Acute Myeloid Leukemia, AML, MDS, Multiple Myeloma, Myelodysplastic Syndrome, NHL, Non-Hodgkins Lymphoma
Conditions
Keywords
Multiple Myeloma, Acute Myeloid Leukemia, Myelodysplastic Syndrome, AML, MDS, MM, Myeloid Cell Leukemia 1 Inhibitor, MCL1 Inhibitor, MCL1
Brief summary
Evaluate the safety and tolerability of AMG 397. Estimate the maximum tolerated doses (MTDs) and/or biologically active doses.
Detailed description
This is a first-in-human (FIH), multicenter, non-randomized, open-label, phase 1 study evaluating AMG 397 administered orally once weekly, as part of a 28-day treatment cycle in adult subjects with selected relapsed or refractory hematological malignancies
Interventions
DRUGAMG 397
AMG 397 will be administered orally once or twice weekly as part of a 28-day treatment cycle.
DRUGDexamethasone
Dexamethasone will be administered intravenously (IV) or orally on Days 1, 8, 15, and 22 of each 28-day cycle.
DRUGAzacitidine
Azacitidine will be administered intravenously (IV) or subcutaneously (SC) daily for the first 7 days of a 28-day cycle.
Sponsors
Amgen
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* Subject has provided informed consent prior to initiation of any study-specific activities/procedures * Age ≥ 18 years old * Pathologically-documented, definitively-diagnosed relapsed or refractory multiple myeloma (MM), myelodysplastic syndrome (MDS), or acute myeloid leukemia (AML) and is intolerant to, or considered ineligible for available therapies known to provide clinical benefit * MM subjects only: Measurable disease per the International Myeloma Working Group (IMWG) response criteria (assessed within 21 days prior to enrollment), as indicated by one or more of the following: cytogenic risk factor: 1q21 amplification/gain, serum M-protein ≥ 0.5 g/dL, Urine M-protein ≥ 200 mg/24 hours. For Subjects who do not meet 1 of the 2 prior criteria: Serum Free Light Chain (sFLC) ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal sFLC ratio (\< 0.26 or \> 1.65) as per the IMWG response criteria * MM subjects only: Hematological function, as follows without transfusion or growth factor support within 2 weeks prior to study day 1: absolute neutrophil count ≥ 1.0 X 109/L, hemoglobin \> 8 g/dL and platelet count ≥ 75 X 109/L * AML subjects only: Pathologically confirmed diagnosis of AML as defined by the World Health Organisation (WHO) Classification, more than 5% blasts in bone marrow and persisting or recurring following one or more treatment courses * MDS subjects only: pathologically confirmed diagnosis of MDS as defined by the WHO Classification, intermediate and high risk MDS and intolerant or refractory to HMA treatment * Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2 * Life expectancy of \> 3 months, based on the opinion of the investigator * Able to swallow and retain orally administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption. * Hepatic function, as follows: * aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \< 3 x upper limit of normal (ULN) * total bilirubin (TBL) \< 1.5 X ULN (except subjects with Gilbert's syndrome) * Cardiac function, as follows: * Cardiac ejection fraction ≥ 50% and no evidence of pericardial effusion as determined by echocardiogram or multigated acquisition (MUGA) scan * no ECG findings representing a recent cardiac injury within 6 months before enrollment * Renal function as follows: * Calculated or measured creatinine clearance (CrCl) of ≥ 30 mL/minute calculated using the formula of Cockcroft and Gault \[(140 - Age) × Mass (kg) / (72 × serum creatinine mg/dL)\]. Multiply result by 0.85 if female
Exclusion criteria
Disease Related * Previously received an allogeneic stem cell transplant within 6 months of study day 1 OR having signs or symptoms of acute or chronic graft-versus-host disease * Autologous stem cell transplant \< 90 days before enrollment * Candidates for stem cell transplant should have failed or are not considered eligible for either allogeneic and autologous transplant Other Medical Conditions * History of other malignancy except: * Malignancy treated with curative intent and with no known active disease present for ≥ 2 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 * Myocardial infarction within 6 months before enrollment * Symptomatic congestive heart failure (New York Heart Association \> Class II) * History of arterial thrombosis (eg, stroke or transient ischemic attack) in the past 6 months before enrollment * Uncontrollable active infection requiring intravenous anti-infective treatments within 1 week before enrollment * Known positive results for human immunodeficiency virus (HIV) * Active 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 * Unresolved toxicities from prior anti-tumor therapy, defined as not having resolved to Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 grade 1, or to levels dictated in the eligibility criteria with the exception of grade 2peripheral neuropathy, alopecia or toxicities from prior anti-tumor therapy that are considered irreversible (defined as having been present and stable for \> 4 weeks prior to study day 1 may be allowed if they are not otherwise described in the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 28 days | DLTs were defined as specific adverse events (AEs) that occurred in a participant during the DLT evaluation period (Day 1 to Day 28), that the investigator assessed as related to AMG 397. The grading and severity of AEs were based on the guidelines provided in the common terminology criteria for adverse events (CTCAE) version 4.03. |
| Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Up to 30 days after last dose (Maximum time on treatment was 18 weeks for part 1a and 13 weeks for part 1b) | A TEAE was defined as any AE starting on or after the first dose of investigational product. Any clinically significant changes in vital signs, physical examinations, electrocardiogram (ECGs) and clinical laboratory test results were recorded as AEs. The grading and severity of adverse events were based on the guidelines provided in the CTCAE version 4.03. Treatment-related TEAEs were any events that the investigator assessed as related to AMG 397. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) for Participants With Acute Myeloid Leukemia (AML) | Up to end of study (a maximum of 48 weeks) | ORR was assessed for participants with AML using response criteria per European Leukemia Network Response Criteria. ORR was defined as the percentage of participants who experienced either of the following based on investigator assessment: * PR * morphological leukemia-free state (MLFS) * complete remission with incomplete hematologic recovery (CRi) * complete remission * complete remission without minimal residual disease (CRmrd-). |
| Progression-free Survival (PFS) | Up to end of study (a maximum of 48 weeks) | PFS was calculated as time from first dose of investigational product date to disease progression date or death due to any cause, whichever was earlier. PFS time in months: (date of disease progression or death - first dose date +1)/30.4. |
| Overall Survival (OS) | Up to end of study (a maximum of 48 weeks) | OS was defined as the time from first dose of investigational product date until death due to any cause. OS time in months: (date of death - first dose date +1)/30.4. |
| Time to Response (TTR) | Up to end of study (a maximum of 48 weeks) | TTR was defined as the time from the first dose of investigational product until the first documentation of objective response. Only participants who achieved an objective response were evaluated for TTR. TTR time in months: (date of the first observation of response - first dose of IP date +1)/30.4. |
| Duration of Response (DOR) | Up to end of study (a maximum of 48 weeks) | DOR was only planned to be calculated for participants who achieved response (PR or better). DOR was defined as time from the first observation indicating a response to the subsequent date of disease progression or death, whichever was earlier. DOR time in months: (date of disease progression or death - date of the first observation of response +1)/30.4. |
| Overall Response Rate (ORR) for Participants With Multiple Myeloma (MM) | Up to end of study (a maximum of 48 weeks) | ORR was assessed for participants with MM using response criteria per International Myeloma Working Group (IMWG). ORR was defined as the percentage of participants who experienced either one of the following based on investigator assessment: * partial response (PR) * very good partial response (VGPR) * complete response (CR) * stringent complete response (sCR) |
| Time to Maximum Observed Concentration (Tmax) for AMG 397 | Cycle 1 (cycle = 28 days): Predose, 1, 2, 3, 5, 8 & 12 hours postdose on Day 1; predose, 1, 2, 3, 5, 8, 12, 24 & 48 hours postdose on Day 2 | Predose data for Day 2 were analyzed/included with the Day 1 data. |
| Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397 | Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22 | — |
| Clearance (CL) of AMG 397 | Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22 | — |
| Half-life (t1/2) of AMG 397 | Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22 | — |
| Maximum Observed Concentration (Cmax) of AMG 397 | Cycle 1 (cycle = 28 days): Predose, 1, 2, 3, 5, 8 & 12 hours postdose on Day 1; predose, 1, 2, 3, 5, 8, 12, 24 & 48 hours postdose on Day 2 | Predose data for Day 2 were analyzed/included with the Day 1 data. |
| Overall Response Rate (ORR) for Participants With Non-Hodgkin's Lymphoma (NHL) | Up to end of study (a maximum of 48 weeks) | ORR was assessed for participants with NHL using response criteria per Lugano Classification. ORR was defined as the percentage of participants who experienced either of the following based on investigator assessment: * partial metabolic response/ PR * complete metabolic response/ CR |
Countries
Australia, France, Greece, Italy, Japan, United States
Participant flow
Recruitment details
Participants were enrolled at 11 research centers in Australia, France, Greece and the United States from 17 August 2018 to 25 July 2019.
Pre-assignment details
Parts 2 and 3 of the trial were not initiated after part 1 data was reviewed. No participants were screened or enrolled for parts 2 or 3.
Participants by arm
| Arm | Count |
|---|---|
| Part 1a: 80 mg AMG 397 Participants with RR MM and/or NHL received 80 mg AMG 397 QD2, as part of a 28-day treatment cycle.
Participants could receive AMG 397 until the participant became intolerant to the investigational product, signs and symptoms of clinical progression were evident as determined by the investigator, or the participant withdrew consent. | 2 |
| Part 1a: 160 mg AMG 397 Participants with RR MM and/or NHL received 160 mg AMG 397 QD2, as part of a 28-day treatment cycle.
Participants could receive AMG 397 until the participant became intolerant to the investigational product, signs and symptoms of clinical progression were evident as determined by the investigator, or the participant withdrew consent. | 6 |
| Part 1a: 320 mg AMG 397 Participants with RR MM received 320 mg AMG 397 QD2, as part of a 28-day treatment cycle.
Participants could receive AMG 397 until the participant became intolerant to the investigational product, signs and symptoms of clinical progression were evident as determined by the investigator, or the participant withdrew consent. | 4 |
| Part 1b: 80 mg AMG 397 Participants with RR AML received 80 mg AMG 397 QD2, as part of a 28-day treatment cycle.
Participants could receive AMG 397 until the participant became intolerant to the investigational product, signs and symptoms of clinical progression were evident as determined by the investigator, or the participant withdrew consent. | 4 |
| Part 1b: 160 mg AMG 397 Participants with RR AML received 160 mg AMG 397 QD2, as part of a 28-day treatment cycle.
Participants could receive AMG 397 until the participant became intolerant to the investigational product, signs and symptoms of clinical progression were evident as determined by the investigator, or the participant withdrew consent. | 5 |
| Part 1b: 320 mg AMG 397 Participants with RR AML received 320 mg AMG 397 QD2, as part of a 28-day treatment cycle.
Participants could receive AMG 397 until the participant became intolerant to the investigational product, signs and symptoms of clinical progression were evident as determined by the investigator, or the participant withdrew consent. | 3 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 |
|---|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 1 | 0 | 2 | 0 | 2 |
| Overall Study | Lost to Follow-up | 0 | 1 | 0 | 0 | 1 | 0 |
| Overall Study | Protocol specified criteria | 0 | 2 | 2 | 0 | 2 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 | 1 | 0 |
Baseline characteristics
| Characteristic | Part 1a: 80 mg AMG 397 | Total | Part 1b: 320 mg AMG 397 | Part 1b: 160 mg AMG 397 | Part 1b: 80 mg AMG 397 | Part 1a: 320 mg AMG 397 | Part 1a: 160 mg AMG 397 |
|---|---|---|---|---|---|---|---|
| Age, Customized 85 years and over | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adolescents (12-17 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Adults (18-64 years) | 1 Participants | 9 Participants | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 3 Participants |
| Age, Customized Children (2-11 years) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized From 65-84 years | 1 Participants | 15 Participants | 3 Participants | 2 Participants | 4 Participants | 2 Participants | 3 Participants |
| Age, Customized Infants and toddlers (28 days-23 months) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized In utero | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Newborns (0-27 days) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Customized Preterm newborn infants (gestational age < 37 wks) | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 22 Participants | 3 Participants | 4 Participants | 4 Participants | 3 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Asian | 0 Participants | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 4 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 2 Participants | 18 Participants | 1 Participants | 3 Participants | 4 Participants | 3 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 11 Participants | 2 Participants | 2 Participants | 3 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 1 Participants | 13 Participants | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 2 | 1 / 6 | 0 / 4 | 2 / 4 | 0 / 5 | 2 / 3 |
| other Total, other adverse events | 2 / 2 | 6 / 6 | 4 / 4 | 4 / 4 | 5 / 5 | 3 / 3 |
| serious Total, serious adverse events | 2 / 2 | 4 / 6 | 2 / 4 | 4 / 4 | 4 / 5 | 3 / 3 |
Outcome results
Primary
Number of Participants Who Experienced a Dose-limiting Toxicity (DLT)
DLTs were defined as specific adverse events (AEs) that occurred in a participant during the DLT evaluation period (Day 1 to Day 28), that the investigator assessed as related to AMG 397. The grading and severity of AEs were based on the guidelines provided in the common terminology criteria for adverse events (CTCAE) version 4.03.
Time frame: 28 days
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1.~DLT evaluable set: All participants who experienced a DLT or who received at least 75% of the planned dose in the DLT window (Day 1 to Day 28).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part 1a: 80 mg AMG 397 | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1a: 160 mg AMG 397 | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1a: 320 mg AMG 397 | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 1 Participants |
| Part 1b: 80 mg AMG 397 | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1b: 160 mg AMG 397 | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 0 Participants |
| Part 1b: 320 mg AMG 397 | Number of Participants Who Experienced a Dose-limiting Toxicity (DLT) | 1 Participants |
Primary
Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
A TEAE was defined as any AE starting on or after the first dose of investigational product. Any clinically significant changes in vital signs, physical examinations, electrocardiogram (ECGs) and clinical laboratory test results were recorded as AEs. The grading and severity of adverse events were based on the guidelines provided in the CTCAE version 4.03. Treatment-related TEAEs were any events that the investigator assessed as related to AMG 397.
Time frame: Up to 30 days after last dose (Maximum time on treatment was 18 weeks for part 1a and 13 weeks for part 1b)
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1.~FAS: All participants who were enrolled and received at least 1 dose of AMG 397.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part 1a: 80 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 2 Participants |
| Part 1a: 80 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 2 Participants |
| Part 1a: 160 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 6 Participants |
| Part 1a: 160 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 6 Participants |
| Part 1a: 320 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 4 Participants |
| Part 1a: 320 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 4 Participants |
| Part 1b: 80 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 4 Participants |
| Part 1b: 80 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 2 Participants |
| Part 1b: 160 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 5 Participants |
| Part 1b: 160 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 4 Participants |
| Part 1b: 320 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | TEAEs | 3 Participants |
| Part 1b: 320 mg AMG 397 | Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE) | Treatment-related TEAEs | 3 Participants |
Secondary
Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397
Time frame: Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22
Population: The PK Analysis Set: All participants who received at least 1 dose of AMG 397 and had at least 1 PK sample collected.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a: 80 mg AMG 397 | Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397 | 635 hr*µg/mL | Geometric Coefficient of Variation 70.8 |
| Part 1a: 160 mg AMG 397 | Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397 | 115 hr*µg/mL | Geometric Coefficient of Variation 123 |
| Part 1a: 320 mg AMG 397 | Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397 | 230 hr*µg/mL | Geometric Coefficient of Variation 266 |
| Part 1b: 80 mg AMG 397 | Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397 | 108 hr*µg/mL | Geometric Coefficient of Variation 115 |
| Part 1b: 160 mg AMG 397 | Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397 | 264 hr*µg/mL | Geometric Coefficient of Variation 306 |
| Part 1b: 320 mg AMG 397 | Area Under the Concentration Time Curve From Time 0 to 168 Hours (AUC0-168) for AMG 397 | 227 hr*µg/mL | Geometric Coefficient of Variation 444 |
Secondary
Clearance (CL) of AMG 397
Time frame: Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22
Population: The PK Analysis Set: All participants who received at least 1 dose of AMG 397 and had at least 1 PK sample collected.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a: 80 mg AMG 397 | Clearance (CL) of AMG 397 | 1.08 L/hr | Geometric Coefficient of Variation 1.13 |
| Part 1a: 160 mg AMG 397 | Clearance (CL) of AMG 397 | 1.17 L/hr | Geometric Coefficient of Variation 1.21 |
| Part 1a: 320 mg AMG 397 | Clearance (CL) of AMG 397 | 1.02 L/hr | Geometric Coefficient of Variation 1.42 |
| Part 1b: 80 mg AMG 397 | Clearance (CL) of AMG 397 | 0.449 L/hr | Geometric Coefficient of Variation 0.488 |
| Part 1b: 160 mg AMG 397 | Clearance (CL) of AMG 397 | 0.563 L/hr | Geometric Coefficient of Variation 0.674 |
| Part 1b: 320 mg AMG 397 | Clearance (CL) of AMG 397 | 0.320 L/hr | Geometric Coefficient of Variation 0.467 |
Secondary
Duration of Response (DOR)
DOR was only planned to be calculated for participants who achieved response (PR or better). DOR was defined as time from the first observation indicating a response to the subsequent date of disease progression or death, whichever was earlier. DOR time in months: (date of disease progression or death - date of the first observation of response +1)/30.4.
Time frame: Up to end of study (a maximum of 48 weeks)
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1. Per the SAP, DOR was only to be calculated if the number of participants who experienced an event (objective response) was 10 or more in either part 1 or part 2.~FAS: All participants who were enrolled and received at least 1 dose of AMG 397.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: 80 mg AMG 397 | Duration of Response (DOR) | NA Months |
| Part 1a: 160 mg AMG 397 | Duration of Response (DOR) | NA Months |
| Part 1a: 320 mg AMG 397 | Duration of Response (DOR) | NA Months |
| Part 1b: 80 mg AMG 397 | Duration of Response (DOR) | NA Months |
| Part 1b: 160 mg AMG 397 | Duration of Response (DOR) | NA Months |
| Part 1b: 320 mg AMG 397 | Duration of Response (DOR) | NA Months |
Secondary
Half-life (t1/2) of AMG 397
Time frame: Cycle 1 (cycle = 28 days): Predose, 3, 5, & 8 hours postdose on days 1 (12 hours postdose on Day 1 only), 8 & 15, predose & 8 hours postdose on Day 22 & days 2, 3, 4, 9, 16, 17, 18 & 23; Cycles 2, 3 & 4 (cycle = 28 days): Predose on days 2, 8, 15 & 22
Population: The PK Analysis Set: All participants who received at least 1 dose of AMG 397 and had at least 1 PK sample collected.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Part 1a: 80 mg AMG 397 | Half-life (t1/2) of AMG 397 | 60.1 hours | Geometric Coefficient of Variation 62.8 |
| Part 1a: 160 mg AMG 397 | Half-life (t1/2) of AMG 397 | 49.7 hours | Geometric Coefficient of Variation 54.9 |
| Part 1a: 320 mg AMG 397 | Half-life (t1/2) of AMG 397 | 76.9 hours | Geometric Coefficient of Variation 90.1 |
| Part 1b: 80 mg AMG 397 | Half-life (t1/2) of AMG 397 | 96.3 hours | Geometric Coefficient of Variation 118 |
| Part 1b: 160 mg AMG 397 | Half-life (t1/2) of AMG 397 | 53.4 hours | Geometric Coefficient of Variation 55.1 |
| Part 1b: 320 mg AMG 397 | Half-life (t1/2) of AMG 397 | 109 hours | Geometric Coefficient of Variation 129 |
Secondary
Maximum Observed Concentration (Cmax) of AMG 397
Predose data for Day 2 were analyzed/included with the Day 1 data.
Time frame: Cycle 1 (cycle = 28 days): Predose, 1, 2, 3, 5, 8 & 12 hours postdose on Day 1; predose, 1, 2, 3, 5, 8, 12, 24 & 48 hours postdose on Day 2
Population: The Pharmacokinetic (PK) Analysis Set: All participants who received at least 1 dose of AMG 397 and had at least 1 PK sample collected.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Part 1a: 80 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 1 | 0.415 µg/mL | Geometric Coefficient of Variation 0.47 |
| Part 1a: 80 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 2 | 1.17 µg/mL | Geometric Coefficient of Variation 1.29 |
| Part 1a: 160 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 1 | 0.468 µg/mL | Geometric Coefficient of Variation 0.606 |
| Part 1a: 160 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 2 | 1.80 µg/mL | Geometric Coefficient of Variation 1.88 |
| Part 1a: 320 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 1 | 0.908 µg/mL | Geometric Coefficient of Variation 1.19 |
| Part 1a: 320 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 2 | 2.822 µg/mL | Geometric Coefficient of Variation 3.17 |
| Part 1b: 80 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 1 | 0.747 µg/mL | Geometric Coefficient of Variation 0.785 |
| Part 1b: 80 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 2 | 1.41 µg/mL | Geometric Coefficient of Variation 1.51 |
| Part 1b: 160 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 1 | 1.31 µg/mL | Geometric Coefficient of Variation 1.87 |
| Part 1b: 160 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 2 | 3.69 µg/mL | Geometric Coefficient of Variation 4.46 |
| Part 1b: 320 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 1 | 2.51 µg/mL | Geometric Coefficient of Variation 2.83 |
| Part 1b: 320 mg AMG 397 | Maximum Observed Concentration (Cmax) of AMG 397 | Day 2 | 4.57 µg/mL | Geometric Coefficient of Variation 5.14 |
Secondary
Overall Response Rate (ORR) for Participants With Acute Myeloid Leukemia (AML)
ORR was assessed for participants with AML using response criteria per European Leukemia Network Response Criteria. ORR was defined as the percentage of participants who experienced either of the following based on investigator assessment: * PR * morphological leukemia-free state (MLFS) * complete remission with incomplete hematologic recovery (CRi) * complete remission * complete remission without minimal residual disease (CRmrd-).
Time frame: Up to end of study (a maximum of 48 weeks)
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1. Participants with AML were only enrolled in part 1b, so therefore data is only presented for part 1b.~FAS: All participants who were enrolled and received at least 1 dose of AMG 397.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| Part 1a: 80 mg AMG 397 | Overall Response Rate (ORR) for Participants With Acute Myeloid Leukemia (AML) | 0.0 Percentage of participants | 95% Confidence Interval 0 |
| Part 1a: 160 mg AMG 397 | Overall Response Rate (ORR) for Participants With Acute Myeloid Leukemia (AML) | 0.0 Percentage of participants | 95% Confidence Interval 0 |
| Part 1a: 320 mg AMG 397 | Overall Response Rate (ORR) for Participants With Acute Myeloid Leukemia (AML) | 0.0 Percentage of participants | 95% Confidence Interval 0 |
Secondary
Overall Response Rate (ORR) for Participants With Multiple Myeloma (MM)
ORR was assessed for participants with MM using response criteria per International Myeloma Working Group (IMWG). ORR was defined as the percentage of participants who experienced either one of the following based on investigator assessment: * partial response (PR) * very good partial response (VGPR) * complete response (CR) * stringent complete response (sCR)
Time frame: Up to end of study (a maximum of 48 weeks)
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1. Participants with MM were only enrolled in part 1a, so therefore data is only presented for part 1a.~FAS: All participants who were enrolled and received at least 1 dose of AMG 397.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a: 80 mg AMG 397 | Overall Response Rate (ORR) for Participants With Multiple Myeloma (MM) | 0.0 Percentage of participants |
| Part 1a: 160 mg AMG 397 | Overall Response Rate (ORR) for Participants With Multiple Myeloma (MM) | 0.0 Percentage of participants |
| Part 1a: 320 mg AMG 397 | Overall Response Rate (ORR) for Participants With Multiple Myeloma (MM) | 0.0 Percentage of participants |
Secondary
Overall Response Rate (ORR) for Participants With Non-Hodgkin's Lymphoma (NHL)
ORR was assessed for participants with NHL using response criteria per Lugano Classification. ORR was defined as the percentage of participants who experienced either of the following based on investigator assessment: * partial metabolic response/ PR * complete metabolic response/ CR
Time frame: Up to end of study (a maximum of 48 weeks)
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1. Participants with NHL were only enrolled in part 1a, so therefore data is only presented for part 1a.~FAS: All participants who were enrolled and received at least 1 dose of AMG 397.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part 1a: 80 mg AMG 397 | Overall Response Rate (ORR) for Participants With Non-Hodgkin's Lymphoma (NHL) | 100.0 Percentage of participants |
| Part 1a: 160 mg AMG 397 | Overall Response Rate (ORR) for Participants With Non-Hodgkin's Lymphoma (NHL) | 0.0 Percentage of participants |
Secondary
Overall Survival (OS)
OS was defined as the time from first dose of investigational product date until death due to any cause. OS time in months: (date of death - first dose date +1)/30.4.
Time frame: Up to end of study (a maximum of 48 weeks)
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1. Per the SAP, OS was only to be calculated if the number of participants who experienced an event (death) was 10 or more in either part 1 or part 2.~FAS: All participants who were enrolled and received at least 1 dose of AMG 397.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: 80 mg AMG 397 | Overall Survival (OS) | NA Months |
| Part 1a: 160 mg AMG 397 | Overall Survival (OS) | NA Months |
| Part 1a: 320 mg AMG 397 | Overall Survival (OS) | NA Months |
| Part 1b: 80 mg AMG 397 | Overall Survival (OS) | NA Months |
| Part 1b: 160 mg AMG 397 | Overall Survival (OS) | NA Months |
| Part 1b: 320 mg AMG 397 | Overall Survival (OS) | NA Months |
Secondary
Progression-free Survival (PFS)
PFS was calculated as time from first dose of investigational product date to disease progression date or death due to any cause, whichever was earlier. PFS time in months: (date of disease progression or death - first dose date +1)/30.4.
Time frame: Up to end of study (a maximum of 48 weeks)
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1. Per the statistical analysis plan (SAP), PFS was only to be calculated if the number of participants who experienced events (disease progression or death) was 10 or more in either part 1 or part 2.~FAS: All participants who were enrolled and received at least 1 dose of AMG 397.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: 80 mg AMG 397 | Progression-free Survival (PFS) | NA Months |
| Part 1a: 160 mg AMG 397 | Progression-free Survival (PFS) | NA Months |
| Part 1a: 320 mg AMG 397 | Progression-free Survival (PFS) | NA Months |
| Part 1b: 80 mg AMG 397 | Progression-free Survival (PFS) | NA Months |
| Part 1b: 160 mg AMG 397 | Progression-free Survival (PFS) | NA Months |
| Part 1b: 320 mg AMG 397 | Progression-free Survival (PFS) | NA Months |
Secondary
Time to Maximum Observed Concentration (Tmax) for AMG 397
Predose data for Day 2 were analyzed/included with the Day 1 data.
Time frame: Cycle 1 (cycle = 28 days): Predose, 1, 2, 3, 5, 8 & 12 hours postdose on Day 1; predose, 1, 2, 3, 5, 8, 12, 24 & 48 hours postdose on Day 2
Population: The PK Analysis Set: All participants who received at least 1 dose of AMG 397 and had at least 1 PK sample collected.
| Arm | Measure | Group | Value (MEDIAN) | Dispersion |
|---|---|---|---|---|
| Part 1a: 80 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 1 | 12 Hours | Full Range 12 |
| Part 1a: 80 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 2 | 4 Hours | Full Range 2.9 |
| Part 1a: 160 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 1 | 18 Hours | Full Range 8 |
| Part 1a: 160 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 2 | 8.3 Hours | Full Range 7.9 |
| Part 1a: 320 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 2 | 7.9 Hours | Full Range 4.9 |
| Part 1a: 320 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 1 | 8.1 Hours | Full Range 5.1 |
| Part 1b: 80 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 1 | 12 Hours | Full Range 8.1 |
| Part 1b: 80 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 2 | 6.6 Hours | Full Range 5 |
| Part 1b: 160 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 1 | 21 Hours | Full Range 7.8 |
| Part 1b: 160 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 2 | 7.2 Hours | Full Range 3.3 |
| Part 1b: 320 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 2 | 8.1 Hours | Full Range 8 |
| Part 1b: 320 mg AMG 397 | Time to Maximum Observed Concentration (Tmax) for AMG 397 | Day 1 | 12 Hours | Full Range 11 |
Secondary
Time to Response (TTR)
TTR was defined as the time from the first dose of investigational product until the first documentation of objective response. Only participants who achieved an objective response were evaluated for TTR. TTR time in months: (date of the first observation of response - first dose of IP date +1)/30.4.
Time frame: Up to end of study (a maximum of 48 weeks)
Population: Parts 2 and 3 were not initiated and did not enrol any participants, therefore results presented only included participants in part 1. Per the SAP, TTR was only to be calculated if the number of participants who experienced an event (objective response) was 10 or more in either part 1 or part 2.~FAS: All participants who were enrolled and received at least 1 dose of AMG 397.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part 1a: 80 mg AMG 397 | Time to Response (TTR) | NA Months |
| Part 1a: 160 mg AMG 397 | Time to Response (TTR) | NA Months |
| Part 1a: 320 mg AMG 397 | Time to Response (TTR) | NA Months |
| Part 1b: 80 mg AMG 397 | Time to Response (TTR) | NA Months |
| Part 1b: 160 mg AMG 397 | Time to Response (TTR) | NA Months |
| Part 1b: 320 mg AMG 397 | Time to Response (TTR) | NA Months |