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

• ClinicalTrials.gov Identifier: NCT02789345
• Recruitment Status: Completed
• First Posted: June 3, 2016
• Results First Posted: February 5, 2024
• Last Update Posted: February 5, 2024
• Sponsor: Eli Lilly and Company
• Collaborator: AstraZeneca
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: May 31, 2016
• First Posted Date: June 3, 2016
• Results First Submitted Date: May 23, 2023
• Results First Posted Date: February 5, 2024
• Last Update Posted Date: February 5, 2024
• Actual Study Start Date: October 24, 2016
• Actual Primary Completion Date: October 19, 2017 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 23, 2023)

Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs) [ Time Frame: Arm A: Cycle 1 through Cycle 2 (14-day cycle); Arm B: Cycle 1 (21-day cycle) ]

A Dose Limiting Toxicity (DLT) was defined as one of the following Adverse Events (AE) that is likely related to the study drug or combination, and fulfils any one of the following criteria, graded according to the NCI-CTCAE Version 4.0:

1. Any nonhematologic Grade ≥3 toxicity, except for toxicities such as liver or renal function abnormality, skin rash that resolves with appropriate therapy, transient hypersensitivity and injection site reactions, myalgia, fatigue, constipation, electrolyte imbalance, nausea, vomiting, diarrhea
2. Hematologic toxicity was considered a DLT as the following:
   1. Grade 4 toxicity lasting ≥7 days, or
   2. Grade 3 or 4 thrombocytopenia if associated with bleeding or requires platelet transfusion, or
   3. Febrile neutropenia
3. Death if considered related to study treatment
4. Any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose limiting

• Original Primary Outcome Measures (submitted: May 31, 2016): Number of Participants with Dose Limiting Toxicities (DLTs) [ Time Frame: Up to Two Cycles (Up to 21 Day Cycles) ]

Current Secondary Outcome Measures (submitted: May 23, 2023)

• Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [ Time Frame: Predose on Day (D) 1 of Cycle (C) 2, Predose on Day 1 of Cycle 4, Predose on Day 1 of Cycle 5, Predose on Day 1 of Cycle 7, Predose on Day 1 of Cycle 13 ]
  Cmin was the concentration of study drug in the blood immediately before the next dose was administered.
• Pharmacokinetics (PK): Minimum Concentration (Cmin) of Necitumumab [ Time Frame: Predose on Day 1 of Cycle 3, Predose on Day 1 of Cycle 5 ]
  Cmin was the concentration of study drug in the blood immediately before the next dose was administered.
• Objective Response Rate (ORR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With a Complete Response (CR) or Partial Response (PR) [ Time Frame: Baseline to Objective Disease Progression (up to 25 months) ]
  ORR was the best overall response of complete response (CR) or partial response (PR) as classified by the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). CR was a disappearance of all target and non-target lesions and normalization of tumor marker level. PR was an at least 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameter) without progression of non-target lesions or appearance of new lesions.
• Disease Control Rate (DCR) for Ramucirumab in Combination With Osimertinib: Percentage of Participants With CR, PR or Stable Disease (SD) [ Time Frame: Baseline to Objective Disease Progression (up to 25 months) ]
  DCR was the best overall response of CR, PR, or SD as defined by RECIST v1.1. CR was defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR was defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD was defined as 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 one or more new lesions.
• Duration of Response (DoR) for Ramucirumab in Combination With Osimertinib [ Time Frame: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (up to 25 months) ]
  Duration of Response (DoR) was defined only for participants with a confirmed CR or PR. It was measured from the date of first evidence of a confirmed CR or PR to the date of objective progression or the date of death due to any cause, whichever is earlier. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date, DOR was censored at the date of the last complete objective progression-free disease assessment.
• Progression Free Survival (PFS) for Ramucirumab in Combination With Osimertinib [ Time Frame: Baseline to Measured Progressive Disease or Death from Any Cause (up to 26 months) ]
  Progression-free survival (PFS) was the time from the date of first study treatment until the date of radiographic documentation of progression (as defined by RECIST v. 1.1) based on investigator assessment or the date of death due to any cause, whichever was earlier. If a participant did not have a complete baseline disease assessment, then the PFS time was censored at the enrollment date, regardless of whether or not objectively determined disease progression or death was observed for the participant; otherwise, 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 complete objective progression-free disease assessment date.
• Overall Survival (OS) for Ramucirumab in Combination With Osimertinib [ Time Frame: Baseline to Death from Any Cause (up to 29 months) ]
  OS was date of first study treatment until death due to any cause. If the participant was alive at the data inclusion cutoff date for the analysis (or was lost to follow-up), OS was censored on the last date the participant was known to be alive.

Original Secondary Outcome Measures (submitted: May 31, 2016)

• Pharmacokinetics (PK): Minimum Concentration (Cmin) of Ramucirumab [ Time Frame: Day 1 Cycle 2 to Day 1 Cycle 13 (14 Day Cycles) ]
• PK: Cmin of Necitumumab [ Time Frame: 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) [ Time Frame: Baseline to Objective Disease Progression (Approximately 30 Months) ]
• Disease Control Rate (DCR): Percentage of Participants with CR, PR or Stable Disease (SD) [ Time Frame: Baseline to Objective Disease Progression (Approximately 30 Months) ]
• Duration of Response (DoR) [ Time Frame: Date of CR or PR to Date of Objective Disease Progression or Death from Any Cause (Approximately 30 Months) ]
• Progression Free Survival (PFS) [ Time Frame: Baseline to Measured Progressive Disease or Death from Any Cause (Approximately 30 Months) ]
• Overall Survival (OS) [ Time Frame: Baseline to Death from Any Cause (Approximately 30 Months) ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of Ramucirumab (LY3009806) or Necitumumab (LY3012211) Plus Osimertinib in Participants With Lung Cancer
• Official Title: 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
• Brief Summary: 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).
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non-small Cell Lung Cancer

Intervention

• Drug: Ramucirumab
  Administered IV
  Other Name: LY3009806
• Drug: Necitumumab
  Administered IV
  Other Name: LY3012211
• Drug: Osimertinib
  Administered orally
  Other Name: AZD9291

Study Arms

• Experimental: Arm A: Ramucirumab + Osimertinib
  Dose Finding: Participants received Ramucirumab 10 milligrams/kilogram (mg/kg) given intravenously (IV) on day 1 every 2 weeks and osimertinib 80 milligrams (mg) given orally daily during each 14-day cycle.
  Interventions:

  • Drug: Ramucirumab
  • Drug: Osimertinib
• Experimental: Arm B: Necitumumab + Osimertinib
  Dose Finding: Participants received Necitumumab 800 mg given IV on days 1 and 8 every 3 weeks and osimertinib 80 mg given orally daily during each 21 day cycle.
  Interventions:

  • Drug: Necitumumab
  • Drug: Osimertinib
• Experimental: Cohort A: Ramucirumab + Osimertinib
  Dose Expansion: Participants received Ramucirumab 10 mg/kg given IV on day 1 every 2 weeks and osimertinib 80 mg given orally daily during each 14-day cycle.
  Interventions:

  • Drug: Ramucirumab
  • Drug: Osimertinib

• Publications *: Yu HA, Paz-Ares LG, Yang JC, Lee KH, Garrido P, Park K, Kim JH, Lee DH, Mao H, Wijayawardana SR, Gao L, Hozak RR, Chao BH, Planchard D. Phase I Study of the Efficacy and Safety of Ramucirumab in Combination with Osimertinib in Advanced T790M-positive EGFR-mutant Non-small Cell Lung Cancer. Clin Cancer Res. 2021 Feb 15;27(4):992-1002. doi: 10.1158/1078-0432.CCR-20-1690. Epub 2020 Oct 12.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 22, 2022): 29
• Original Estimated Enrollment (submitted: May 31, 2016): 74
• Actual Study Completion Date: May 9, 2022
• Actual Primary Completion Date: October 19, 2017 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: France, Korea, Republic of, Spain, Taiwan, United States
• Removed Location Countries: Hong Kong, Italy

Administrative Information

• NCT Number: NCT02789345
• Other Study ID Numbers: 16357; I4T-MC-JVDL ( Other Identifier: Eli Lilly and Company ); 2015-005296-25 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Same as current
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: AstraZeneca

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

• PRS Account: Eli Lilly and Company
• Verification Date: May 2023