A Phase 1, Open-Label, Dose Escalation Study Evaluating the Safety, Tolerability and Pharmacokinetics of Trebananib (AMG 386) in Adult Japanese Patients With Advanced Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- Trebananib 3 mg/kg
- Conditions
- Neoplasms, Advanced Solid
- Sponsor
- Takeda
- Enrollment
- 18
- Primary Endpoint
- Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose
- Status
- Completed
- Last Updated
- 10 years ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Histologically or cytologically documented and definitively diagnosed, advanced solid tumor that is refractory to standard treatment or for which no curative therapy is available.
- •Has Eastern Cooperative Oncology Group (ECOG) of 0 or 1 (within 2 weeks prior to enrollment).
- •Men or women, 20 to 74 years old at the time the written informed consent is obtained.
- •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)
- •Life expectancy of 3 months, in the judgment of the investigator.
Exclusion Criteria
- •Has primary central nervous system (CNS) tumors, including any CNS lymphoma.
- •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.)
- •Has hematological malignancies.
- •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/exclusion criteria with the exception of alopecia.
- •Has clinically significant cardiovascular disease within 1 year prior to enrollment, including myocardial infarction, unstable angina, New York Heart Association class 2 or greater heart failure, peripheral vascular disease, cerebrovascular accident, transient ischemic attack, or arrhythmias not controlled by outpatient medication.
- •Has uncontrolled hypertension \[diastolic \>90 millimeter of mercury \[mmHg\]; systolic \>150 mmHg\]. Participant on antihypertensive medication must meet these parameters on a stable antihypertensive.
- •Has history of arterial or venous (deep vein) thrombosis within 1 year before enrollment.
- •Has presence of ascites or pleural effusion requiring medical intervention (example, drainage.)
- •Has history of bleeding diathesis or clinically significant bleeding including hemoptysis within 6 months of enrollment.
- •Has non-healing wound, ulcer or fracture.
Arms & Interventions
Trebananib 3 mg/kg
Trebananib (AMG 386) 3 milligram/kilogram (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).
Intervention: Trebananib 3 mg/kg
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).
Intervention: Trebananib 10 mg/kg
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).
Intervention: Trebananib 30 mg/kg
Outcomes
Primary Outcomes
Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose
Time Frame: 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
Time Frame: 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
Time Frame: 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
Time Frame: 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.
Accumulation Ratio (AR) for AMG 386
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
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.
Number of Participants With Dose Limiting Toxicity (DLT)
Time Frame: 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 With Significant Change From Baseline in Electrocardiogram (ECG)
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
Change relative to baseline in electrocardiogram measured throughout study. Significant change in ECG observed at any time point was summarized and reported.
Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 1 Dose
Time Frame: 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.
Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs)
Time Frame: 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 Clinically Significant Change From Baseline in Vital Signs
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)
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.
Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 1 Dose
Time Frame: 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.
Number of Participants With Abnormal Laboratory Values
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)
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 4 Dose
Time Frame: 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 4 Dose
Time Frame: 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
Time Frame: 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
Time Frame: 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).
Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 1 Dose
Time Frame: Week 2: predose
Cmin was the observed serum concentration at 168 hours postdose.
Secondary Outcomes
- 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)
- 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)
- 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)
- 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)
- 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))