A Study of Emibetuzumab in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer

• ClinicalTrials.gov Identifier: NCT02082210
• Recruitment Status: Completed
• First Posted: March 10, 2014
• Results First Posted: December 19, 2020
• Last Update Posted: December 19, 2020
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Study Description

Brief Summary:

The purpose of this study is to find a recommended schedule and dose range for Emibetuzumab when given with ramucirumab that may be safely given to participants with cancer. In Part A of this study, escalating doses of Emibetuzumab will be given in combination with a fixed dose of ramucirumab to evaluate the safety of the combination. After a recommended schedule and dose range of Emibetuzumab and ramucirumab has been established, Part B of the study will confirm safety and to see how well certain tumors respond to the combination of study drugs. The average amount of time on study is expected to be about 6 months.

Condition or disease	Intervention/treatment	Phase
Advanced Cancer; Gastric Adenocarcinoma; Gastroesophageal Junction Adenocarcinoma; Hepatocellular Cancer; Renal Cell Carcinoma; Non-Small Cell Lung Cancer	Drug: Emibetuzumab; Drug: Ramucirumab	Phase 1; Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 97 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1b/2 Study of Ramucirumab in Combination With LY2875358 in Patients With Advanced Cancer
• Actual Study Start Date: March 7, 2014
• Actual Primary Completion Date: December 5, 2017
• Actual Study Completion Date: January 24, 2018

Arms and Interventions

Arm	Intervention/treatment
Experimental: Emibetuzumab + Ramucirumab (Part A); Part A: Dose escalation (750mg, 2000mg) of Emibetuzumab administered intravenously (IV), on days 1 and 15 every 28 day cycle in combination with a fixed dose of 8mg/kg ramucirumab administered IV on Days 1 and 15 every 28 day cycle.	Drug: Emibetuzumab; Administered Intravenously (IV); Other Name: LY2875358; Drug: Ramucirumab; Administered Intravenously (IV); Other Names: LY3009806; IMC-1121B
Experimental: Emibetuzumab + Ramucirumab (Part B); Part B: Recommended 750mg Emibetuzumab dose from Part A to be administered IV, on days 1 and 15 every 28 day cycle in combination with a fixed dose of 8mg/kg ramucirumab administered IV on Days 1 and 15 every 28 day cycle.	Drug: Emibetuzumab; Administered Intravenously (IV); Other Name: LY2875358; Drug: Ramucirumab; Administered Intravenously (IV); Other Names: LY3009806; IMC-1121B

Outcome Measures

Primary Outcome Measures :

1. Number of Participants Who Experienced Dose-Limiting Toxicities (DLTs) [ Time Frame: Baseline through Cycle 1 (28 day cycle) ]

   DLT is defined as an adverse event during Cycle1 that is possibly, probably, or definitely related to treatment with Emibetuzumab in combination with fixed regimen of Ramucirumab & fulfills any 1 of the following criterion using NCI CTCAE Version 4.03:

   Grade 3 non-hematological toxicity. Exceptions will be made for:Nausea, vomiting, diarrhea, constipation, or skin rash that persists for ≤3 days following appropriate supportive care intervention. Grade 3 hypertension in which systolic BP ≥160 mmHg and/or diastolic BP ≥100 mmHg persist <7 days after intensified antihypertensive therapy is initiated.

   Grade 4 hematological toxicity of ≥7 days duration.

   ≥Grade 3 thrombocytopenia with ≥Grade 2 bleeding.

   Any febrile neutropenia.

   Any other significant toxicity deemed by the primary investigator & Lilly clinical research personnel to be dose-limiting (eg, any toxicity that is possibly related to the study medication that requires the withdrawal of participant from study Cycle1).

2. Part B: Percentage of Participants Who Exhibit Complete Response (CR) or Partial Response (PR) [Overall Response Rate (ORR)] [ Time Frame: Baseline through Measured Progressive Disease or Death (Up to 17 months) ]
   ORR is the percentage of participants achieving a best overall response (BOR) of complete response (CR) or partial response (PR) as per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameters (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. 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 5mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.

Secondary Outcome Measures :

1. Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Emibetuzumab [ Time Frame: Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h, 334h, 335h and 336h Post dose ]
   Pharmacokinetics (PK): Maximum Observed Plasma Concentration (Cmax) of Emibetuzumab.
2. Part B: Percentage of Participants Who Exhibit Stable Disease (SD) or Confirmed Response (CR) or Partial Response (PR) (Disease Control Rate [DCR]) [ Time Frame: Baseline through Measured Progressive Disease (Up to 17 months) ]
   DCR is the proportion of participants who exhibit a SD or confirmed CR or PR relative to baseline. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the 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 PD for target lesions, no progression of non-target lesions, and no appearance of new lesions. 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 5mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
3. Part B: Progression Free Survival (PFS) [ Time Frame: Baseline to Measured Progressive Disease or Death (Up to 17 Months) ]
   PFS was defined as the time from the date of first dose of study drug until first observation of objective (radiographically documented) PD as defined by RECIST v1.1 or death from any cause, whichever comes first. 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.
4. Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) From Time Zero to Tlast of Emibetuzumab [ Time Frame: Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h, 334h, 335h and 336h Post dose ]
   Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) from time zero to tlast of Emibetuzumab.
5. Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Ramucirumab [ Time Frame: Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h and 336h Post dose ]
   Pharmacokinetics: Area Under the Concentration-Time Curve (AUC) of Ramucirumab.
6. Number of Participants With Treatment Emergent Anti-Emibetuzumab Antibodies [ Time Frame: Baseline through 46 Months ]
   Participants were considered as treatment-emergent anti drug antibodies (TE ADA) positive if there is a ≥4-fold increase from baseline when ADAs were detected at baseline. If no ADAs were detected at baseline, TE ADA were defined as those with a titer 2 fold (1 dilution) greater than the minimum required dilution (MRD) of the screening assay (1:4 for anti-emibetuzumab antibodies).
7. Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Ramucirumab [ Time Frame: Cycle 1: Day1 Predose, End of infusion, 3 Hours (h), 5h, 8h, 21h, 168h and 336h Post dose ]
   Pharmacokinetics: Maximum Observed Plasma Concentration (Cmax) of Ramucirumab.
8. Number of Participants With Treatment Emergent Anti-Ramucirumab Antibodies [ Time Frame: Baseline through 46 Months ]
   Participants were considered as treatment-emergent anti drug antibodies (TE ADA) positive if there is a ≥4-fold increase from baseline when ADAs were detected at baseline. If no ADAs were detected at baseline, TE ADA were defined as those with a titer 2 fold (1 dilution) greater than the minimum required dilution (MRD) of the screening assay (1:10 for anti-ramucirumab antibodies).

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:

• Participants must have histological or cytological confirmed diagnosis of the following tumor types that is advanced and/or metastatic cancer and must be, in the judgment of the investigator, an appropriate participant for experimental therapy

  • Part A: Any type of solid tumor ("all comer")
  • Part B1: Gastric or Gastroesophageal Junction (GEJ) adenocarcinoma
  • Part B2: Hepatocellular cancer (excluding fibrolamellar carcinoma)
  • Part B3: Renal cell carcinoma (any histology)
  • Part B4: Non-small cell lung cancer (squamous or non-squamous)
• Have at least 1 measurable lesion outside of the central nervous system (CNS) whose presence is assessable using standard techniques by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• Availability of a tumor sample taken after progression on the most recent line of systemic tumor therapy or willing to undergo a tumor biopsy pre-study treatment.
• Have a performance status of ≤ 2 on the Eastern Cooperative Oncology Group (ECOG) scale in Part A and ≤ 1 on the ECOG scale in Part B.
• Have adequate organ function.
• Routine urinalysis showing ≤1+ protein or protein/creatinine ratio <0.5. For proteinuria ≥2+ or urine protein/creatinine ratio ≥0.5, 24-hour urine must be collected and the level must be <1 gram of protein in 24 hours for subject enrollment.
• Have discontinued all previous cancer therapies and any agents that have not received regulatory approval for any indication, for at least 21 days or 5 halflives prior to study enrollment, whichever is shorter, and recovered from the acute effects for therapy.
• Have an estimated life expectancy, in the judgment of the investigator, that will permit the participant to complete 8 weeks (2 cycles) of treatment.
• Males and females with reproductive potential: Must agree to use medically approved contraceptive precautions during the study and for at least 3 months following the last dose of study drug. Females with childbearing potential must have had a negative serum pregnancy test 7 days before the first dose of study drug and must not be breast-feeding.

Exclusion Criteria:

• Have serious pre-existing medical conditions (at the discretion of the investigator, such as severe acute or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation).
• Have a history of hypertensive crisis or hypertensive encephalopathy or current poorly controlled hypertension despite standard medical management.
• Participant has experienced any arterial thromboembolic event (ATE), including myocardial infarction, unstable angina pectoris, cerebrovascular accident, or transient ischemic attack, within 6 months prior to receiving study drugs.
• Have a history of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolic event during the 3 months prior to receiving study drugs.
• Are receiving therapeutic anticoagulation with warfarin, low-molecular weight heparin, or similar agents. Participants receiving prophylactic, low-dose anticoagulation therapy are eligible provided that they are on low-molecular weight heparin or oral factor Xa inhibitors.
• The participant is receiving chronic therapy with nonsteroidal anti-inflammatory drugs or other antiplatelet agents. Aspirin use at doses up to 325 mg/day is permitted.
• Have significant bleeding disorders, vasculitis, or had a significant bleeding episode from the gastrointestinal (GI) tract within 3 months prior to receiving study drugs.
• Have a history of GI perforation and/or fistulae within 6 months prior to receiving study drugs.
• Have congestive heart failure (CHF) New York Heart Association class ≥3 or symptomatic or poorly controlled cardiac arrhythmia.
• Have undergone major surgery within 28 days prior to receiving study drugs.
• Have a serious or nonhealing wound, peptic ulcer, or bone fracture within 28 days prior to receiving study drugs.
• Have a known active fungal, bacterial, and/or known viral infection. Hepatocellular cancer participants with chronic viral (B or C) hepatitis are eligible if they retain adequate liver function.
• Have liver cirrhosis with a Child-Pugh Stage of B or C.
• Have symptomatic CNS malignancy (with the exception of medulloblastoma) or metastasis.
• Have corrected QT (QTc) interval of >470 milliseconds on screening electrocardiogram (ECG).
• Have received previous treatment with ramucirumab or Emibetuzumab, except for participants enrolled in cohort B1 (Gastric or GEJ adenocarcinoma) and B4 (non- small cell lung cancer) who may have received previous ramucirumab treatment.
• Known hypersensitivity to any of the treatment components of ramucirumab or Emibetuzumab.
• Have a second primary malignancy that, in the judgment of the investigator and sponsor, may affect the interpretation of results.
• Are pregnant or breastfeeding.

• For Part B4 (non-small cell lung cancer) only:

  • The participant has radiologically documented evidence of major blood vessel invasion or encasement by cancer
  • Participants with a history of gross hemoptysis within 2 months prior to study treatment
  • The participant has radiographic evidence of intratumor cavitation, regardless of tumor histology

Contacts and Locations

Locations

United States, Massachusetts

Massachusetts General Hospital

Boston, Massachusetts, United States, 02114-3117

Dana Farber Cancer Institute

Boston, Massachusetts, United States, 02115

United States, New York

Memorial Sloan Kettering Cancer Center

New York, New York, United States, 10065

United States, Tennessee

Tennessee Oncology PLLC

Nashville, Tennessee, United States, 37203

Sponsors and Collaborators

Eli Lilly and Company

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:

Study Protocol  [PDF] March 13, 2015

Statistical Analysis Plan  [PDF] November 21, 2014

More Information

Additional Information:

Click here for more information about this study: A Study of LY2875358 in Combination With Ramucirumab (LY3009806) in Participants With Advanced Cancer 

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT02082210
• Other Study ID Numbers: 15246; I4C-MC-JTBF ( Other Identifier: Eli Lilly and Company )
• First Posted: March 10, 2014
• Results First Posted: December 19, 2020
• Last Update Posted: December 19, 2020
• Last Verified: March 2018

Additional relevant MeSH terms:

Adenocarcinoma; Carcinoma, Renal Cell; Neoplasms; Liver Neoplasms; Carcinoma, Hepatocellular; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Kidney Neoplasms; Urologic Neoplasms; Urogenital Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Kidney Diseases; Urologic Diseases; Male Urogenital Diseases; Digestive System Neoplasms; Digestive System Diseases; Liver Diseases; Ramucirumab; Antineoplastic Agents