Cancer, Solid Tumor
Conditions
Keywords
Advanced Solid tumor, Antibodies, Monoclonal, QTc, Metastatic, Malignant
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
Interventions
BIOLOGICALIMC-1121B
IMC-1121B (Ramucirumab) 10 mg/kg intravenously (IV) over 60 minutes, once every 3 weeks for minimum of 9 weeks.
DRUGMoxifloxacin
Administered orally
DRUGDiphenhydramine
Administered IV
Sponsors
Eli Lilly and Company
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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). |
| 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. |
| 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). |
| 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). |
Countries
United States
Participant flow
Pre-assignment details
68 participants signed the informed consent.
Participants by arm
| Arm | Count |
|---|---|
| IMC-1121B (Ramucirumab) Ramucirumab: 10 milligrams/kilogram (mg/kg) infused intravenously, every 3 weeks (Day 1 of every 21-day cycle). Treatment continued for a minimum of 9 weeks without a break in between until there was evidence of disease progression or intolerable toxicity.
Diphenhydramine: For Cycle 1 only, 25 to 50 milligrams (mg) diphenhydramine infused intravenously 1 day before ramucirumab therapy. For Cycles 1, 2, 3, and 4, 25 to 50 mg diphenhydramine infused intravenously 15 minutes before ramucirumab therapy. For Cycle 5 and beyond, premedication with diphenhydramine was at the discretion of the investigator. Each participant was administered the same dose of diphenhydramine at all time points.
Moxifloxacin: The first 16 participants enrolled received a single dose of moxifloxacin (400 mg tablet orally by mouth) 1 week prior to being treated with ramucirumab. | 66 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 1 |
| Overall Study | Lost to Follow-up | 2 |
| Overall Study | Physician Decision | 2 |
| Overall Study | Withdrawal by Subject | 3 |
Baseline characteristics
| Characteristic | IMC-1121B (Ramucirumab) |
|---|---|
| Age, Customized >=65 years | 26 participants |
| Age, Customized Between 18 and 65 years | 40 participants |
| Ethnicity Hispanic or Latino | 4 participants |
| Ethnicity Non-Hispanic or Latino | 62 participants |
| Race/Ethnicity, Customized Asian | 1 participants |
| Race/Ethnicity, Customized Black | 5 participants |
| Race/Ethnicity, Customized White | 60 participants |
| Region of Enrollment United States | 66 participants |
| Sex: Female, Male Female | 30 Participants |
| Sex: Female, Male Male | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 61 / 66 |
| serious Total, serious adverse events | 32 / 66 |
Outcome results
Primary
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.
Time frame: Baseline, Cycle 3 (1 cycle=21 days)
Population: Participants who received a full study dose of ramucirumab in Cycle 3 and had at least 1 pretreatment ECG and postinfusion ECG at scheduled times as specified in the protocol.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| IMC-1121B (Ramucirumab) | Change From Baseline to Cycle 3 in QT/Corrected QT (QTc) Interval Prolongation in Participants | 3.9132 milliseconds (msec) |
p-value: 0.0161Mixed Models Analysis
Secondary
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).
Time frame: Cycle 1 [2.25 hours (h), 3.25 h, 4.25 h, 72 h, 168 h, 336 h postdose]
Population: Participants who received a full dose of ramucirumab and have evaluable AUC data during Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-1121B (Ramucirumab) | Area Under Concentration (AUC) During Cycle 1 | 67400 hours*micrograms/milliliter (h*mcg/mL) | Geometric Coefficient of Variation 38 |
Secondary
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).
Time frame: Approximately Week 3 (Cycle 1, Day 15)
Population: No participants analyzed.
Secondary
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).
Time frame: Approximately Week 1 (Cycle 1, Day 4)
Population: No participants were analyzed.
Secondary
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).
Time frame: Approximately Week 2 (Cycle 1, Day 8)
Population: No participants were analyzed.
Secondary
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.
Time frame: Approximately Week 1 (Cycle 2, Day 1)
Population: No participants were analyzed.
Secondary
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).
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]
Population: Participants who received a full dose of ramucirumab and have evaluable AUC data during Cycle 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-1121B (Ramucirumab) | Area Under Concentration (AUC) During Cycle 3 | 69900 hours*micrograms/milliliter (h*mcg/mL) | Geometric Coefficient of Variation 41 |
Secondary
Maximum Concentration (Cmax) During Cycle 1
Maximum observed concentration of IMC-1121B (ramucirumab) in serum during Cycle 1 (1 cycle=21 days).
Time frame: Cycle 1 [2.25 hours (h), 3.25 h, 4.25 h, 72 h, 168 h, 336 h postdose]
Population: Participants who received a full dose of ramucirumab and have evaluable Cmax data during Cycle 1.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-1121B (Ramucirumab) | Maximum Concentration (Cmax) During Cycle 1 | 485 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 43 |
Secondary
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.
Time frame: Approximately Week 3 (Cycle 1, Day 15)
Population: No participants were analyzed.
Secondary
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.
Time frame: Approximately Week 1 (Cycle 1, Day 4)
Population: No participants were analyzed.
Secondary
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.
Time frame: Approximately Week 2 (Cycle 1, Day 8)
Population: No participants were analyzed.
Secondary
Maximum Concentration (Cmax) During Cycle 2
Cmax was not calculated due to the sparse pharmacokinetic sampling employed on Cycle 2, Day 1.
Time frame: Cycle 2 (predose and 1.25 hours postdose)
Population: No participants were analyzed.
Secondary
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).
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]
Population: Participants who received a full dose of ramucirumab and have evaluable Cmax data during Cycle 3.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| IMC-1121B (Ramucirumab) | Maximum Concentration (Cmax) During Cycle 3 | 571 micrograms per milliliter (mcg/mL) | Geometric Coefficient of Variation 41 |
Secondary
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.
Time frame: Baseline up to data cut off (approximately 105.6 weeks)
Population: Safety population: participants who received any quantity of ramucirumab, regardless of their eligibility for the study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| IMC-1121B (Ramucirumab) | Number of Participants With Drug-Related Adverse Events (AEs) | Related TEAE | 42 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Drug-Related Adverse Events (AEs) | Related SAE | 11 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Drug-Related Adverse Events (AEs) | Related Grade 3 or higher TEAE | 14 participants |
| IMC-1121B (Ramucirumab) | Number of Participants With Drug-Related Adverse Events (AEs) | Related AE leading to discontinuation | 6 participants |