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

• ClinicalTrials.gov Identifier: NCT01017731
• Recruitment Status: Completed
• First Posted: November 23, 2009
• Results First Posted: June 18, 2014
• Last Update Posted: June 10, 2015
• 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 determine if Ramucirumab (IMC-1121B) causes prolongation of the QT/QTc interval in participants with advanced cancer.

Condition or disease	Intervention/treatment	Phase
Cancer; Solid Tumor	Biological: IMC-1121B; Drug: Moxifloxacin; Drug: Diphenhydramine	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 68 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Official Title: A Study to Evaluate the Relationship Between Ramucirumab (IMC-1121B) Therapy and Corrected QT (QTc) Interval Changes in Patients With Advanced Cancer
• Study Start Date: November 2009
• Actual Primary Completion Date: April 2010
• Actual Study Completion Date: May 2014

Arms and Interventions

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.

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: Ramucirumab; LY3009806; Drug: Moxifloxacin; Administered orally; Drug: Diphenhydramine; Administered IV

Outcome Measures

Primary Outcome Measures :

1. Change From Baseline to Cycle 3 in QT/Corrected QT (QTc) Interval Prolongation in Participants [ Time Frame: Baseline, Cycle 3 (1 cycle=21 days) ]
   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.

Secondary Outcome Measures :

1. Number of Participants With Drug-Related Adverse Events (AEs) [ Time Frame: Baseline up to data cut off (approximately 105.6 weeks) ]
   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.
2. Maximum Concentration (Cmax) During Cycle 1 [ Time Frame: Cycle 1 [2.25 hours (h), 3.25 h, 4.25 h, 72 h, 168 h, 336 h postdose] ]
   Maximum observed concentration of IMC-1121B (ramucirumab) in serum during Cycle 1 (1 cycle=21 days).
3. Maximum Concentration (Cmax) During Cycle 1, Day 4 [ Time Frame: Approximately Week 1 (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.
4. Maximum Concentration (Cmax) During Cycle 1, Day 8 [ Time Frame: Approximately Week 2 (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.
5. Maximum Concentration (Cmax) During Cycle 1, Day 15 [ Time Frame: Approximately Week 3 (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.
6. Maximum Concentration (Cmax) During Cycle 2 [ Time Frame: Cycle 2 (predose and 1.25 hours postdose) ]
   Cmax was not calculated due to the sparse pharmacokinetic sampling employed on Cycle 2, Day 1.
7. Maximum Concentration (Cmax) During Cycle 3 [ Time Frame: 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] ]
   The maximum observed serum concentration of IMC-1121B (ramucirumab) at steady state (Cmax,ss) during Cycle 3 (1 cycle=21 days).
8. Area Under Concentration (AUC) During Cycle 1 [ Time Frame: Cycle 1 [2.25 hours (h), 3.25 h, 4.25 h, 72 h, 168 h, 336 h postdose] ]
   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).
9. Area Under Concentration (AUC) During Cycle 1, Day 4 [ Time Frame: Approximately Week 1 (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).
10. Area Under Concentration (AUC) During Cycle 1, Day 8 [ Time Frame: Approximately Week 2 (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).
11. Area Under Concentration (AUC) During Cycle 1, Day 15 [ Time Frame: Approximately Week 3 (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).
12. Area Under Concentration (AUC) During Cycle 2, Day 1 [ Time Frame: Approximately Week 1 (Cycle 2, Day 1) ]
    AUC was not calculated due to the sparse pharmacokinetic sampling employed on Cycle 2, Day 1.
13. Area Under Concentration (AUC) During Cycle 3 [ Time Frame: 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] ]
    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).

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:

• 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

Contacts and Locations

Locations

United States, Georgia

ImClone Investigational Site

Atlanta, Georgia, United States, 30322

United States, Louisiana

ImClone Investigational Site

Metairie, Louisiana, United States, 70006

United States, Michigan

ImClone Investigational Site

Ann Arbor, Michigan, United States, 48109

United States, Pennsylvania

ImClone Investigational Site

Philadelphia, Pennsylvania, United States, 19111

United States, Rhode Island

ImClone Investigational Site

Providence, Rhode Island, United States, 02903

United States, Texas

ImClone Investigational Site

Houston, Texas, United States, 77024

United States, Washington

ImClone Investigational Site

Seattle, Washington, United States, 98109

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

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Eli Lilly and Company
• ClinicalTrials.gov Identifier: NCT01017731
• Other Study ID Numbers: 13915; CP12-0712 ( Other Identifier: ImClone Systems ); I4T-IE-JVBK ( Other Identifier: Eli Lilly and Company )
• First Posted: November 23, 2009
• Results First Posted: June 18, 2014
• Last Update Posted: June 10, 2015
• Last Verified: May 2015

Keywords provided by Eli Lilly and Company:

Advanced Solid tumor; Antibodies, Monoclonal; QTc; Metastatic; Malignant

Additional relevant MeSH terms:

Diphenhydramine; Promethazine; Moxifloxacin; Ramucirumab; Anti-Bacterial Agents; Anti-Infective Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Physiological Effects of Drugs; Sleep Aids, Pharmaceutical; Hypnotics and Sedatives; Central Nervous System Depressants; Anesthetics, Local; Anesthetics; Sensory System Agents; Peripheral Nervous System Agents; Antiemetics; Autonomic Agents; Gastrointestinal Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Neurotransmitter Agents; Anti-Allergic Agents; Antipruritics; Dermatologic Agents