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

Phase 2

Completed

• Conditions: Cancer; Solid Tumor
• Interventions: Biological: IMC-1121B; Drug: Moxifloxacin; Drug: Diphenhydramine

• Registration Number: NCT01017731
• Lead Sponsor: Eli Lilly and Company

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.

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 Timeline

• Study Start: 2009-11
• Study First Submitted: 2009-11-19
• Study First Submitted QC: 2009-11-20
• Study First Posted: 2009-11-23
• Primary Completion: 2010-04
• Disposition First Submitted: 2010-07-29
• Disposition First Submitted QC: 2010-09-01
• Disposition First Posted: 2010-09-06
• Study Completion: 2014-05
• Results First Submitted: 2014-05-16
• Results First Submitted QC: 2014-05-16
• Results First Posted: 2014-06-18
• Status Verified: 2015-05
• Last Update Submitted: 2015-05-15
• Last Update Posted: 2015-06-10

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 68

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
IMC-1121B	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.
IMC-1121B	Moxifloxacin	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.
IMC-1121B	Diphenhydramine	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.

Primary Outcome Measures

Name	Time	Method
Change From Baseline to Cycle 3 in QT/Corrected QT (QTc) Interval Prolongation in Participants	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

Name	Time	Method
Number of Participants With Drug-Related Adverse Events (AEs)	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.
Maximum Concentration (Cmax) During Cycle 1	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).
Maximum Concentration (Cmax) During Cycle 1, Day 4	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.
Maximum Concentration (Cmax) During Cycle 1, Day 8	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.
Maximum Concentration (Cmax) During Cycle 1, Day 15	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.
Maximum Concentration (Cmax) During Cycle 2	Cycle 2 (predose and 1.25 hours postdose)	Cmax was not calculated due to the sparse pharmacokinetic sampling employed on Cycle 2, Day 1.
Maximum Concentration (Cmax) During Cycle 3	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).
Area Under Concentration (AUC) During Cycle 1	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).
Area Under Concentration (AUC) During Cycle 1, Day 4	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).
Area Under Concentration (AUC) During Cycle 1, Day 8	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).
Area Under Concentration (AUC) During Cycle 1, Day 15	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).
Area Under Concentration (AUC) During Cycle 2, Day 1	Approximately Week 1 (Cycle 2, Day 1)	AUC was not calculated due to the sparse pharmacokinetic sampling employed on Cycle 2, Day 1.
Area Under Concentration (AUC) During Cycle 3	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).

Trial Locations

Locations (1)

ImClone Investigational Site; 🇺🇸 Seattle, Washington, United States