The primary objective of this study is to evaluate the safety, tolerability, and maximum tolerated dose (MTD)/maximum tolerated combination dose (MTCD) or recommended phase 2 dose (RP2D) of AMG 994 as monotherapy and AMG 994 in combination with AMG 404 in participants with advanced solid tumors.
AMG 994 will be administered by short term intravenous (IV) infusion once weekly in each 28-day cycle and AMG 404 will be administered by short-term IV infusion once every 4 weeks (Q4W) in a 28 day cycle (on day 1 of cycle 2 and beyond). The study will be conducted in 2 parts: Part 1 - Dose Exploration and Part 2 - Dose Expansion.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
11
City of Hope National Medical Center
Duarte, California, United States
Henry Ford Hospital, Henry Ford Health Systems
Detroit, Michigan, United States
Number of Participants Who Experienced Dose Limiting Toxicities (DLTs)
DLTs were defined as: * Grade 5 events * Grade 4 neutropenia/thrombocytopenia of any duration * Grade 3 thrombocytopenia w/ clin significant bleeding or lasting \>7 days * Febrile neutropenia * Grade 4 anemia * Grade 3/4 non-hematologic toxicity, except: Grade 3 nausea/vomiting or diarrhea \< 72 hours; Grade 3 fatigue \< 1 week; Asymptomatic grade 3 electrolyte abnormalities that last \< 72 hours, are not clinically complicated, and resolve spontaneously or respond to conventional medical interventions; Grade 3 amylase/ lipase elevations; Other laboratory parameters of grade 3, not considered clinically relevant and improved to grade ≤ 2 within 72 hours. * Any grade 3 event requiring hospitalization * Recurrent grade 2 pneumonitis * Delay in cycle 2 treatment for \> 14 days due to an adverse event in the dose escalation portion of the study * Any event requiring discontinuation of AMG 994
Time frame: Up to Day 28 of Cycle 1 (one cycle = 28 days)
Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs)
TEAEs were those that occurred after the first intervention dose. A serious adverse event (SAE) included outcomes such as death, life-threatening situations, hospitalization or an extended hospital stay, significant incapacity, congenital defects, or other crucial medical events. AE severity followed the CTCAE Version 5.0 scale: grade 1 (mild), grade 2 (moderate), grade 3 (severe), grade 4 (life-threatening), and grade 5 (death). Clinically significant laboratory results or other assessments (e.g., ECGs, scans, vital signs) that worsened from baseline and were deemed important by the investigator, independent of disease progression, were also considered.
Time frame: From first dose of investigational product through 140 days after last dose (AMG 994 or AMG 404, whichever is later), or end of study (whichever is first); median (min, max) duration was 12.5 ( 1.48, 19.32) months.
Objective Response (OR) Per Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
OR was defined as achieving complete response (CR) or partial response (PR) per the modified RECIST 1.1 where CR is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm and PR is at 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum of diameters.
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University Hospitals Cleveland Medical Center
Cleveland, Ohio, United States
Sarah Cannon Research Institute
Nashville, Tennessee, United States
University of Texas MD Anderson Cancer Center
Houston, Texas, United States
Monash Medical Centre
Clayton, Victoria, Australia
Linear Clinical Research Limited
Nedlands, Western Australia, Australia
Universitair Ziekenhuis Gent
Ghent, Belgium
Princess Margaret Cancer Centre
Toronto, Ontario, Canada
Centre Leon Berard
Lyon, France
...and 7 more locations
Time frame: Up to approximately 19.32 months
Duration of Response (DoR) Per Modified RECIST 1.1
DoR was defined as the number of months between first OR to disease progression or death (due to any cause), whichever occurs first. Median and 95% CI estimates of survival time were based on the Kaplan-Meier analysis.
Time frame: Up to approximately 19.32 months
Overall Survival (OS) Per Modified RECIST 1.1
OS was defined as the time from initiation of AMG 994 until event of death due to any cause. Median and 95% CI estimates of survival time were based on the Kaplan-Meier analysis.
Time frame: Up to approximately 19.32 months
Progression-free Survival Per Modified RECIST 1.1
PFS was defined as the time from initiation of AMG 994 until disease progression or death whichever occurs first. Death due to any cause counted as the event. Median and 95% CI estimates of survival time were based on the Kaplan-Meier analysis.
Time frame: Up to approximately 19.32 months
Time to Progression (TTP) Per Modified RECIST 1.1
TTP was defined as time from initiation of AMG 994 until disease progression. Median and 95% CI estimates of survival time were based on the Kaplan-Meier analysis.
Time frame: Up to approximately 19.32 months
Time to Subsequent Therapy
Time to subsequent therapy was defined as the time from initiation of AMG 994 until the first subsequent therapy. Median and 95% CI estimates of survival time were based on the Kaplan-Meier analysis.
Time frame: Up to approximately 19.32 months
Maximum Serum Concentration (Cmax) of AMG 994
Time frame: Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose)
Time to Maximum Serum Concentration (Tmax) of AMG 994
Time frame: Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose)
Minimum Observed Serum Concentration (Cmin) of AMG 994
Time frame: Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose)
Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of AMG 994
Time frame: Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose)
Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994
Time frame: Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose)
Terminal Half-life (t1/2) of AMG 994
Time frame: Cycle 1 and 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose); Cycle 1, Day 22 (pre-dose, EOI, 6, and 12 hours post dose)
Cmax of AMG 404
Time frame: Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose)
Tmax of AMG 404
Time frame: Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose)
Cmin of AMG 404
Time frame: Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose)
AUClast of AMG 404
Time frame: Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose)
AUCtau of AMG 404
Time frame: Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose)
T1/2 of AMG 404
Time frame: Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose)