the recommended abemaciclib dose for Part B in Part A will be taken into account for the safety interim analysis. The interim analysis will be conducted to permit evaluation of safety data by the sponsor.
All endpoints:approximately 5 month after enrollment completion
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
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| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 5 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 18 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 11 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 11 |
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