Clinical trial NCT02525536: A Phase 1 Study Evaluating the Safety, Tolerability and Pharmacokinetics of Trebananib (AMG 386 ) in Adult Japanese Participants With Advanced Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms, Advanced Solid
Keywords: Drug Therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2015-08-17
Enrollment: 18
Sex: ALL
Minimum age (years): 20
Maximum age (years): 74
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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/exclusion criteria with the exception of alopecia. 5. 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. 6. Has uncontrolled hypertension \[diastolic \>90 millimeter of mercury \[mmHg\]; systolic \>150 mmHg\]. Participant on antihypertensive medication must meet these parameters on a stable antihypertensive. 7. Has history of arterial or venous (deep vein) thrombosis within 1 year before enrollment. 8. Has presence of ascites or pleural effusion requiring medical intervention (example, drainage.) 9. Has history of bleeding diathesis or clinically significant bleeding including hemoptysis within 6 months of enrollment. 10. Has non-healing wound, ulcer or fracture. 11. With head and neck cancer. 12. Has squamous cell tumor or lung cancer with large central (located adjacent to or within the hilum or mediastinum) tumor lesions \>=3 centimeter (cm), regardless of histology. 13. Has positive test for human immunodeficiency virus infection. 14. Has positive test for hepatitis C virus infection (positive hepatitis C virus antibody \[HCVAb\] or hepatitis B infection (positive hepatitis B virus antigen \[HBsAg\] or positive hepatitis B virus antibody \[HBcAb\])). 15. Had major surgery (requiring general anesthesia) within 4 weeks before enrollment. 16. Has minor surgery, placement of central venous catheter, or fine needle aspiration within 7 days prior to enrollment. 17. Is unable to tolerate IV administration, in the judgment of the investigator. 18. Has prior anti-tumor therapies, defined as: •Treatment with tumor directed antibody therapy within 4 weeks prior to Study Day 1, with the exception of bevacizumab and other monoclonal antibodies with a half-life \>10 days, which must be discontinued at least 8 weeks prior to Study Day 1. •Anti-cancer therapy including chemotherapy and retinoid therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin) before Study Day 1. •Hormonal anti-tumor therapy within 4 weeks before Study Day 1. Does not include hormones for non-cancer related conditions (example, insulin for diabetes, hormone replacement therapy). •Therapeutic or palliative radiation therapy within 4 weeks before Study Day 1 (participants must have resolution of any significant adverse effects from radiation therapy received prior to 2 weeks before Study Day 1). 19. Has any elective surgeries scheduled during their participation in the study. 20. Has prior radiation to abdomen. 21. Has concurrent or prior (within 4 weeks before Study Day 1) anticoagulation therapy excluding aspirin and anti-platelet agents. The concurrent use of low molecular weight heparin or low dose warfarin (\<=1 mg daily) for prophylaxis against thrombosis is acceptable. 22. Has concurrent immunosuppressant therapy (cyclosporine, tacrolimus, or chronic treatment with prednisolone \[\> 5 mg daily\]) within 4 weeks prior to Study Day 1. 23. Currently or previously treated with angiopoietin inhibitors, or inhibitors of Tie-1 or Tie-2 including, but not limited to, AMG 386, XL880, XL820. 24. Is enrolled in the clinical study for other investigational products or devices or within 4 weeks since the last administration at the enrollment. 25. Is pregnant (example, positive human choriogonadotropin \[HCG\] test) or breastfeeding. 26. Has a childbearing potential, or participant who has a partner of childbearing potential, who is not using adequate contraceptive precautions, and participant unwilling for 6 months after the last AMG 386 infusion. 27. Has any kind of disorder that compromises the ability of the participant to give written informed consent and/or comply with study procedures. 28. Has any co-morbid medical condition that would increase the risk of toxicity, in the judgement of the investigator or the sponsor. 29. The investigator has determined the participant has difficulties that would prevent the participant's ability to participate in the study. 30. Has a history of allergic reactions to bacterially produced proteins. 31. Has a history of severe drug hypersensitivity.

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicity (DLT)
timeFrame: Day 1 up to Day 28
measure: Number of Participants Reporting One or More Treatment-emergent Adverse Events (AEs) and Serious Adverse Event (SAEs)
timeFrame: Baseline up to 4 weeks after the last dose of study drug, where last dose was given up to Week 249
measure: Number of Participants With Significant Change From Baseline in Electrocardiogram (ECG)
timeFrame: 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
measure: Number of Participants With Clinically Significant Change From Baseline in Vital Signs
timeFrame: 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)
measure: Number of Participants With Abnormal Laboratory Values
timeFrame: 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)
measure: Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 1 Dose
timeFrame: Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose
measure: Cmax: Maximum Observed Serum Concentration for AMG 386 After Week 4 Dose
timeFrame: Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion
measure: Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 1 Dose
timeFrame: Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose
measure: Tmax: Time to Reach the Maximum Serum Concentration (Cmax) for AMG 386 After Week 4 Dose
timeFrame: Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion
measure: 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
timeFrame: Week 1: predose, 1, 2, 6, 24, 48 and 96 hours after end of infusion, Week 2: predose
measure: 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
timeFrame: Week 4: predose, 1, 2, 6, 24, 48, 96, and 168 hours after end of infusion
measure: Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 1 Dose
timeFrame: Week 2: predose
measure: Cmin: Minimum Observed Serum Trough Concentration for AMG 386 After Week 4 Dose
timeFrame: Week 4: 168 hours after end of infusion
measure: Vss: Volume of Distribution at Steady State for AMG 386
timeFrame: Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion
measure: Terminal Phase Elimination Half-life (T1/2) for AMG 386
timeFrame: Week 4: predose, 1, 2, 6, 24, 48, 96, 168 and 264 hours after end of infusion
measure: Systemic Clearance at Steady State (CLss) for AMG 386
timeFrame: Week 4: predose, 1, 2, 6, 24, 48, 96 and 168 hours after end of infusion
measure: Accumulation Ratio (AR) for AMG 386
timeFrame: 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
Secondary outcomes:
measure: Number of Participants With Best Overall Response
timeFrame: 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
measure: Percentage of Participants With Objective Response
timeFrame: 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
measure: Time to Progression (TTP)
timeFrame: 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
measure: Percent Change From Baseline to Post-baseline in the Sum of the Longest Diameters of Tumor
timeFrame: 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
measure: Number of Participant With Anti-AMG 386 Antibody
timeFrame: 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)
Other outcomes:
Locations:
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Doi T, Ohtsu A, Fuse N, Yoshino T, Tahara M, Shibayama K, Takubo T, Weinreich DM. Phase 1 study of trebananib (AMG 386), an angiogenesis targeting angiopoietin-1/2 antagonist, in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol. 2013 Jan;71(1):227-35. doi: 10.1007/s00280-012-2000-1. Epub 2012 Nov 3.