A Study of Ramucirumab (LY3009806) or Necitumumab (LY3012211) Plus Osimertinib in Participants With Lung Cancer

Study Overview
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Brief Summary
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The main purpose of this study is to evaluate the safety of ramucirumab or necitumumab in combination with osimertinib in participants with non-small cell lung cancer (NSCLC).

Official Title
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An Open-Label, Multicenter, Phase 1 Study With Expansion Cohorts of Ramucirumab or Necitumumab in Combination With Osimertinib in Patients With Advanced T790M-Positive EGFR-Mutant Non-Small Cell Lung Cancer After Progression on First-Line EGFR TKI Therapy

Conditions
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Non-small Cell Lung Cancer

Intervention / Treatment
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* Drug: Ramucirumab
* Drug: Necitumumab
* Drug: Osimertinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a diagnosis of NSCLC with at least 1 measurable lesion assessable using standard techniques by the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1). Have T790M-positive status using a test validated and performed locally after disease progression on EGFR tyrosine kinase inhibitor (TKI) treatment. Have Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 at the time of enrollment. Have serum albumin that is ≥25 grams per liter at the time of enrollment. Have adequate organ function, with all screening labs performed within 7 days of treatment initiation. Have a life expectancy of ≥3 months. Have resolution, except where otherwise stated in the inclusion criteria, of all clinically significant toxic effects of prior systemic cancer therapy, surgery, or radiotherapy to Grade ≤1 by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Exclusion Criteria: Previous treatment with an EGFR monoclonal antibody (except for past treatment for squamous cell carcinoma of head and neck or metastatic colorectal cancer). Previous treatment with osimertinib or third generation EGFR TKIs. Participants with symptomatic or growing brain metastases less than 4 weeks prior to enrollment. History of drug-induced interstitial lung disease (ILD), ILD, or radiation pneumonitis requiring treatment with steroid prior to study enrollment, or any evidence of clinically active ILD. Have a significant bleeding disorder or vasculitis or had a Grade ≥3 bleeding episode within 12 weeks prior to enrollment. Participants with a history of gross hemoptysis (defined as bright red blood of ≥1/2 teaspoon) within 2 months prior to enrollment are excluded. Have experienced any arterial thrombotic event or arterial thromboembolic event, including myocardial infarction, unstable angina (history or evidence of current clinically relevant coronary artery disease of current ≥Class III as defined by Canadian Cardiovascular Society Angina Grading Scale or congestive heart failure of current ≥Class III as defined by the New York Heart Association), cerebrovascular accident, or transient ischemic attack, within 6 months prior to enrollment. Have a history of deep vein thrombosis, pulmonary embolism, or any other significant venous thromboembolism (venous catheter thrombosis or superficial venous thrombosis not considered significant) during the 3 months prior to study enrollment. Participants with venous thromboembolism occurring 3 to 6 months prior to study enrollment are allowed, if being treated with low molecular weight heparin. Have a history of gastrointestinal perforation and/or fistula within 6 months prior to enrollment. Have a bowel obstruction, history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea. Have uncontrolled hypertension, as defined in CTCAE Version 4.0, prior to initiating study treatment, despite antihypertensive intervention. CTCAE Version 4.0 defines uncontrolled hypertension as Grade >2 hypertension; clinically, the participant continues to experience elevated blood pressure (systolic >160 millimeters of mercury [mmHg] and/or diastolic >100 mmHg) despite medications. Are receiving chronic therapy with any of the following medications within 7 days prior to enrollment: nonsteroidal anti-inflammatory agents (NSAIDs; such as indomethacin, ibuprofen, naproxen, or similar agents). other anti-platelet agents (such as clopidogrel, ticlopidine, dipyridamole, or anagrelide). Have radiologically documented evidence of major blood vessel invasion or encasement by cancer. Have radiographic evidence of pulmonary intratumor cavitation, regardless of tumor histology. Are receiving concurrent treatment with other anticancer therapy, including other chemotherapy, immunotherapy, hormonal therapy, chemoembolization, or targeted therapy or radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks prior to enrollment. Have abnormal cardiac findings. Have undergone chest irradiation within 2 weeks prior to study drug administration, have not recovered from all radiation-related toxicities, or requires corticosteroids. A 2-week washout is permitted for focal palliative radiation to non-central nervous system disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ramucirumab + Osimertinib<br>Dose Finding: Ramucirumab given intravenously (IV) on day 1 every 2 weeks (Q2W) and osimertinib given orally daily during each 14 day cycle. Expansion: Ramucirumab given IV on day 1 Q2W and osimertinib given orally daily during each 14 day cycle. | Drug: Ramucirumab<br>* Administered IV<br>* Other names: LY3009806;Drug: Osimertinib<br>* Administered orally<br>* Other names: AZD9291;|
| Experimental: Necitumumab + Osimertinib<br>Dose Finding: Necitumumab given IV on days 1 and 8 every 3 weeks (Q3W) and osimertinib given orally daily during each 21 day cycle. Expansion: Necitumumab given IV on days 1 and 8 Q3W and osimertinib given orally daily during each 21 day cycle. | Drug: Necitumumab<br>* Administered IV<br>* Other names: LY3012211;Drug: Osimertinib<br>* Administered orally<br>* Other names: AZD9291;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Dose Limiting Toxicities (DLTs) |  | Up to Two Cycles (Up to 21 Day Cycles) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab |  | Day 1 Cycle 2 to Day 1 Cycle 13 (14 Day Cycles) | 
| PK: Cmin of Necitumumab |  | Day 1 Cycle 3 to Day 1 Cycle 9 (21 Day Cycles) | 
| Objective Response Rate (ORR): Percentage of Participants with a Complete Response (CR) or Partial Response (PR) |  | Baseline to Objective Disease Progression (Approximately 30 Months) | 
| Disease Control Rate (DCR): Percentage of Participants with CR, PR or Stable Disease (SD) |  | Baseline to Objective Disease Progression (Approximately 30 Months) | 
| Duration of Response (DoR) |  | Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Approximately 30 Months) | 
| Progression Free Survival (PFS) |  | Baseline to Measured Progressive Disease or Death from Any Cause (Approximately 30 Months) | 
| Overall Survival (OS) |  | Baseline to Death from Any Cause (Approximately 30 Months) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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T790M, epidermal growth factor receptor (EGFR)