Advanced Solid Tumors
Conditions
Keywords
Mesothelin expression
Brief summary
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.
Detailed description
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.
Interventions
DRUGAMG 994
Administered as an intravenous (IV) infusion.
DRUGAMG 404
Administered as an intravenous (IV) infusion.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 100 Years
Healthy volunteers
No
Inclusion criteria
* Participant has provided informed consent/assent prior to initiation of any study specific activities/procedures. * Age ≥ 18 years at the time of signing informed consent. * Life expectancy of \> 3 months, in the opinion of the investigator. * Participant must have histologically or cytologically proven metastatic or locally advanced solid tumors of known MSLN expression who have relapsed after and/or are refractory to established and available therapies with known clinical benefit, for which: * No standard systemic therapy exists; or * Standard systemic therapy has failed or is not available. * Dose Expansion (Part 2): Participant must have one of the following malignancies: mesothelioma, pancreatic adenocarcinoma, MSLN positive NSCLC squamous cell carcinoma or adenocarcinoma, high grade serous ovarian carcinoma. * At least 1 measurable or evaluable lesion as defined by modified RECIST 1.1 guidelines. * Participants must be willing to undergo a biopsy prior to enrollment and during treatment with AMG 994. * Participants with treated brain metastases are eligible provided they meet the following criteria: * Definitive therapy was completed at least 2 weeks prior to enrollment. * No evidence of radiographic central nervous system (CNS) progression or CNS disease following definitive therapy and by the time of study screening. Patients manifesting progression in lesions previously treated with stereotactic radiosurgery may still be eligible if pseudoprogression can be demonstrated by appropriate means and after discussion with the medical monitor. * Any CNS disease is asymptomatic, any neurologic symptoms due to CNS disease have returned to baseline, or non-serious CNS diseases that are asymptomatic and deemed irreversible (eg, peripheral neuropathy), the patient is off steroids for at least 7 days (physiologic doses of steroids are permitted), and the patient is off or on stable doses of anti-epileptic drugs for malignant CNS disease and has not had a seizure within 1 month prior to the screening visit. * Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 2. * Hematologic function, as follows (transfusions or growth factor support must not be administered within 7 days prior to obtaining screening labs): * Absolute neutrophil count (ANC) ≥ 1.5 x 109/L * Platelet count ≥ 75 x 109/L * Hemoglobin ≥ 9 g/dL * Adequate renal laboratory assessments, as follows: • Estimated glomerular filtration rate based on Modification of Diet in Renal Disease (MDRD) calculation ≥ 45 mL/min/1.73 m2 * Hepatic function, as follows: * Total bilirubin (TBL) ≤ 1.5 x upper limit of normal (ULN) or ≤ 3 x ULN for participants with liver metastasis * Aspartate transaminase (AST) ≤ 3 x ULN or ≤ 5 x ULN for participants with liver metastasis * Alanine aminotransferase (ALT) ≤ 3 x ULN or ≤ 5 x ULN for participants with liver metastasis * Alkaline phosphatase ≤ 2.5 x ULN or ≤ 5 x ULN for participants with liver metastasis
Exclusion criteria
Disease Related * Primary brain tumor, untreated or symptomatic brain metastases and leptomeningeal disease. Other Medical Conditions * History of other malignancy within the past 2 years, with the following exception\[s\]: * Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before enrollment and felt to be at low risk for recurrence by the treating physician. * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. * Adequately treated cervical carcinoma in situ without evidence of disease. * Adequately treated breast ductal carcinoma in situ without evidence of disease. * Prostatic intraepithelial neoplasia without evidence of prostate cancer. * Adequately treated urothelial papillary noninvasive carcinoma or carcinoma in situ. * Participants with NSCLC squamous cell carcinoma (Part 1), MSLN negative NSCLC squamous cell carcinoma (Part 2), or MSLN negative NSCLC adenocarcinoma (Part 2) once the participant has been screened for MSLN expression. * Participants with sarcomatoid mesothelioma and small cell lung cancer will be excluded from both the Dose Exploration (Part 1) and Dose Expansion (Part 2) parts of the study. * History of solid organ transplantation. * Major surgery within 28 days of study day 1. Prior/Concomitant Therapy * Anti-tumor therapy (radiotherapy, chemotherapy, antibody therapy, molecular targeted therapy, or investigational agent) within 21 days prior to study day 1. * Treatment with a checkpoint inhibitor within 9 weeks prior to study day 1. * Live vaccine therapy within 4 weeks prior to study drug administration. * Current treatment or within 14 days of day 1 with immunosuppressive corticosteroid defined as \> 10 mg prednisone daily or equivalent. Steroids with no minimal systemic effect (such as topical or inhalation) are permitted. Prior/Concurrent Clinical Study Experience * Currently receiving treatment in another investigational device or drug study, or less than 21 days prior to study day 1 since ending treatment on another investigational device or drug study(ies). * Evidence of active or radiological sequelae of non-infectious pneumonitis. * History of any immune-related colitis. Infectious colitis is allowed if evidence of adequate treatment and clinical recovery exists and at least 3 months interval observed since diagnosis of colitis. * History of allergic reactions or acute hypersensitivity reaction to antibody therapies. * Positive/non-negative test results for human immunodeficiency virus (HIV). * Hepatitis B and C based on the following results: * Positive for hepatitis B surface antigen (HBsAg) (indicative of chronic hepatitis B or recent acute hepatitis B) * Negative HBsAG and positive for hepatitis B core antibody: hepatitis B virus DNA by polymerase chain reaction (PCR) is necessary. Detectable hepatitis B virus DNA suggests occult hepatitis B. * Positive hepatitis C virus antibody (HCVAb): hepatitis C virus RNA by PCR is necessary. Detectable hepatitis C virus RNA suggests chronic hepatitis C. * Active infection requiring oral or intravenous therapy. * Active or history of any autoimmune disease or immunodeficiencies. Participants with diabetes Type 1, vitiligo, psoriasis, hypo- or hyper-thyroid disease not requiring immunosuppressive treatment are permitted. * Myocardial infarction within 6 months of study day 1, symptomatic congestive heart failure (New York Heart Association \> class II), unstable angina, or cardiac arrhythmia requiring medication. * Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 1, or are stable and well controlled with minimal, local, or noninvasive intervention AND there is agreement to allow by both the investigator and the Amgen Medical Monitor. * Any history of grade 3 or higher colitis, pneumonitis, or neurological toxicity OR * Unresolved toxicities from prior checkpoint inhibitor therapy, defined as not having resolved to CTCAE v5.0 grade 1. * Exception: - clinically stable hypothyroid status managed with hormone replacement therapy, is permitted Other Exclusions * Female participant is pregnant or breastfeeding or planning to become pregnant or breastfeed during treatment and for an additional 6 months after the last dose of AMG 994 and/or AMG 404. * Female participants of childbearing potential unwilling to use 1 highly effective method of contraception during treatment and for an additional 6 months after the last dose of AMG 994 and/or AMG 404. * Female participants of childbearing potential with a positive pregnancy test assessed at day 1 by a serum pregnancy test. * Male participants with a female partner of childbearing potential who are unwilling to practice sexual abstinence (refrain from heterosexual intercourse) or use contraception during treatment and for an additional 8 months after the last dose of AMG 994 and/or AMG 404. * Male participants unwilling to abstain from donating sperm during treatment and for an additional 8 months after the last dose of AMG 994 and/or AMG 404. * Participant has known sensitivity to any of the products or components to be administered during dosing. * Participant likely to not be available to complete all protocol-required study visits or procedures, and/or to comply with all required study procedures to the best of the participant and investigator's knowledge. * History or evidence of any other clinically significant disorder, condition or disease (with the exception of those outlined above) that, in the opinion of the investigator or Amgen physician, if consulted, would pose a risk to participant safety or interfere with the study evaluation, procedures or completion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | Up to Day 28 of Cycle 1 (one cycle = 28 days) | 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 |
| Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | 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. | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) Per Modified RECIST 1.1 | Up to approximately 19.32 months | 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. |
| Progression-free Survival Per Modified RECIST 1.1 | Up to approximately 19.32 months | 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 to Progression (TTP) Per Modified RECIST 1.1 | Up to approximately 19.32 months | 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 to Subsequent Therapy | Up to approximately 19.32 months | 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. |
| Maximum Serum Concentration (Cmax) of AMG 994 | 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 | 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 | 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 | 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) | — |
| Objective Response (OR) Per Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | Up to approximately 19.32 months | 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. |
| Terminal Half-life (t1/2) of AMG 994 | 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 | Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose) | — |
| Tmax of AMG 404 | Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose) | — |
| Cmin of AMG 404 | Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose) | — |
| AUClast of AMG 404 | Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose) | — |
| AUCtau of AMG 404 | 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 | Cycle 2, Day 1 (pre-dose, end of infusion [EOI], 2, 4.5, 6.5, and 12 hours post dose) | — |
| Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994 | 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) | — |
| Duration of Response (DoR) Per Modified RECIST 1.1 | Up to approximately 19.32 months | 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. |
Countries
Australia, Belgium, Canada, France, Germany, Japan, Poland, Spain, United Kingdom, United States
Participant flow
Recruitment details
This study was conducted at 7 centers in Belgium, France, Japan, Poland, Spain, and the United States between 29 April 2021 and 05 June 2023.
Pre-assignment details
The study was planned to be conducted in 2 parts: part 1 (dose exploration) and part 2 (dose expansion); however, no participants enrolled beyond Cohort 2 due to a business decision to discontinue development of AMG 994. This decision was unrelated to the safety or efficacy.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Low Dose) Participants were administered AMG 994 as a monotherapy treatment at dose level 1 via short-term IV infusion QW for cycles 1 to 12 (on days 1, 8, 15, and 22). From Cycle 2, participants were also administered AMG 404 via short-term IV infusion Q4W for up to 12 cycles (cycle= 28 days). | 3 |
| Cohort 2 (High Dose) Participants were administered AMG 994 as a monotherapy treatment at dose level 2 via short-term IV infusion QW for cycles 1 to 12 (on days 1, 8, 15, and 22). From Cycle 2, participants were also administered AMG 404 via short-term IV infusion Q4W for up to 12 cycles (cycle= 28 days). | 8 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 2 | 6 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Cohort 2 (High Dose) | Total | Cohort 1 (Low Dose) |
|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 11.8 | 62.5 years STANDARD_DEVIATION 10.6 | 66.0 years STANDARD_DEVIATION 7.2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 9 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 8 Participants | 2 Participants |
| Sex: Female, Male Female | 3 Participants | 3 Participants | 0 Participants |
| Sex: Female, Male Male | 5 Participants | 8 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 3 | 6 / 8 |
| other Total, other adverse events | 3 / 3 | 8 / 8 |
| serious Total, serious adverse events | 3 / 3 | 6 / 8 |
Outcome results
Primary
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)
Population: Early DLT evaluable analysis set: included participants that were enrolled and received at least 1 dose of AMG 994 with an evaluable early DLT endpoint (evaluable in AMG 994 monotherapy cohort).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | 0 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | 3 Number of participants |
Primary
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.
Population: Safety analysis set: defined as all participants that are enrolled and receive at least 1 dose of AMG 994 or AMG 404.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 3 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 3 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All Grade ≥ 3 TEAEs | 3 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All Fatal AEs (FAEs) | 2 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All AMG 994 related TEAEs | 2 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 994 related Grade ≥ 3 TEAEs | 0 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 994 related SAEs | 0 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 994 related FAEs | 0 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All AMG 404 related TEAEs | 1 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 404 related TEAEs Grade ≥ 3 TEAEs | 0 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 404 related SAEs | 0 Number of participants |
| Cohort 1 (Low Dose) | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 404 related FAEs | 0 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 404 related SAEs | 0 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 994 related SAEs | 0 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All TEAEs | 8 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 404 related TEAEs Grade ≥ 3 TEAEs | 1 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All Grade ≥ 3 TEAEs | 6 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All SAEs | 6 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 994 related FAEs | 0 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All Fatal AEs (FAEs) | 6 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 404 related FAEs | 0 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All AMG 994 related TEAEs | 4 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | All AMG 404 related TEAEs | 4 Number of participants |
| Cohort 2 (High Dose | Number of Participants Who Experienced Treatment-emergent Adverse Events (TEAEs) | AMG 994 related Grade ≥ 3 TEAEs | 1 Number of participants |
Secondary
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)
Population: Only participants with available data are included for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Low Dose) | Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994 | Cycle 1, Day 1 | 20300 h*ng/mL | Standard Deviation 35200 |
| Cohort 1 (Low Dose) | Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994 | Cycle 1, Day 22 | 24500 h*ng/mL | Standard Deviation 18400 |
| Cohort 1 (Low Dose) | Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994 | Cycle 2, Day 1 | 8260 h*ng/mL | Standard Deviation 10100 |
| Cohort 2 (High Dose | Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994 | Cycle 1, Day 1 | 20400 h*ng/mL | Standard Deviation 21400 |
| Cohort 2 (High Dose | Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994 | Cycle 1, Day 22 | 45400 h*ng/mL | Standard Deviation 61100 |
| Cohort 2 (High Dose | Area Under the Serum Concentration-time Curve During a Dosing Interval (AUCtau) of AMG 994 | Cycle 2, Day 1 | 29500 h*ng/mL | Standard Deviation 31100 |
Secondary
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)
Population: Only participants with available data are included for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Low Dose) | Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of AMG 994 | Cycle 1, Day 1 | 12100 h*ng/mL | — |
| Cohort 1 (Low Dose) | Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of AMG 994 | Cycle 1, Day 22 | 18900 h*ng/mL | Standard Deviation 15000 |
| Cohort 1 (Low Dose) | Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of AMG 994 | Cycle 2, Day 1 | 6460 h*ng/mL | Standard Deviation 8010 |
| Cohort 2 (High Dose | Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of AMG 994 | Cycle 1, Day 1 | 15000 h*ng/mL | Standard Deviation 16700 |
| Cohort 2 (High Dose | Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of AMG 994 | Cycle 1, Day 22 | 21900 h*ng/mL | Standard Deviation 23100 |
| Cohort 2 (High Dose | Area Under the Serum Concentration-time Curve From Time Zero to Time of Last Quantifiable Concentration (AUClast) of AMG 994 | Cycle 2, Day 1 | 22900 h*ng/mL | Standard Deviation 23300 |
Secondary
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)
Population: Only participants with available data are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Low Dose) | AUClast of AMG 404 | 1280 h*ng/mL | Standard Deviation 322 |
| Cohort 2 (High Dose | AUClast of AMG 404 | 1160 h*ng/mL | Standard Deviation 618 |
Secondary
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)
Population: Only participants with available data are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Low Dose) | AUCtau of AMG 404 | 1280 h*ng/mL | Standard Deviation 322 |
| Cohort 2 (High Dose | AUCtau of AMG 404 | 1290 h*ng/mL | Standard Deviation 576 |
Secondary
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)
Population: Only participants with available data are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Low Dose) | Cmax of AMG 404 | 158 ng/mL | Standard Deviation 22.1 |
| Cohort 2 (High Dose | Cmax of AMG 404 | 145 ng/mL | Standard Deviation 47.9 |
Secondary
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)
Population: Only participants with available data are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Low Dose) | Cmin of AMG 404 | 20.8 ng/mL | Standard Deviation 11.1 |
| Cohort 2 (High Dose | Cmin of AMG 404 | 22.8 ng/mL | Standard Deviation 18.2 |
Secondary
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
Population: Safety analysis set: defined as all participants that are enrolled and receive at least 1 dose of AMG 994 or AMG 404. Only participants with response are included in duration of response analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 2 (High Dose | Duration of Response (DoR) Per Modified RECIST 1.1 | 11.09 Months |
Secondary
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)
Population: Only participants with available data are included for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Low Dose) | Maximum Serum Concentration (Cmax) of AMG 994 | Cycle 1, Day 1 | 667 ng/mL | Standard Deviation 1150 |
| Cohort 1 (Low Dose) | Maximum Serum Concentration (Cmax) of AMG 994 | Cycle 1, Day 22 | 4450 ng/mL | Standard Deviation 3020 |
| Cohort 1 (Low Dose) | Maximum Serum Concentration (Cmax) of AMG 994 | Cycle 2, Day 1 | 2340 ng/mL | Standard Deviation 3180 |
| Cohort 2 (High Dose | Maximum Serum Concentration (Cmax) of AMG 994 | Cycle 1, Day 1 | 2450 ng/mL | Standard Deviation 1140 |
| Cohort 2 (High Dose | Maximum Serum Concentration (Cmax) of AMG 994 | Cycle 1, Day 22 | 2550 ng/mL | Standard Deviation 1290 |
| Cohort 2 (High Dose | Maximum Serum Concentration (Cmax) of AMG 994 | Cycle 2, Day 1 | 2830 ng/mL | Standard Deviation 1260 |
Secondary
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)
Population: Only participants with available data are included for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Low Dose) | Minimum Observed Serum Concentration (Cmin) of AMG 994 | Cycle 1, Day 1 | 0.00 ng/mL | Standard Deviation 0 |
| Cohort 1 (Low Dose) | Minimum Observed Serum Concentration (Cmin) of AMG 994 | Cycle 1, Day 22 | 0.00 ng/mL | Standard Deviation 0 |
| Cohort 1 (Low Dose) | Minimum Observed Serum Concentration (Cmin) of AMG 994 | Cycle 2, Day 1 | 0.00 ng/mL | Standard Deviation 0 |
| Cohort 2 (High Dose | Minimum Observed Serum Concentration (Cmin) of AMG 994 | Cycle 1, Day 1 | 0.00 ng/mL | Standard Deviation 0 |
| Cohort 2 (High Dose | Minimum Observed Serum Concentration (Cmin) of AMG 994 | Cycle 1, Day 22 | 0.00 ng/mL | Standard Deviation 0 |
| Cohort 2 (High Dose | Minimum Observed Serum Concentration (Cmin) of AMG 994 | Cycle 2, Day 1 | 0.00 ng/mL | Standard Deviation 0 |
Secondary
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.
Time frame: Up to approximately 19.32 months
Population: Safety analysis set: defined as all participants that are enrolled and receive at least 1 dose of AMG 994 or AMG 404.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Low Dose) | Objective Response (OR) Per Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | CR | 0 Number of participants |
| Cohort 1 (Low Dose) | Objective Response (OR) Per Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | PR | 0 Number of participants |
| Cohort 2 (High Dose | Objective Response (OR) Per Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | CR | 0 Number of participants |
| Cohort 2 (High Dose | Objective Response (OR) Per Modified Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 | PR | 2 Number of participants |
Secondary
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
Population: Safety analysis set: defined as all participants that are enrolled and receive at least 1 dose of AMG 994 or AMG 404.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Low Dose) | Overall Survival (OS) Per Modified RECIST 1.1 | 5.99 Months |
| Cohort 2 (High Dose | Overall Survival (OS) Per Modified RECIST 1.1 | 12.50 Months |
Secondary
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
Population: Safety analysis set: defined as all participants that are enrolled and receive at least 1 dose of AMG 994 or AMG 404.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Low Dose) | Progression-free Survival Per Modified RECIST 1.1 | 2.63 Months |
| Cohort 2 (High Dose | Progression-free Survival Per Modified RECIST 1.1 | 1.61 Months |
Secondary
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)
Population: Only participants with available data are included.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 (Low Dose) | T1/2 of AMG 404 | 13.0 hours |
| Cohort 2 (High Dose | T1/2 of AMG 404 | 9.55 hours |
Secondary
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)
Population: Only participants with available data are included for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Low Dose) | Terminal Half-life (t1/2) of AMG 994 | Cycle 1, Day 22 | 5.24 hours | — |
| Cohort 2 (High Dose | Terminal Half-life (t1/2) of AMG 994 | Cycle 1, Day 1 | 4.97 hours | Standard Deviation 2.9 |
| Cohort 2 (High Dose | Terminal Half-life (t1/2) of AMG 994 | Cycle 2, Day 1 | 4.76 hours | Standard Deviation 3.55 |
Secondary
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)
Population: Only participants with available data are included for each time point.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Low Dose) | Time to Maximum Serum Concentration (Tmax) of AMG 994 | Cycle 1, Day 1 | 8.4 hours | Standard Deviation 15 |
| Cohort 1 (Low Dose) | Time to Maximum Serum Concentration (Tmax) of AMG 994 | Cycle 1, Day 22 | 3.7 hours | Standard Deviation 1.1 |
| Cohort 1 (Low Dose) | Time to Maximum Serum Concentration (Tmax) of AMG 994 | Cycle 2, Day 1 | 3.0 hours | Standard Deviation 0.0096 |
| Cohort 2 (High Dose | Time to Maximum Serum Concentration (Tmax) of AMG 994 | Cycle 1, Day 1 | 1.4 hours | Standard Deviation 0.68 |
| Cohort 2 (High Dose | Time to Maximum Serum Concentration (Tmax) of AMG 994 | Cycle 1, Day 22 | 1.5 hours | Standard Deviation 0.74 |
| Cohort 2 (High Dose | Time to Maximum Serum Concentration (Tmax) of AMG 994 | Cycle 2, Day 1 | 2.7 hours | Standard Deviation 2 |
Secondary
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
Population: Safety analysis set: defined as all participants that are enrolled and receive at least 1 dose of AMG 994 or AMG 404.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Low Dose) | Time to Progression (TTP) Per Modified RECIST 1.1 | 2.63 Months |
| Cohort 2 (High Dose | Time to Progression (TTP) Per Modified RECIST 1.1 | 1.74 Months |
Secondary
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
Population: Safety analysis set: defined as all participants that are enrolled and receive at least 1 dose of AMG 994 or AMG 404.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Low Dose) | Time to Subsequent Therapy | NA Months |
| Cohort 2 (High Dose | Time to Subsequent Therapy | NA Months |
Secondary
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)
Population: Only participants with available data are included.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Low Dose) | Tmax of AMG 404 | 0.080 hours | Standard Deviation 0.049 |
| Cohort 2 (High Dose | Tmax of AMG 404 | 0.11 hours | Standard Deviation 0.074 |