Neoplasms, Advanced Solid
Conditions
Keywords
Drug Therapy
Brief summary
The purpose of this study is to evaluate the safety, tolerability and pharmacokinetic (PK) profile of trebananib (AMG 386) after intravenous administration in adult Japanese participants with advanced solid tumors.
Detailed description
The drug being tested in this study is called trebananib (AMG 386). Trebananib (AMG 386) is being tested to treat people with advanced solid tumors. This study will look at the safety, tolerability and pharmacokinetic (PK) profile of trebananib and response to treatment. The study will enroll approximately 18 participants. Once enrolled, participants will be assigned sequentially into 1 of the 3 cohorts: * Trebananib 3 milligram/kilogram (mg/kg), * Trebananib 10 mg/kg, * Trebananib 30 mg/kg. All participants will receive trebananib via 60 minute intravenous infusion. This study will be conducted in Japan. The overall time to participate in this study is 14 weeks or more. Participants will attend the end-of-treatment visit 28 days after the last dose of study drug.
Interventions
DRUGTrebananib 3 mg/kg
Trebananib (AMG 386) 3 mg/kg, intravenous infusion.
DRUGTrebananib 10 mg/kg
Trebananib (AMG 386) 10 mg/kg, intravenous infusion.
DRUGTrebananib 30 mg/kg
Trebananib (AMG 386) 30 mg/kg, intravenous infusion.
Sponsors
Takeda
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
20 Years to 74 Years
Healthy volunteers
No
Inclusion criteria
1. Histologically or cytologically documented and definitively diagnosed, advanced solid tumor that is refractory to standard treatment or for which no curative therapy is available. 2. Has Eastern Cooperative Oncology Group (ECOG) of 0 or 1 (within 2 weeks prior to enrollment). 3. Men or women, 20 to 74 years old at the time the written informed consent is obtained. 4. Those meeting the following laboratory criteria (within 2 weeks prior to enrollment): A. Hematological function, as follows: • Absolute neutrophil count \>=1500 /microliter (mcL) (without granulocyte colony stimulating factor support within 2 weeks of enrollment). • Platelet count \>=10\*10\^4 /mcL (without transfusion within 2 weeks of enrollment). • Hemoglobin \>=9 grams per deciliter (g/dL) (without transfusion within 2 weeks of enrollment). B. Renal function, as follows: • Calculated creatinine clearance (CCr) \>40 milliliter per minute (mL/min) according to the Cockcroft-Gault formula. • Urinary protein quantitative value of less than or equal to (\<=) 30 mg/dL in urinalysis or \<=1+ on dipstick, unless quantitative protein is \<=1,000 mg in a 24 hour urine sample. C. Hepatic function, as follows: • AST \<=2.5\*ULN (if liver metastases are present, \<=5\*ULN). • ALT \<=2.5\*ULN (if liver metastases are present, \<=5\*ULN). • Alkaline phosphatase \<=2.0\*ULN (if bone or liver metastates present \<=5\*ULN). • Total bilirubin \<=2.0\*ULN. D. Hemostatic function, as follows: • Prothrombin time (PT) or activated partial thromboplastin time (APTT) \<=1.5\*ULN. E. ECG • Normal sinus rhythm (no clinical significant 12-lead ECG changes) 5. Life expectancy of 3 months, in the judgment of the investigator.
Exclusion criteria
1. Has primary central nervous system (CNS) tumors, including any CNS lymphoma. 2. Has history of CNS metastases (including previously treated metastases) (The brain imaging test by CT or MRI will be performed at screening. If the imaging test was performed within 3 months prior to written informed consent, the result can be used to confirm the exclusion criterion.) 3. Has hematological malignancies. 4. Has unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to CTCAE grade 0 or 1, or to levels specified in the inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Accumulation Ratio (AR) for AMG 386 | Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose, Week 4: predose, 1, 2, 6, 24, 48, 96, and 168 hours after end of infusion | Accumulation ratio (AR) was calculated by dividing the individual AUC (0-tau) value at Week 4 by the corresponding individual AUC (0-tau) value at Week 1. |
| Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 1 Dose | Week 2: predose | Cmin was the observed serum concentration at 168 hours postdose. |
| Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose | Week 4: 168 hours after end of infusion | Cmin was the observed serum concentration at 168 hours postdose. |
| Vss: Volume of Distribution at Steady State for AMG 386 | Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion | Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state, estimated as: Vss = MRTinf \*CLss, where MRTinf is mean residence time of drug extrapolated to infinity and CLss is the systemic clearance at the steady state. Vss was normalized to participant's body weight. |
| Terminal Phase Elimination Half-life (T1/2) for AMG 386 | Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion | Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the serum. |
| Systemic Clearance at Steady State (CLss) for AMG 386 | Week 4: predose, 1, 2, 6, 24, 48, 96 and 168 hours after end of infusion | CL is a quantitative measure of the rate at which a drug substance is removed from the body. Systemic clearance at steady state (CLss) was calculated as the ratio of dose administered to AUC (0 - tau), where AUC (0 - tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen). CLss was normalized to participant's body weight. |
| Number of Participants With Dose Limiting Toxicity (DLT) | Day 1 up to Day 28 | DLT is defined as any treatment-related, grade 4 or higher hematologic or grade 3 or higher non-hematologic toxicity (according to the Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0; hematologic toxicity means any toxicities which are categorized in blood/bone marrow category of CTCAE), except for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and infusion reaction, occurred during the first 28 days after the initial administration (before examination on Study Day 29). DLT also includes AST or ALT: \>10\*upper limit of normal (ULN) international units per liter (IU/L). |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs) | Baseline up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249 | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. Treatment emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event. |
| Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG) | Week 1: predose, 1, 6 hours after end of infusion, Week 4: predose, 1 hour after end of infusion, Week 8, 16: predose, thereafter predose of every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249 | Change relative to baseline in electrocardiogram measured throughout study. Significant change in ECG observed at any time point was summarized and reported. |
| Number of Participants With Clinically Significant Change From Baseline in Vital Signs | Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after infusion end, Week 2, 3, 4: predose and 1 hour after infusion end, thereafter predose of every 4 weeks starting from Week 8 up to 4 weeks after the last dose of study drug (last dose=Week 249) | Vital signs included body temperature, diastolic and systolic blood pressure, and pulse (beats per minutes). clinically significant change in vital signs observed at any time point was summarized and reported. |
| Number of Participants With Abnormal Laboratory Values | Week 1: predose, 24, 48 and 96 hours after infusion end, Week 2 and 3: predose, Week 4: predose and 1 hour after infusion end, thereafter every 4 weeks starting from Week 8 up to 4 weeks after the last dose of study drug (last dose=Week 249) | The number of participants with any abnormal standard safety laboratory values collected throughout study. Parameters assessed were hematology, chemistry, coagulation and urinalysis. Abnormal laboratory values observed at any time point was summarized and reported. |
| Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 1 Dose | Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose | Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve. |
| Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 4 Dose | Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion | Cmax is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve. |
| Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 1 Dose | Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose | Tmax is the time to reach the maximum serum concentration (Cmax), equal to time (hours) to Cmax. |
| Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 4 Dose | Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion | Tmax is the time to reach the maximum serum concentration (Cmax), equal to time (hours) to Cmax. |
| AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 1 Dose | Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose | AUC (0-tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen). |
| AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 4 Dose | Week 4: predose, 1, 2, 6, 24, 48, 96, and 168 hours after end of infusion | AUC (0-tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Objective Response | Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249 | Objective response rate defined as the rate of participants with CR or PR based on RECIST 1.0 criteria. CR: disappearance of all target lesions, non-target lesions and normalization of tumor marker level. PR: at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. |
| Time to Progression (TTP) | Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249 | TTP is defined as the time from the date of first administration of study treatment to the date of first documentation of PD or death caused by progression. For participants who did not have a documented PD or died owing to causes other than progression, TTP was censored at the time of last response assessment. PD is defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions. |
| Percent Change From Baseline to Post-baseline in the Sum of the Longest Diameters of Tumor | Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249 | The percent change from baseline to post-baseline is the largest percent reduction from baseline among all post-dose measures of the sum of the longest diameter of the tumor burden. |
| Number of Participant With Anti-AMG 386 Antibody | Week 1: predose,1,2,6,24,48 and 98 hours after infusion end, Week 3: predose, Week 4: predose, 1,2,6,24,48,96,168 and 264 hours after infusion end, thereafter predose every 4 weeks starting from Week 8 up to 8 weeks after last dose (last dose=Week 249) | The immunogenicity of AMG 386 was evaluated with an immunoassay that detects anti-AMG 386 binding antibodies. Antibody formation reported at any of the time points was summarized. |
| Number of Participants With Best Overall Response | Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249 | Best overall response for a participant is the best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Complete Response (CR): disappearance of all target lesions, non-target lesions and normalization of tumor marker level. Partial Response (PR): at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the baseline smallest sum of longest diameter; persistence of 1 or more non-target lesion(s) or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions. |
Participant flow
Recruitment details
Participants took part in the study at 1 investigative site in Japan from 26 June 2009 to 28 May 2014.
Pre-assignment details
Participants with a historical diagnosis of advanced solid tumor were enrolled in 1 of 3 treatment groups: trebananib 3 milligram/kilogram (mg/kg); trebananib 10 mg/kg; trebananib 30 mg/kg.
Participants by arm
| Arm | Count |
|---|---|
| Trebananib 3 mg/kg Trebananib (AMG 386) 3 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks). | 6 |
| Trebananib 10 mg/kg Trebananib (AMG 386) 10 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks). | 6 |
| Trebananib 30 mg/kg Trebananib (AMG 386) 30 mg/kg, 60-minute infusion, intravenously once weekly on Days 1, 8, 15 and 22 and thereafter once weekly starting from Day 36 (Week 6) until intolerance to investigational product, progressive disease, consent withdrawn, or lost to follow-up (up to approximately 249 weeks). | 6 |
| Total | 18 |
Baseline characteristics
| Characteristic | Trebananib 3 mg/kg | Total | Trebananib 30 mg/kg | Trebananib 10 mg/kg |
|---|---|---|---|---|
| Age, Continuous | 57.7 years STANDARD_DEVIATION 10.41 | 57.9 years STANDARD_DEVIATION 8.22 | 60.7 years STANDARD_DEVIATION 6.71 | 55.3 years STANDARD_DEVIATION 7.71 |
| Age, Customized Greater than or equal to (>=) 65 years | 2 participants | 6 participants | 3 participants | 1 participants |
| Age, Customized Less than (<) 65 years | 4 participants | 12 participants | 3 participants | 5 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG performance status 0 | 6 participants | 17 participants | 5 participants | 6 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status ECOG performance status 1 | 0 participants | 1 participants | 1 participants | 0 participants |
| Height | 162.28 centimeter STANDARD_DEVIATION 6.233 | 161.28 centimeter STANDARD_DEVIATION 7.938 | 160.48 centimeter STANDARD_DEVIATION 3.136 | 161.08 centimeter STANDARD_DEVIATION 12.788 |
| Medical and surgical history With medical and surgical history | 6 participants | 15 participants | 5 participants | 4 participants |
| Medical and surgical history Without medical and surgical history | 0 participants | 3 participants | 1 participants | 2 participants |
| Method of Tumor Assessment Computed Tomography (CT) | 6 participants | 18 participants | 6 participants | 6 participants |
| Method of Tumor Assessment Magnetic Resonance Imaging (MRI) | 0 participants | 0 participants | 0 participants | 0 participants |
| Number of Target Lesions 1 Target Lesion | 0 participants | 2 participants | 1 participants | 1 participants |
| Number of Target Lesions 2 Target Lesion | 2 participants | 4 participants | 2 participants | 0 participants |
| Number of Target Lesions 3 Target Lesion | 2 participants | 2 participants | 0 participants | 0 participants |
| Number of Target Lesions 4 Target Lesion | 0 participants | 2 participants | 2 participants | 0 participants |
| Number of Target Lesions >=5 Target Lesion | 2 participants | 8 participants | 1 participants | 5 participants |
| Presence of Non-Target Lesions With Non-Target Lesions | 6 participants | 18 participants | 6 participants | 6 participants |
| Presence of Non-Target Lesions Without Non-Target Lesions | 0 participants | 0 participants | 0 participants | 0 participants |
| Primary Tumor Type Neoplasm, bladder | 0 participants | 1 participants | 1 participants | 0 participants |
| Primary Tumor Type Neoplasm, breast | 0 participants | 1 participants | 0 participants | 1 participants |
| Primary Tumor Type Neoplasm, colon | 1 participants | 2 participants | 0 participants | 1 participants |
| Primary Tumor Type Neoplasm, pancreatic | 1 participants | 3 participants | 1 participants | 1 participants |
| Primary Tumor Type Neoplasm, rectal | 1 participants | 4 participants | 1 participants | 2 participants |
| Primary Tumor Type Neoplasm, stomach | 3 participants | 6 participants | 3 participants | 0 participants |
| Primary Tumor Type Neoplasm, uterine | 0 participants | 1 participants | 0 participants | 1 participants |
| Prior Other Cancer Medication Without prior other cancer medication | 0 participants | 0 participants | 0 participants | 0 participants |
| Prior Other Cancer Medication With prior other cancer medication | 6 participants | 18 participants | 6 participants | 6 participants |
| Prior Radiotherapy Without prior radiotherapy | 6 participants | 16 participants | 6 participants | 4 participants |
| Prior Radiotherapy With prior radiotherapy | 0 participants | 2 participants | 0 participants | 2 participants |
| Region of Enrollment | 6 participants | 18 participants | 6 participants | 6 participants |
| Sex: Female, Male Female | 2 Participants | 8 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Male | 4 Participants | 10 Participants | 3 Participants | 3 Participants |
| Sum of the Longest Diameter of Target Lesions | 112.3 millimeters STANDARD_DEVIATION 98.7 | 129.5 millimeters STANDARD_DEVIATION 91.04 | 96.8 millimeters STANDARD_DEVIATION 63.07 | 179.3 millimeters STANDARD_DEVIATION 99.23 |
| Weight | 52.80 kilogram STANDARD_DEVIATION 10.208 | 55.74 kilogram STANDARD_DEVIATION 10.257 | 50.40 kilogram STANDARD_DEVIATION 3.683 | 64.03 kilogram STANDARD_DEVIATION 10.623 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 6 / 6 | 6 / 6 | 6 / 6 |
| serious Total, serious adverse events | 2 / 6 | 0 / 6 | 1 / 6 |
Outcome results
Primary
Accumulation Ratio (AR) for AMG 386
Accumulation ratio (AR) was calculated by dividing the individual AUC (0-tau) value at Week 4 by the corresponding individual AUC (0-tau) value at Week 1.
Time frame: Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose, Week 4: predose, 1, 2, 6, 24, 48, 96, and 168 hours after end of infusion
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Accumulation Ratio (AR) for AMG 386 | 1.235 ratio | Standard Deviation 0.05143 |
| Trebananib 10 mg/kg | Accumulation Ratio (AR) for AMG 386 | 1.193 ratio | Standard Deviation 0.06862 |
| Trebananib 30 mg/kg | Accumulation Ratio (AR) for AMG 386 | 1.211 ratio | Standard Deviation 0.2139 |
Primary
AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 1 Dose
AUC (0-tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen).
Time frame: Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 1 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 1 Dose | 1760 microgram*hour/milliliter (mcg*hr/mL) | Standard Deviation 582.1 |
| Trebananib 10 mg/kg | AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 1 Dose | 4629 microgram*hour/milliliter (mcg*hr/mL) | Standard Deviation 924.5 |
| Trebananib 30 mg/kg | AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 1 Dose | 18040 microgram*hour/milliliter (mcg*hr/mL) | Standard Deviation 4489 |
Primary
AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 4 Dose
AUC (0-tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen).
Time frame: Week 4: predose, 1, 2, 6, 24, 48, 96, and 168 hours after end of infusion
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 4 Dose | 2171 mcg*hr/mL | Standard Deviation 715.4 |
| Trebananib 10 mg/kg | AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 4 Dose | 5880 mcg*hr/mL | Standard Deviation 559.6 |
| Trebananib 30 mg/kg | AUC (0-tau): Area Under the Serum Concentration-time Curve From Time 0 to Time Tau Over the Dosing Interval for AMG 386 After Week 4 Dose | 21170 mcg*hr/mL | Standard Deviation 2912 |
Primary
Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 1 Dose
Maximum observed serum concentration (Cmax) is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.
Time frame: Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 1 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 1 Dose | 52.33 microgram per milliliter (mcg/mL) | Standard Deviation 11.27 |
| Trebananib 10 mg/kg | Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 1 Dose | 239.0 microgram per milliliter (mcg/mL) | Standard Deviation 47.11 |
| Trebananib 30 mg/kg | Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 1 Dose | 551.2 microgram per milliliter (mcg/mL) | Standard Deviation 86.76 |
Primary
Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 4 Dose
Cmax is the peak serum concentration of a drug after administration, obtained directly from the serum concentration-time curve.
Time frame: Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 4 Dose | 59.02 mcg/mL | Standard Deviation 10.09 |
| Trebananib 10 mg/kg | Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 4 Dose | 277.0 mcg/mL | Standard Deviation 48.79 |
| Trebananib 30 mg/kg | Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 4 Dose | 688.7 mcg/mL | Standard Deviation 104.5 |
Primary
Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 1 Dose
Cmin was the observed serum concentration at 168 hours postdose.
Time frame: Week 2: predose
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 1 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 1 Dose | 2.702 mcg/mL | Standard Deviation 1.226 |
| Trebananib 10 mg/kg | Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 1 Dose | 3.857 mcg/mL | Standard Deviation 1.018 |
| Trebananib 30 mg/kg | Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 1 Dose | 20.20 mcg/mL | Standard Deviation 5.06 |
Primary
Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose
Cmin was the observed serum concentration at 168 hours postdose.
Time frame: Week 4: 168 hours after end of infusion
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose | 5.323 mcg/mL | Standard Deviation 2.536 |
| Trebananib 10 mg/kg | Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose | 7.266 mcg/mL | Standard Deviation 1.521 |
| Trebananib 30 mg/kg | Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose | 45.07 mcg/mL | Standard Deviation 16.24 |
Primary
Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs)
An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. Treatment emergent adverse event (TEAE) is defined as an adverse event with an onset that occurs after receiving study drug. A serious adverse event (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; or congenital anomaly; or a medically important event.
Time frame: Baseline up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249
Population: Safety analysis set: all participants who received at least 1 dose of AMG 386.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trebananib 3 mg/kg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs) | AEs | 6 participants |
| Trebananib 3 mg/kg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs) | SAEs | 2 participants |
| Trebananib 10 mg/kg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs) | AEs | 6 participants |
| Trebananib 10 mg/kg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs) | SAEs | 0 participants |
| Trebananib 30 mg/kg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs) | AEs | 6 participants |
| Trebananib 30 mg/kg | Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs) | SAEs | 1 participants |
Primary
Number of Participants With Abnormal Laboratory Values
The number of participants with any abnormal standard safety laboratory values collected throughout study. Parameters assessed were hematology, chemistry, coagulation and urinalysis. Abnormal laboratory values observed at any time point was summarized and reported.
Time frame: Week 1: predose, 24, 48 and 96 hours after infusion end, Week 2 and 3: predose, Week 4: predose and 1 hour after infusion end, thereafter every 4 weeks starting from Week 8 up to 4 weeks after the last dose of study drug (last dose=Week 249)
Population: Safety analysis set: all participants who received at least 1 dose of AMG 386.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trebananib 3 mg/kg | Number of Participants With Abnormal Laboratory Values | Coagulation | 3 participants |
| Trebananib 3 mg/kg | Number of Participants With Abnormal Laboratory Values | Hematology | 5 participants |
| Trebananib 3 mg/kg | Number of Participants With Abnormal Laboratory Values | Urinalysis | 2 participants |
| Trebananib 3 mg/kg | Number of Participants With Abnormal Laboratory Values | Chemistry | 6 participants |
| Trebananib 10 mg/kg | Number of Participants With Abnormal Laboratory Values | Coagulation | 0 participants |
| Trebananib 10 mg/kg | Number of Participants With Abnormal Laboratory Values | Chemistry | 6 participants |
| Trebananib 10 mg/kg | Number of Participants With Abnormal Laboratory Values | Urinalysis | 2 participants |
| Trebananib 10 mg/kg | Number of Participants With Abnormal Laboratory Values | Hematology | 4 participants |
| Trebananib 30 mg/kg | Number of Participants With Abnormal Laboratory Values | Urinalysis | 3 participants |
| Trebananib 30 mg/kg | Number of Participants With Abnormal Laboratory Values | Hematology | 6 participants |
| Trebananib 30 mg/kg | Number of Participants With Abnormal Laboratory Values | Chemistry | 6 participants |
| Trebananib 30 mg/kg | Number of Participants With Abnormal Laboratory Values | Coagulation | 0 participants |
Primary
Number of Participants With Clinically Significant Change From Baseline in Vital Signs
Vital signs included body temperature, diastolic and systolic blood pressure, and pulse (beats per minutes). clinically significant change in vital signs observed at any time point was summarized and reported.
Time frame: Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after infusion end, Week 2, 3, 4: predose and 1 hour after infusion end, thereafter predose of every 4 weeks starting from Week 8 up to 4 weeks after the last dose of study drug (last dose=Week 249)
Population: Safety analysis set: all participants who received at least 1 dose of AMG 386.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trebananib 3 mg/kg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 participants |
| Trebananib 10 mg/kg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 participants |
| Trebananib 30 mg/kg | Number of Participants With Clinically Significant Change From Baseline in Vital Signs | 0 participants |
Primary
Number of Participants With Dose Limiting Toxicity (DLT)
DLT is defined as any treatment-related, grade 4 or higher hematologic or grade 3 or higher non-hematologic toxicity (according to the Common Terminology Criteria for Adverse Events \[CTCAE\] version 3.0; hematologic toxicity means any toxicities which are categorized in blood/bone marrow category of CTCAE), except for aspartate aminotransferase (AST), alanine aminotransferase (ALT) and infusion reaction, occurred during the first 28 days after the initial administration (before examination on Study Day 29). DLT also includes AST or ALT: \>10\*upper limit of normal (ULN) international units per liter (IU/L).
Time frame: Day 1 up to Day 28
Population: DLT analysis set: all participants who experience at least 1 DLT in the first 28 days of treatment, or who received all planned AMG 386 dose and are followed until the day before the treatment on Study Day 29.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trebananib 3 mg/kg | Number of Participants With Dose Limiting Toxicity (DLT) | 0 participants |
| Trebananib 10 mg/kg | Number of Participants With Dose Limiting Toxicity (DLT) | 0 participants |
| Trebananib 30 mg/kg | Number of Participants With Dose Limiting Toxicity (DLT) | 0 participants |
Primary
Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG)
Change relative to baseline in electrocardiogram measured throughout study. Significant change in ECG observed at any time point was summarized and reported.
Time frame: Week 1: predose, 1, 6 hours after end of infusion, Week 4: predose, 1 hour after end of infusion, Week 8, 16: predose, thereafter predose of every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249
Population: Safety analysis set: all participants who received at least 1 dose of AMG 386.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trebananib 3 mg/kg | Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG) | 0 participants |
| Trebananib 10 mg/kg | Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG) | 0 participants |
| Trebananib 30 mg/kg | Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG) | 0 participants |
Primary
Systemic Clearance at Steady State (CLss) for AMG 386
CL is a quantitative measure of the rate at which a drug substance is removed from the body. Systemic clearance at steady state (CLss) was calculated as the ratio of dose administered to AUC (0 - tau), where AUC (0 - tau) is the area under the serum concentration-time curve during a dosing interval, where tau is the length of the dosing interval (168 hours for once weekly regimen). CLss was normalized to participant's body weight.
Time frame: Week 4: predose, 1, 2, 6, 24, 48, 96 and 168 hours after end of infusion
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Systemic Clearance at Steady State (CLss) for AMG 386 | 1.495 milliliter/hour/kilogram(mL/hr/kg) | Standard Deviation 0.4231 |
| Trebananib 10 mg/kg | Systemic Clearance at Steady State (CLss) for AMG 386 | 1.713 milliliter/hour/kilogram(mL/hr/kg) | Standard Deviation 0.1653 |
| Trebananib 30 mg/kg | Systemic Clearance at Steady State (CLss) for AMG 386 | 1.439 milliliter/hour/kilogram(mL/hr/kg) | Standard Deviation 0.1912 |
Primary
Terminal Phase Elimination Half-life (T1/2) for AMG 386
Terminal phase elimination half-life (T1/2) is the time required for half of the drug to be eliminated from the serum.
Time frame: Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Terminal Phase Elimination Half-life (T1/2) for AMG 386 | 95.86 hr | Standard Deviation 35.05 |
| Trebananib 10 mg/kg | Terminal Phase Elimination Half-life (T1/2) for AMG 386 | 95.41 hr | Standard Deviation 14.84 |
| Trebananib 30 mg/kg | Terminal Phase Elimination Half-life (T1/2) for AMG 386 | 93.89 hr | Standard Deviation 25.57 |
Primary
Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 1 Dose
Tmax is the time to reach the maximum serum concentration (Cmax), equal to time (hours) to Cmax.
Time frame: Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 1 assessment available.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 1 Dose | 1.067 hour (hr) | Full Range 582.1 |
| Trebananib 10 mg/kg | Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 1 Dose | 1.033 hour (hr) | Full Range 924.5 |
| Trebananib 30 mg/kg | Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 1 Dose | 1.167 hour (hr) | Full Range 4489 |
Primary
Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 4 Dose
Tmax is the time to reach the maximum serum concentration (Cmax), equal to time (hours) to Cmax.
Time frame: Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 4 Dose | 1.067 hr | Full Range 35.05 |
| Trebananib 10 mg/kg | Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 4 Dose | 1.017 hr | Full Range 14.84 |
| Trebananib 30 mg/kg | Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 4 Dose | 1.508 hr | Full Range 25.57 |
Primary
Vss: Volume of Distribution at Steady State for AMG 386
Volume of distribution is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired blood concentration of a drug. Vss is the apparent volume of distribution at steady-state, estimated as: Vss = MRTinf \*CLss, where MRTinf is mean residence time of drug extrapolated to infinity and CLss is the systemic clearance at the steady state. Vss was normalized to participant's body weight.
Time frame: Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion
Population: Pharmacokinetic analysis set: all participants who had at least 1 evaluable serum concentrations, received at least 1 dose of AMG 386, and had Week 4 assessment available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Vss: Volume of Distribution at Steady State for AMG 386 | 158.2 milliliter per kilogram (mL/kg) | Standard Deviation 49.02 |
| Trebananib 10 mg/kg | Vss: Volume of Distribution at Steady State for AMG 386 | 121.0 milliliter per kilogram (mL/kg) | Standard Deviation 22.18 |
| Trebananib 30 mg/kg | Vss: Volume of Distribution at Steady State for AMG 386 | 136.6 milliliter per kilogram (mL/kg) | Standard Deviation 30.26 |
Secondary
Number of Participants With Best Overall Response
Best overall response for a participant is the best observed post-baseline disease response as per Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 criteria. Complete Response (CR): disappearance of all target lesions, non-target lesions and normalization of tumor marker level. Partial Response (PR): at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter. Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the baseline smallest sum of longest diameter; persistence of 1 or more non-target lesion(s) or maintenance of tumor marker level above the normal limits. PD: at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions.
Time frame: Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249
Population: Response evaluable analysis set: a subset of participants in the full analysis set (FAS) with at least 1 measurable lesion at baseline using the RECIST 1.0. FAS consisted of all participants who had evaluable data and received at least 1 dose of AMG 386.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Trebananib 3 mg/kg | Number of Participants With Best Overall Response | CR | 0 participants |
| Trebananib 3 mg/kg | Number of Participants With Best Overall Response | PR | 1 participants |
| Trebananib 3 mg/kg | Number of Participants With Best Overall Response | SD | 0 participants |
| Trebananib 3 mg/kg | Number of Participants With Best Overall Response | PD | 5 participants |
| Trebananib 10 mg/kg | Number of Participants With Best Overall Response | PD | 5 participants |
| Trebananib 10 mg/kg | Number of Participants With Best Overall Response | CR | 0 participants |
| Trebananib 10 mg/kg | Number of Participants With Best Overall Response | SD | 1 participants |
| Trebananib 10 mg/kg | Number of Participants With Best Overall Response | PR | 0 participants |
| Trebananib 30 mg/kg | Number of Participants With Best Overall Response | PD | 4 participants |
| Trebananib 30 mg/kg | Number of Participants With Best Overall Response | PR | 1 participants |
| Trebananib 30 mg/kg | Number of Participants With Best Overall Response | SD | 1 participants |
| Trebananib 30 mg/kg | Number of Participants With Best Overall Response | CR | 0 participants |
Secondary
Number of Participant With Anti-AMG 386 Antibody
The immunogenicity of AMG 386 was evaluated with an immunoassay that detects anti-AMG 386 binding antibodies. Antibody formation reported at any of the time points was summarized.
Time frame: Week 1: predose,1,2,6,24,48 and 98 hours after infusion end, Week 3: predose, Week 4: predose, 1,2,6,24,48,96,168 and 264 hours after infusion end, thereafter predose every 4 weeks starting from Week 8 up to 8 weeks after last dose (last dose=Week 249)
Population: Safety analysis set: all participants who received at least 1 dose of AMG 386.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trebananib 3 mg/kg | Number of Participant With Anti-AMG 386 Antibody | 2 participants |
| Trebananib 10 mg/kg | Number of Participant With Anti-AMG 386 Antibody | 1 participants |
| Trebananib 30 mg/kg | Number of Participant With Anti-AMG 386 Antibody | 0 participants |
Secondary
Percentage of Participants With Objective Response
Objective response rate defined as the rate of participants with CR or PR based on RECIST 1.0 criteria. CR: disappearance of all target lesions, non-target lesions and normalization of tumor marker level. PR: at least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum of longest diameter.
Time frame: Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249
Population: Response evaluable analysis set: a subset of participants in the FAS with at least 1 measurable lesion at baseline using the RECIST 1.0. FAS consisted of all participants who had evaluable data and received at least 1 dose of AMG 386.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Trebananib 3 mg/kg | Percentage of Participants With Objective Response | 17 Percentage of participants |
| Trebananib 10 mg/kg | Percentage of Participants With Objective Response | 0 Percentage of participants |
| Trebananib 30 mg/kg | Percentage of Participants With Objective Response | 17 Percentage of participants |
Secondary
Percent Change From Baseline to Post-baseline in the Sum of the Longest Diameters of Tumor
The percent change from baseline to post-baseline is the largest percent reduction from baseline among all post-dose measures of the sum of the longest diameter of the tumor burden.
Time frame: Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249
Population: Response evaluable analysis set: a subset of participants in the FAS with at least 1 measurable lesion at baseline using the RECIST 1.0 and valid post-baseline tumor lesion assessment available. FAS consisted of all participants who had evaluable data and received at least 1 dose of AMG 386.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Trebananib 3 mg/kg | Percent Change From Baseline to Post-baseline in the Sum of the Longest Diameters of Tumor | -1.53 percent change | Standard Deviation 48.655 |
| Trebananib 10 mg/kg | Percent Change From Baseline to Post-baseline in the Sum of the Longest Diameters of Tumor | 16.36 percent change | Standard Deviation 18.455 |
| Trebananib 30 mg/kg | Percent Change From Baseline to Post-baseline in the Sum of the Longest Diameters of Tumor | 5.53 percent change | Standard Deviation 46.907 |
Secondary
Time to Progression (TTP)
TTP is defined as the time from the date of first administration of study treatment to the date of first documentation of PD or death caused by progression. For participants who did not have a documented PD or died owing to causes other than progression, TTP was censored at the time of last response assessment. PD is defined as at least 20% increase in the sum of the longest diameter of target lesions, taking as reference the baseline smallest sum of longest diameter or appearance of 1 or more new lesions or unequivocal progression of existing non-target lesions.
Time frame: Baseline, assessed every 8 weeks up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249
Population: Response evaluable analysis set: a subset of participants in the FAS with at least 1 measurable lesion at baseline using the RECIST 1.0. FAS consisted of all participants who had evaluable data and received at least 1 dose of AMG386.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Trebananib 3 mg/kg | Time to Progression (TTP) | 48.0 Days |
| Trebananib 10 mg/kg | Time to Progression (TTP) | 46.0 Days |
| Trebananib 30 mg/kg | Time to Progression (TTP) | 45.5 Days |