Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as AMG 386, Angiogenesis inhibitor, Amgen 386
trebananib · 16 trials · 43 indications
AE: any untoward medical occurrence that does not necessarily have a causal relationship with treatment. SAE: an AE that: is fatal; is life threatening; requires in-patient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; is an other significant medical hazard. Treatment-emergent AEs (TEAEs) are those that occurred after the first administration of study drug through 30 days after the last study drug administration. Severity was graded according to Common Terminology Criteria (CTCAE) version 3.0, as grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death).
A trebananib dose was considered delayed if it was administered 11 or more days from the previous trebananib infusion. A sunitinib dose was considered delayed if it was administered 3 or more days from the previous dose, except during holidays.
Participants who had a sunitinib dose modification within 12 weeks from their first dose due to adverse event, laboratory toxicity, or laboratory toxicity and adverse event.
Severity was graded according to Common Terminology Criteria (CTCAE) version 3.0, as grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), grade 5 (death).
PFS6 is the proportion of patients remaining alive and progression-free at 6-months from study entry. Progressive disease was established based on Response Assessment in Neuro-Oncology (RANO) criteria (Wen et al JCO 2010). RANO criteria has 5 potential categories: Complete Response (CR), Partial Response (PR), Stable Disease (SD), Progressive disease (PD) and Unknown status. CR: disappearance of all enhancing lesions, stable or improved non-enhancing lesions, and stable or improved clinically. PR: \>= 50% decrease in sum of perpendicular diameters of all measurable enhancing lesions, no progression of non-measurable disease, stable or improved non- enhancing lesions, and stable or improved clinically. PD: \> 25% increase in sum of perpendicular diameters of all measurable enhancing lesions, significant increase of non-enhancing lesions, any new lesions, clear clinical deterioration, failure to return for evaluation due to death or deteriorating condition. SD: d
The MTD of weekly AMG 386 intravenously (IV) in combination with bevacizumab 10 mg/kg intravenously (IV) on days 1 and 15 of each 28 day cycle is determined by the number of participants who experience a dose limiting toxicity (DLT). See subsequent primary outcome measure for the DLT definition. The MTD is defined as the highest dose at which fewer than one-third of patients experience a DLT. If no DLTs are observed, the MTD is not reached but the highest dose received may be the Recommended Phase II Dose (RP2D).
A DLT is defined as an adverse event that (a) is related to the AMG 386 and/or bevacizumab with an attribution of possible, probable, or definite, and (b) occurs during and/or begins during the first 28 days of the study treatment, and (c) meets any of the following criteria: \>= grade 3 thrombocytopenia; grade 4 neutropenia lasting \> 7 days; grade 4 anemia lasting \> 7 days despite transfusion or growth factors; febrile neutropenia if ANC\<0.5x10\^9/L; clinically significant grade 3 non-hematologic toxicity despite maximal medical therapy lasting \> 7 days, with the exception of grade 3 proteinuria which was considered a DLT if lasting \> 14 days; grade 3 non-hematologic toxicity resulting in study drug discontinuation; grade 4 non-hematologic toxicity; \>= grade 1 new CNS hemorrhage; \>= grade 2 non-CNS hemorrhage.
Adverse events will be tabulated overall and by arm.
A population PK/PD model will be developed to characterize the time course of AMG 386 concentrations in relation to target inhibition and hematological response. Model-predicted PK parameters will be generated, such as individual areas-under-the-curve (AUCs) and Cmax for AMG 386, to correlate with targeted biomarkers, such as Ang1, and Ang2, and VEGF as well as leukocyte count.
A population PK/PD model will be developed to characterize the time course of AMG 386 concentrations in relation to target inhibition and hematological response. Model-predicted PK parameters will be generated, such as individual AUCs and Cmax for AMG 386, to correlate with targeted biomarkers, such as Ang1, and Ang2, and VEGF as well as leukocyte count.
Paclitaxel PK parameters with and without the co-administration of AMG 386.
| Arm | Type | Description |
|---|---|---|
| AMG 386 | EXPERIMENTAL | Arm A: Paclitaxel 80mg/m2 IV QW and Blinded AMG 386 15mg/kg IV QW |
| AMG 386 Placebo | PLACEBO_COMPARATOR | Arm B: Paclitaxel 80mg/m2 IV QW and Blinded AMG 386 Placebo IV QW |
| 15mg/ kg cohort | EXPERIMENTAL | AMG 386 15mg/kg intravenously once weekly and Sorafenib 400mg orally twice daily in an every 4 weeks dosing schedule. |
| 10 mg/kg cohort | EXPERIMENTAL | AMG 386 10mg/kg intravenously once weekly and Sorafenib 400mg orally twice daily in an every 4 weeks dosing schedule. |
| Trebananib 10 mg/kg + Sunitinib | EXPERIMENTAL | Trebananib 10 mg/kg intravenously (IV) once weekly (QW) plus sunitinib 50 mg orally (PO) once daily (QD) 4 weeks on/2 weeks off |
| Trebananib 15 mg/kg + Sunitinib | EXPERIMENTAL | Trebananib 15 mg/kg IV QW plus sunitinib 50 mg PO QD 4 weeks on/2 weeks off |
| 2 | PLACEBO_COMPARATOR | AMG 386 placebo QW, FOLFIRI Q2W |
| 1 | ACTIVE_COMPARATOR | Arm 1 : AMG 386 10 mg/kg QW, FOLFIRI Q2W |
| B | EXPERIMENTAL | - |
| A | EXPERIMENTAL | - |
| C | ACTIVE_COMPARATOR | - |
| Arm A | EXPERIMENTAL | Paclitaxel 80 mg/m2 IV QW (3 on/1 off) + AMG 386 10 mg/kg IV QW |
| Arm B | EXPERIMENTAL | Paclitaxel 80 mg/m2 IV QW (3 on/1 off) + AMG 386 3 mg/kg IV QW |
| Arm C | ACTIVE_COMPARATOR | Paclitaxel 80 mg/m2 IV QW (3 on/1 off) + AMG 386 placebo |
| D | EXPERIMENTAL | Paclitaxel 90 mg/m² IV QW (3 on/1 off) + Open Label AMG 386 10 mg/kg IV QW |
| Amgen 386 | EXPERIMENTAL | Cohort A will assess recurrent Glioblastoma Multiforme (GBM) patients who receive AMG 386 monotherapy at 30mg/kg every week. As of August 1, 2013, Cohort A was closed to new accrual following early interim analysis of first 10 participants enrolled on study. None of these patients had achieved stable disease or response at their initial evaluation after 1-2 months of study therapy. Therefore, study investigators and sponsor agreed that the level of single-agent anti-tumor activity associated with AMG386 for recurrent glioblastoma patients is most likely insufficient to satisfy the stopping rule for low efficacy outlined in Section 14.5 for Cohort A. |
| Amgen 386 and Bevacizumab | EXPERIMENTAL | Cohort B will assess recurrent Glioblastoma Multiforme(GBM) patients who receive AMG 386 plus bevacizumab. Because the maximum tolerated dose of this combination therapy has not yet been established, a 3x3 Phase I study was used to determine the maximum tolerated dose. As of June 6, 2014, the MTD was determined to be AMG386 30 mg/kg administered intravenously every week(dose level +1) in combination with bevacizumab at 10mg/kg administered intravenously every other week. As of July 25, 2014 the Cohort B, Phase II portion of the study was opened to accrual. |
| Arm A (trebananib) | EXPERIMENTAL | Patients receive trebananib IV over 30-60 minutes on days 1, 8, 15, and 22. |
| Arm B (trebananib, cytarabine) | EXPERIMENTAL | Patients receive trebananib as in Arm A. Patients also receive cytarabine SC BID on days 1-14 of course 1 and days 1-7 of subsequent courses. |
| AMG 386 15mg/kg and paclitaxel 80mg/m2 | EXPERIMENTAL | - |
| Group 1 | EXPERIMENTAL | Cancer subjects with normal renal function. |
| Group 3 | EXPERIMENTAL | Cancer subjects with moderate renal impairment. |
| Group 4 | EXPERIMENTAL | Cancer subjects with severe renal impairment. |
| Group 2 | EXPERIMENTAL | Cancer subjects with mild renal impairment. |
| AMG 386, paclitaxel and carboplatin | EXPERIMENTAL | 15 mg/Kg AMG 386 IV (intravenous) weekly plus paclitaxel and carboplatin IV Q3W for 18 weeks, followed by 15mg/Kg AMG 386 IV (intravenous) weekly alone for an additional 18 months. |
| Cohort A1 | EXPERIMENTAL | - |
| Cohort A3 | EXPERIMENTAL | - |
| Cohort B1 | EXPERIMENTAL | - |
| Cohort B3 | EXPERIMENTAL | - |
| Name | Type | Description |
|---|---|---|
| AMG 386 | DRUG | Weekly Intravenous (IV) AMG 386 15 mg/kg |
| AMG 386 Placebo | DRUG | Weekly Intravenous (IV) placebo 15 mg/kg |
| Paclitaxel | DRUG | Paclitaxel 80 mg/m2 intravenous (IV) weekly (3 on/1 off) |
| Sorafenib | DRUG | Sorafenib 400 mg PO BID orally twice daily in an every 4 week dosing schedule for 15mg/kg cohort \& 10mg/kg cohort |
| Sunitinib | DRUG | Sunitinib will be administered 50 mg QD and is considered to be the background therapy as it is licensed for treatment of reneal cell cancer (RCC) and will be administered to all participants. |
| Trebananib | DRUG | Administered until a participant develops disease progression, clinical progression, unacceptable toxicity, withdraws consent, or death. |
| FOLFIRI | DRUG | Administration of FOLFIRI chemotherapy will commence on day 1 of each dosing week following the administration of AMG 386. FOLFIRI Q2W regimen: irinotecan 180 mg/m2 IV over 90 (+-15) minutes on Day 1, leucovorin 400 mg/m2 IV over 2 hrs on Day 1, 5 FU 400mg/m2 IV bolus, followed by 2400 mg/m2 continuous IV infusion over 46 hrs +- 2 hours. FOLFIRI will be administered until disease progression, FOLFIRI intolerability, death, or study withdrawal by the subject, investigator, or sponsor, whichever occurs earliest. |
| AMG 386 10mg/kg | DRUG | AMG 386 10 mg/kg IV QW until radiographic disease progression, clinical progression, unacceptable toxicity, subject withdrawal of consent, or death |
| AMG 386 3mg/kg | DRUG | AMG 386 3 mg/kg IV QW until radiographic disease progression, clinical progression, unacceptable toxicity, subject withdrawal of consent, or death |
| Cisplatin | DRUG | Cisplatin 80 mg/m2 IV Q3W until radiographic disease progression, clinical progression, unacceptable toxicity, subject withdrawal of consent, or death |
| Capecitabine | DRUG | Capecitabine1000 mg/m2 PO BID x 14 days Q3W until radiographic disease progression, clinical progression, unacceptable toxicity, subject withdrawal of consent, or death |
| Bevacizumab | DRUG | Bevacizumab 10mg/kg IV Q2W |
| AMG 386 placebo IV | DRUG | AMG 386 placebo IV |
| Amgen 386 | DRUG | For Cohort A, AMG 386 will be administered intravenously at 30 mg/kg every week. For Cohort B Phase I, AMG 386 will be administered intravenously at beginning at starting dose level of 15 mg/kg every week. For Cohort B Phase II, AMG 386 will be administered intravenously at the maximum tolerated dose determined in the Phase I portion of the study every week. |
| cytarabine | DRUG | Given SC |
| laboratory biomarker analysis | OTHER | Correlative studies |
| pharmacological study | OTHER | Correlative studies |
| Pemetrexed | DRUG | Pemetrexed 500 mg/m2 |
| Carboplatin | DRUG | Carboplatin AUC 6 |
| AMG 386 + Paclitaxel | DRUG | 15 mg/kg IV (in the vein) of AMG 386 weekly + 80 mg/m\^2 IV (in the vein) 3 weeks on/1 week off, optional beginning week 6 until progression, unacceptable toxicity, or withdrawal of consent. |
| AMG 386, paclitaxel and carboplatin | DRUG | 15 mg/Kg AMG 386 IV (intravenous) weekly plus paclitaxel and carboplatin IV Q3W for 18 weeks, followed by 15mg/Kg AMG 386 IV (intravenous) weekly alone for an additional 18 months. |
| AMG 386 30 mg/kg, Paclitaxel and Trastuzumab | DRUG | AMG 386 30 mg/kg IV QW, paclitaxel 80 mg/m2 IV QW, trastuzumab: initial dose 8 mg/kg IV week 1, then 6 mg/kg IV Q3W |
| AMG 386 30 mg/kg, Capecitabine and Lapatinib | DRUG | AMG 386 30 mg/kg IV QW, capecitabine 2000 mg/m2 divided into 2 doses given PO Q12 hrs, days 1-14 every 21 days, lapatinib 1250 mg PO QD |
| AMG 386 10 mgkg, Paclitaxel and Trastuzumab | DRUG | AMG 386 10 mg/kg IV QW, paclitaxel 80 mg/m2 IV QW, trastuzumab: initial dose 8 mg/kg IV week 1, then 6 mg/kg IV Q3W |
| AMG 386 10 mg/kg, Capecitabine and Lapatinib | DRUG | AMG 386 10 mg/kg IV QW, capecitabine 2000 mg/m2 divided into 2 doses given PO Q12 hrs, days 1-14 every 21 days, lapatinib 1250 mg PO QD |
Inclusion Criteria: * Female 18 years of age or older at the time the written informed consent is obtained * Gynecologic Oncology Group (GOG) Performance Status of 0 or 1 * Life expectancy \>= 3 months (per investigator opinion) * Histologically or cytologically documented invasive epithelial ovari...
Trebananib is an investigational monoclonal antibody developed by Amgen Inc. (ticker AMGN) as a cancer therapy. It has been studied in Phase 1 and Phase 2 clinical trials for hematologic and solid tumor indications, including adult acute megakaryoblastic leukemia (M7) and advanced renal cell carcinoma.
Trebananib has been studied in adult acute megakaryoblastic leukemia (M7) and other acute myeloid leukemia subtypes, as well as in advanced renal cell carcinoma. It is an investigational agent and is not an approved treatment for these or any other indications.
Trebananib targets ANGPT1 and ANGPT2, also known as angiopoietin-1 and angiopoietin-2. It acts as an inhibitor of these angiopoietin proteins, which are involved in blood vessel formation. By binding these ligands, trebananib is designed to interfere with angiogenesis in tumors.
Trebananib is developed by Amgen Inc., which trades under the ticker AMGN. Amgen sponsored the clinical studies of trebananib, including the Phase 1 trial in acute myeloid leukemia and the Phase 2 trial in advanced renal cell carcinoma.
Trebananib is in Phase 1 development for adult acute megakaryoblastic leukemia (M7), with earlier Phase 2 study also conducted in advanced renal cell carcinoma. It is investigational and has not been approved by the FDA for any indication.
Trebananib has been evaluated in two completed trials. NCT01555268 was a Phase 1 study of trebananib with or without low-dose cytarabine in acute myeloid leukemia, enrolling 24 patients. NCT00853372 was a Phase 2 open-label study in advanced renal cell carcinoma combining trebananib with sunitinib, enrolling 85 patients.