Study of Ramucirumab (IMC-1121B) Therapy and Corrected QT (QTc) Interval Changes

A Study to Evaluate the Relationship Between Ramucirumab (IMC-1121B) Therapy and Corrected QT (QTc) Interval Changes in Patients With Advanced Cancer

The purpose of this study is to determine if Ramucirumab (IMC-1121B) causes prolongation of the QT/QTc interval in participants with advanced cancer.

Study Overview

• Status: Completed
• Conditions: Cancer; Solid Tumor
• Intervention / Treatment: Drug: Moxifloxacin; Biological: IMC-1121B; Drug: Diphenhydramine

Detailed Description

The primary purpose of this study is to determine if treatment with ramucirumab causes prolongation of the QTc/QT interval in participants with advanced cancer, to assess the safety and tolerability of ramucirumab therapy, and to evaluate the pharmacokinetic (PK) characteristics of ramucirumab

• Study Type: Interventional
• Enrollment (Actual): 68
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • ImClone Investigational Site
  • Louisiana
    • Metairie, Louisiana, United States, 70006
      • ImClone Investigational Site
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • ImClone Investigational Site
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19111
      • ImClone Investigational Site
  • Rhode Island
    • Providence, Rhode Island, United States, 02903
      • ImClone Investigational Site
  • Texas
    • Houston, Texas, United States, 77024
      • ImClone Investigational Site
  • Washington
    • Seattle, Washington, United States, 98109
      • ImClone Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The participant has histologically documented advanced or metastatic malignant cancer of solid tumor origin which has not responded to standard therapy or for which no standard therapy is available
• The participant has resolution of adverse events from prior anticancer therapies
• Performance status of 0 to 2
• The participant is ≥ 18 years of age
• The participant is able to provide informed written consent and is amenable to compliance with protocol schedules and testing
• The participant has adequate liver, kidney, blood, and blood clotting functions as defined in trial entrance criteria
• The participant agrees to use adequate contraception during the study period and for 8 weeks after the last dose of study treatment

Exclusion Criteria:

• The participant had anticancer therapy within 14 days (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
• The participant had therapeutic radiotherapy within 14 days prior to entering the study
• The participant has ongoing side effects ≥ Grade 2 due to prior anticancer therapy
• The participant has brain or leptomeningeal metastases
• The participant has a history of uncontrolled or severe cardiac disease
• The participant has a history of severe congestive heart failure (CHF)
• The participant has a known history of arterial thrombotic events
• The participant has a known history of significant peripheral arterial disease (PAD)
• The participant has an implantable pacemaker or automatic implantable cardioverter defibrillator (AICD)
• The participant has a history of risk factors for ventricular tachycardia or Torsades de pointes (TdP) [for example, family history (parents or siblings) of long QT syndrome], history of fainting, unexplained loss of consciousness, or convulsions
• The participant has a systolic blood pressure (SBP) of > 150 millimeters of mercury (mmHg) or < 90 mmHg or a diastolic blood pressure (DBP) of < 45 or > 95 mmHg. (Participants with a history of hypertension who are receiving antihypertensive therapy are permitted on study provided blood pressure is within the parameters detailed above)
• The participant has a heart rate < 50 beats per minute (bpm) or > 100 bpm at rest
• The participant has a clinically relevant abnormality on the ECG, preventing an accurate measurement of the QT interval
• The participant is using a medication that is known to prolong the ECG QT interval
• The participant has a known allergy to any of the treatment components including fluoroquinolone antibiotics
• The participant has received an investigational new drug or device within 14 days prior to enrollment into this study (excluding placement of an intravenous access device)
• The participant has undergone major surgery within 28 days prior to enrollment
• The participant has known human immunodeficiency virus (HIV) infection
• The participant, if female, is pregnant or lactating
• The participant is receiving chronic daily treatment with aspirin [> 325 milligrams per day (mg/day)]
• The participant has a concurrent active malignancy other than adequately treated nonmelanomatous skin cancer, other noninvasive carcinoma, or in situ neoplasm
• The participant has psychological, familial, sociological, or geographical conditions which do not permit adequate study follow-up, compliance with the protocol, or signature of Informed Consent

Study Plan

How is the study designed?

Design Details

• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: IMC-1121B; Active-control participants (first 16 participants) will receive one dose of moxifloxacin orally 7 days before the first treatment with ramucirumab. All participants will undergo triplicate electrocardiogram (ECG) tests (consisting of three individual ECGs performed consecutively within a period of 4 minutes) and vital signs at various times over the trial period. For Cycle 1, all participants will also receive 2 infusions of diphenhydramine before ramucirumab therapy (the first infusion is 1 day before therapy and the second infusion is 15 minutes before therapy). For Cycles 2, 3, and 4, all participants will receive diphenhydramine 15 minutes before ramucirumab therapy. For Cycle 5 and beyond, diphenhydramine infusions before ramucirumab therapy are at the investigator's discretion. Ramucirumab [10 milligrams per kilogram (mg/kg)] intravenously over 60 minutes, once every 3 weeks for minimum of 9 weeks without a break in between.

Drug: Moxifloxacin; Administered orally; Biological: IMC-1121B; IMC-1121B (Ramucirumab) 10 mg/kg intravenously (IV) over 60 minutes, once every 3 weeks for minimum of 9 weeks.; Other Names: LY3009806; Ramucirumab; Drug: Diphenhydramine; Administered IV

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Cycle 3 in QT/Corrected QT (QTc) Interval Prolongation in Participants	All electrocardiogram (ECG) tests were performed in triplicate prior to ramucirumab treatment. QT is the interval between the Q and T waves and QTc is the QT corrected for heart rate using Fridericia's formula: QTc = QT/RR^0.33 where RR is the interval between 2 R waves. Each participant's mean QT/QTc value was calculated for each ECG test during Cycle 3 and compared to his/her mean pretreatment QT/QTc value. The greatest change from baseline during Cycle 3 was reported. QTc prolongation is defined as a QTc exceeding 10 milliseconds (msec) with a lower 90% confidence interval (CI) exceeding 5 msec at any postdose time points per the International Conference on Harmonization (ICH) E14 guidelines for non-thorough QT studies (ICH 2005; ICH 2008). Least squares (LS) mean was calculated using a linear mixed model for repeated measures (MMRM) and adjusted for serum concentration.	Baseline, Cycle 3 (1 cycle=21 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Drug-Related Adverse Events (AEs)	Data presented are the number of participants who experienced treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), Grade 3 or higher TEAEs, or adverse events (AEs) leading to discontinuation of treatment that were considered to be related to ramucirumab. A summary of SAEs and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events section.	Baseline up to data cut off (approximately 105.6 weeks)
Maximum Concentration (Cmax) During Cycle 1	Maximum observed concentration of IMC-1121B (ramucirumab) in serum during Cycle 1 (1 cycle=21 days).	Cycle 1 [2.25 hours (h), 3.25 h, 4.25 h, 72 h, 168 h, 336 h postdose]
Maximum Concentration (Cmax) During Cycle 1, Day 4	Cmax was summarized once per cycle because participants only received 1 dose of IMC-1121B (ramucirumab) per cycle. Refer to secondary outcome measure 3 for Cmax during Cycle 1.	Approximately Week 1 (Cycle 1, Day 4)
Maximum Concentration (Cmax) During Cycle 1, Day 8	Cmax was summarized once per cycle because participants only received 1 dose of IMC-1121B (ramucirumab) per cycle. Refer to secondary outcome measure 3 for Cmax during Cycle 1.	Approximately Week 2 (Cycle 1, Day 8)
Maximum Concentration (Cmax) During Cycle 1, Day 15	Cmax was summarized once per cycle because participants only received 1 dose of IMC-1121B (ramucirumab) per cycle. Refer to secondary outcome measure 3 for Cmax during Cycle 1.	Approximately Week 3 (Cycle 1, Day 15)
Maximum Concentration (Cmax) During Cycle 2	Cmax was not calculated due to the sparse pharmacokinetic sampling employed on Cycle 2, Day 1.	Cycle 2 (predose and 1.25 hours postdose)
Maximum Concentration (Cmax) During Cycle 3	The maximum observed serum concentration of IMC-1121B (ramucirumab) at steady state (Cmax,ss) during Cycle 3 (1 cycle=21 days).	Cycle 3 [predose and 1.25 hours (h), 2.25 h, 3.25 h, 4.25 h, 72 h, 168 h, 336 h, and 504 h postdose]
Area Under Concentration (AUC) During Cycle 1	The area under the concentration versus time curve from time 0 to infinity [AUC(0-inf)] is reported during Cycle 1 (1 cycle=21 days).	Cycle 1 [2.25 hours (h), 3.25 h, 4.25 h, 72 h, 168 h, 336 h postdose]
Area Under Concentration (AUC) During Cycle 1, Day 4	AUC was summarized once per cycle because participants only received 1 dose of IMC-1121B (ramucirumab) per cycle. Refer to secondary outcome measure 9 for AUC during Cycle 1 (Day 1 through Day 15).	Approximately Week 1 (Cycle 1, Day 4)
Area Under Concentration (AUC) During Cycle 1, Day 8	AUC was summarized once per cycle because participants only received 1 dose of IMC-1121B (ramucirumab) per cycle. Refer to secondary outcome measure 9 for AUC during Cycle 1 (Day 1 through Day 15).	Approximately Week 2 (Cycle 1, Day 8)
Area Under Concentration (AUC) During Cycle 1, Day 15	AUC was summarized once per cycle because participants only received 1 dose of IMC-1121B (ramucirumab) per cycle. Refer to secondary outcome measure 9 for AUC during Cycle 1 (Day 1 through Day 15).	Approximately Week 3 (Cycle 1, Day 15)
Area Under Concentration (AUC) During Cycle 2, Day 1	AUC was not calculated due to the sparse pharmacokinetic sampling employed on Cycle 2, Day 1.	Approximately Week 1 (Cycle 2, Day 1)
Area Under Concentration (AUC) During Cycle 3	The area under the concentration versus time curve over the dosing interval at steady state [AUC(tau,ss)] is reported during Cycle 3 (1 cycle=21 days).	Cycle 3 [predose and 1.25 hours (h), 2.25 h, 3.25 h, 4.25 h, 72 h, 168 h, 336 h, and 504 h postdose]

Collaborators and Investigators

• Sponsor: Eli Lilly and Company

Publications and helpful links

General Publications

• Olszanski AJ, Smith DC, Camacho LH, Thompson J, Ramalingam SS, Harvey RD, Campos L, Ferry D, Tang S, Gao L, Safran H. Electrocardiographic Characterization of Ramucirumab on the Corrected QT Interval in a Phase II Study of Patients With Advanced Solid Tumors. Oncologist. 2016 Apr;21(4):402-3. doi: 10.1634/theoncologist.2015-0467. Epub 2016 Mar 16.

Study record dates

Study Major Dates

• Study Start: November 1, 2009
• Primary Completion (Actual): April 1, 2010
• Study Completion (Actual): May 1, 2014

Study Registration Dates

• First Submitted: November 19, 2009
• First Submitted That Met QC Criteria: November 20, 2009
• First Posted (Estimate): November 23, 2009

Study Record Updates

• Last Update Posted (Estimate): June 10, 2015
• Last Update Submitted That Met QC Criteria: May 15, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Metastatic; Malignant; Antibodies, Monoclonal; QTc; Advanced Solid tumor
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Central Nervous System Depressants; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Anesthetics; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Dermatologic Agents; Anti-Bacterial Agents; Hypnotics and Sedatives; Anesthetics, Local; Anti-Allergic Agents; Sleep Aids, Pharmaceutical; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Moxifloxacin; Ramucirumab; Diphenhydramine; Promethazine
• Other Study ID Numbers: 13915; CP12-0712 (Other Identifier: ImClone Systems); I4T-IE-JVBK (Other Identifier: Eli Lilly and Company)