Acute Myeloid Leukemia, Oncology
Conditions
Brief summary
A Phase 1 Dose-Escalation Study of LAM-003 in Patients with Acute Myeloid Leukemia
Detailed description
This clinical trial is a Phase 1 study evaluating the safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LAM-003 across a range of LAM-003 dose levels when administered to subjects with previously treated relapsed or refractory cute Myeloid Leukemia (AML). Subjects will self-administer oral LAM-003 either once or twice per day as long as they are safely benefitting from therapy. Cohorts of 3 to 6 subjects will be sequentially enrolled at progressively higher dose levels of LAM-003 using a standard 3+3 dose-escalation design. Based on the pattern of dose-limiting toxicities observed in the first 4 weeks of therapy, escalation will proceed to define a recommended LAM-003 dosing regimen.
Interventions
DRUGOpen Label LAM-003
LAM-003
Sponsors
OrphAI Therapeutics
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open Label, Dose-Escalation
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Men and women of age ≥18 years. 2. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 3. Presence of measurable AML that has progressed during or relapsed after prior therapy 4. All acute toxic effects of any prior antitumor therapy resolved to Grade 1. 5. Adequate hepatic profile. 6. Adequate renal function. 7. Adequate coagulation profile. 8. Negative antiviral serology for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C. 9. For female subjects of childbearing potential, a negative serum pregnancy test. 10. For both male and female subjects, willingness to use adequate contraception. 11. Willingness and ability of the subject to comply with study activities. 12. Evidence of a personally signed informed consent document.
Exclusion criteria
1. Leukemic blast cell count \>50 × 10\^9/L before the start of study therapy and despite the use hydroxyurea, cytarabine, and/or cyclophosphamide. 2. Presence of known central nervous system (CNS) leukemia. 3. Presence of another major cancer. 4. Ongoing Grade \>1 proliferative or nonproliferative retinopathy. 5. Significant cardiovascular disease or ECG abnormalities. 6. Significant gastrointestinal disease 7. Uncontrolled ongoing infection. 8. Pregnancy or breastfeeding. 9. Major surgery within 4 weeks before the start of study therapy. 10. Subject was a candidate for hematopoietic stem cell transplantation (HSCT). 11. Ongoing severe graft-versus-house disease (GVHD) with Grade ≥2 serum bilirubin, Grade ≥3 skin involvement, or Grade ≥3 diarrhea at the start of study therapy. 12. Prior solid organ transplantation. 13. Ongoing immunosuppressive therapy other than corticosteroids. 14. Use of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4. 15. Use of a drug known to prolong the cardiac QT interval. 16. Concurrent participation in another therapeutic or imaging clinical trial. 17. Presence of a concomitant medical condition that (in the judgement of the investigator) interferes with the ability of the subject to participate in the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose (MTD) | At the end of the 28-day observation period for Cycle 1. | A primary objective was to determine the LAM-003 MTD and/or recommended dosing regimen (RDR) based on the pattern of dose-limiting toxicities (DLTs) in Cycle 1 of therapy. MTD as determined by DLTs. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Plasma Concentration (Cmax) | Cycle 1 Days 1, 2 and 8 (1 cycle = 28 days) | The pharmacokinetic parameter Cmax was determined in plasma for the active metabolite of LAM-003A and LAM-003 (prodrug) |
| Time of Maximum Concentration [Tmax] | Cycle 1 Days 1, 2 and 8 (1 cycle = 28 days) | The pharmacokinetic parameter Tmax was determined in plasma for the active metabolite of LAM-003A and LAM-003 (prodrug) |
| Adverse Event Assessment | Weekly during the first 4 weeks and then every 4 weeks for up to 48 weeks. | Number and percentage of participants with an adverse event (AE). |
| Objective Response Rate | Every 8 to 12 weeks for up to 48 weeks. | Tumor response by AML response criteria (Cheson 2003). |
| Event-Free Survival (EFS) and Overall Survival (OS) | Every 8 to 12 weeks for up to 48 weeks. | Event-free survival (EFS), defined as the interval from the start of study therapy to the earliest of the first documentation of disease relapse, disease progression, treatment failure (TF), or death from any cause. Overall survival (OS), defined as the interval from the start of study therapy to death from any cause. |
| Area Under the Curve [AUC] | Cycle 1 Days 1, 2 and 8 (1 cycle = 28 days) | The pharmacokinetic parameter area under the concentration-time curve was determined in plasma for the active metabolite of LAM-003A and LAM-003 (prodrug). AUClast is the area under the concentration-time curve from time-zero to the time of the last quantifiable concentration. AUCtau is the area under the concentration-time curve during the dosing interval where tau=24hours for once daily (QD) dosing. AUCtau was not calculated for LAM-003. |
Countries
United States
Participant flow
Recruitment details
This study was conducted by 6 investigators located in medical centers throughout the United States.
Pre-assignment details
The study included a screening period (up to 28 days) prior to the study drug administration period. Discontinuation of prior antitumor therapy was required except that subjects with rapidly proliferative disease could receive AML cytoreduction with hydroxyurea, cytarabine, and/or cyclophosphamide before the start of LAM-003 and during Cycle 1 of LAM-003 administration.
Participants by arm
| Arm | Count |
|---|---|
| LAM-003 200 mg QD 6 participants were accrued at starting dose level of 200 mg QD. | 6 |
| LAM-003 300 mg QD 3 participants were accrued at 300 mg QD. | 3 |
| LAM-003 450 mg QD 4 participants were accrued at 450 mg QD. Intrasubject dose escalations were implemented in 1 subject. Subject 006-006 received LAM-003 450 mg QD during Cycles 1 and 2 and received LAM-003 600 mg QD during Cycles 3 and 4. | 4 |
| LAM-003 600 mg QD 4 Participant were accrued at 600 mg QD. Intrasubject dose escalations were implemented in 2 subjects:
* Subject 005-011 received LAM-003 600 mg QD during Cycle 1 and received LAM-003 750 mg QD during Cycles 2 and 3.
* Subject 006-007 received LAM-003 600 mg QD during Cycle 1 and received LAM-003 750 mg QD during Cycle 2. | 4 |
| Total | 17 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 1 |
| Overall Study | AML relapse or progression | 2 | 1 | 2 | 2 |
| Overall Study | Treatment failure | 3 | 2 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | LAM-003 300 mg QD | LAM-003 200 mg QD | Total | LAM-003 600 mg QD | LAM-003 450 mg QD |
|---|---|---|---|---|---|
| Age, Continuous | 34 years | 71 years | 68 years | 67.5 years | 75 years |
| BMI | 27.6 kg/m^2 | 32.4 kg/m^2 | 27.6 kg/m^2 | 21.6 kg/m^2 | 27.5 kg/m^2 |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 0 = Fully active | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 1 = Restricted in physically strenuous activity but ambulatory | 2 Participants | 5 Participants | 10 Participants | 2 Participants | 1 Participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status 2 = Ambulatory and capable of all self-care but unable to carry out any work activities | 1 Participants | 1 Participants | 6 Participants | 1 Participants | 3 Participants |
| Elevated peripheral blood AML blast % | 41.40 percentage | 24.75 percentage | 30.40 percentage | 34.05 percentage | 22.15 percentage |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 2 Participants | 3 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 4 Participants | 14 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Number of prior anticancer treatment regimens | 4.0 number of treatments | 3.0 number of treatments | 4.0 number of treatments | 4.0 number of treatments | 3.5 number of treatments |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 13 Participants | 4 Participants | 4 Participants |
| Region of Enrollment United States | 3 Participants | 6 Participants | 17 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 6 Participants | 1 Participants | 2 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 11 Participants | 3 Participants | 2 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 |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 6 | 1 / 3 | 2 / 4 | 1 / 4 | 2 / 3 |
| other Total, other adverse events | 6 / 6 | 3 / 3 | 4 / 4 | 4 / 4 | 3 / 3 |
| serious Total, serious adverse events | 3 / 6 | 3 / 3 | 3 / 4 | 2 / 4 | 2 / 3 |
Outcome results
Primary
Maximum Tolerated Dose (MTD)
A primary objective was to determine the LAM-003 MTD and/or recommended dosing regimen (RDR) based on the pattern of dose-limiting toxicities (DLTs) in Cycle 1 of therapy. MTD as determined by DLTs.
Time frame: At the end of the 28-day observation period for Cycle 1.
Population: Participants were considered evaluable for Cycle 1 DLT assessment if they either had a Cycle 1 DLT or completed 21/28 study drug doses during Cycle 1 and were observed ≥4 weeks from the start of study drug administration without having a DLT.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| LAM-003 200 mg QD | Maximum Tolerated Dose (MTD) | 0 DLTs |
| LAM-003 300 mg QD | Maximum Tolerated Dose (MTD) | 0 DLTs |
| LAM-003 450 mg QD | Maximum Tolerated Dose (MTD) | 0 DLTs |
| LAM-003 600 mg QD | Maximum Tolerated Dose (MTD) | 0 DLTs |
Secondary
Adverse Event Assessment
Number and percentage of participants with an adverse event (AE).
Time frame: Weekly during the first 4 weeks and then every 4 weeks for up to 48 weeks.
Population: All participants who received ≥1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 TEAE of Grade ≥3 | 5 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 AE | 6 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 AESI | 0 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With AEs (other than AML progression) resulting in permanent discontinuation of study drug | 1 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With AEs resulting in death within 30 days from the last dose of study drug | 1 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 study-drug-related treatment-emergent SAE | 0 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 study-drug-related TEAE of Grade ≥3 | 0 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 SAE | 3 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With AEs resulting in drug interruption of study drug | 0 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 study-drug-related TEAE | 3 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 TEAE | 6 Participants |
| LAM-003 200 mg QD | Adverse Event Assessment | With ≥1 treatment-emergent SAE | 3 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With AEs resulting in drug interruption of study drug | 0 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 TEAE of Grade ≥3 | 3 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 study-drug-related TEAE of Grade ≥3 | 0 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 SAE | 3 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With AEs (other than AML progression) resulting in permanent discontinuation of study drug | 0 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 AESI | 0 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 AE | 3 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 TEAE | 3 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 study-drug-related TEAE | 2 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 treatment-emergent SAE | 3 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With ≥1 study-drug-related treatment-emergent SAE | 0 Participants |
| LAM-003 300 mg QD | Adverse Event Assessment | With AEs resulting in death within 30 days from the last dose of study drug | 1 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 study-drug-related TEAE | 1 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 study-drug-related TEAE of Grade ≥3 | 0 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With AEs resulting in death within 30 days from the last dose of study drug | 2 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 study-drug-related treatment-emergent SAE | 0 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 TEAE | 4 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With AEs (other than AML progression) resulting in permanent discontinuation of study drug | 0 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 SAE | 3 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 TEAE of Grade ≥3 | 4 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 AESI | 0 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With AEs resulting in drug interruption of study drug | 1 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 treatment-emergent SAE | 3 Participants |
| LAM-003 450 mg QD | Adverse Event Assessment | With ≥1 AE | 4 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 treatment-emergent SAE | 2 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 SAE | 2 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With AEs (other than AML progression) resulting in permanent discontinuation of study drug | 1 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 TEAE | 4 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 study-drug-related TEAE | 2 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 study-drug-related TEAE of Grade ≥3 | 0 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With AEs resulting in death within 30 days from the last dose of study drug | 1 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 AE | 4 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 study-drug-related treatment-emergent SAE | 0 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With AEs resulting in drug interruption of study drug | 0 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 AESI | 0 Participants |
| LAM-003 600 mg QD | Adverse Event Assessment | With ≥1 TEAE of Grade ≥3 | 3 Participants |
Secondary
Area Under the Curve [AUC]
The pharmacokinetic parameter area under the concentration-time curve was determined in plasma for the active metabolite of LAM-003A and LAM-003 (prodrug). AUClast is the area under the concentration-time curve from time-zero to the time of the last quantifiable concentration. AUCtau is the area under the concentration-time curve during the dosing interval where tau=24hours for once daily (QD) dosing. AUCtau was not calculated for LAM-003.
Time frame: Cycle 1 Days 1, 2 and 8 (1 cycle = 28 days)
Population: The PK population included all evaluable participants who were dosed and had sufficient concentration-time data to estimate at least one of the planned PK parameters, as determined by the study pharmacokineticist.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LAM-003 200 mg QD | Area Under the Curve [AUC] | LAM-003A AUCtau for Day 1 | 26000 h*ng/mL | Standard Deviation 43900 |
| LAM-003 200 mg QD | Area Under the Curve [AUC] | LAM-003 AUClast for Day 8 | 0.383 h*ng/mL | Standard Deviation 0.311 |
| LAM-003 200 mg QD | Area Under the Curve [AUC] | LAM-003A AUCtau for Day 8 | 42300 h*ng/mL | Standard Deviation 4840 |
| LAM-003 200 mg QD | Area Under the Curve [AUC] | LAM-003A AUClast for Day 1 | 43100 h*ng/mL | Standard Deviation 23200 |
| LAM-003 200 mg QD | Area Under the Curve [AUC] | LAM-003A AUClast for Day 8 | 24400 h*ng/mL | Standard Deviation 5680 |
| LAM-003 200 mg QD | Area Under the Curve [AUC] | LAM-003 AUClast for Day 1 | 0.287 h*ng/mL | Standard Deviation 0.254 |
| LAM-003 300 mg QD | Area Under the Curve [AUC] | LAM-003A AUClast for Day 1 | 112000 h*ng/mL | Standard Deviation 45100 |
| LAM-003 300 mg QD | Area Under the Curve [AUC] | LAM-003A AUClast for Day 8 | 53600 h*ng/mL | Standard Deviation 10400 |
| LAM-003 300 mg QD | Area Under the Curve [AUC] | LAM-003A AUCtau for Day 1 | 113000 h*ng/mL | Standard Deviation 46100 |
| LAM-003 300 mg QD | Area Under the Curve [AUC] | LAM-003 AUClast for Day 1 | 0.958 h*ng/mL | Standard Deviation 0.745 |
| LAM-003 300 mg QD | Area Under the Curve [AUC] | LAM-003 AUClast for Day 8 | 1.18 h*ng/mL | Standard Deviation 1.84 |
| LAM-003 450 mg QD | Area Under the Curve [AUC] | LAM-003A AUCtau for Day 8 | 113000 h*ng/mL | — |
| LAM-003 450 mg QD | Area Under the Curve [AUC] | LAM-003A AUCtau for Day 1 | 132000 h*ng/mL | — |
| LAM-003 450 mg QD | Area Under the Curve [AUC] | LAM-003A AUClast for Day 1 | 131000 h*ng/mL | — |
| LAM-003 450 mg QD | Area Under the Curve [AUC] | LAM-003A AUClast for Day 8 | 52800 h*ng/mL | — |
| LAM-003 450 mg QD | Area Under the Curve [AUC] | LAM-003 AUClast for Day 1 | 1.72 h*ng/mL | — |
| LAM-003 450 mg QD | Area Under the Curve [AUC] | LAM-003 AUClast for Day 8 | 0.90 h*ng/mL | — |
| LAM-003 600 mg QD | Area Under the Curve [AUC] | LAM-003A AUCtau for Day 8 | 103000 h*ng/mL | Standard Deviation 33900 |
| LAM-003 600 mg QD | Area Under the Curve [AUC] | LAM-003A AUClast for Day 8 | 56400 h*ng/mL | Standard Deviation 18000 |
| LAM-003 600 mg QD | Area Under the Curve [AUC] | LAM-003 AUClast for Day 1 | 0.935 h*ng/mL | Standard Deviation 1.1 |
| LAM-003 600 mg QD | Area Under the Curve [AUC] | LAM-003 AUClast for Day 8 | 0.833 h*ng/mL | Standard Deviation 0.837 |
| LAM-003 600 mg QD | Area Under the Curve [AUC] | LAM-003A AUCtau for Day 1 | 110000 h*ng/mL | Standard Deviation 47300 |
| LAM-003 600 mg QD | Area Under the Curve [AUC] | LAM-003A AUClast for Day 1 | 105000 h*ng/mL | Standard Deviation 39800 |
Secondary
Event-Free Survival (EFS) and Overall Survival (OS)
Event-free survival (EFS), defined as the interval from the start of study therapy to the earliest of the first documentation of disease relapse, disease progression, treatment failure (TF), or death from any cause. Overall survival (OS), defined as the interval from the start of study therapy to death from any cause.
Time frame: Every 8 to 12 weeks for up to 48 weeks.
Population: All participants who received ≥1 dose of study drug.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LAM-003 200 mg QD | Event-Free Survival (EFS) and Overall Survival (OS) | EFS | 0.6 months |
| LAM-003 200 mg QD | Event-Free Survival (EFS) and Overall Survival (OS) | OS | 3 months |
| LAM-003 300 mg QD | Event-Free Survival (EFS) and Overall Survival (OS) | OS | 5.1 months |
| LAM-003 300 mg QD | Event-Free Survival (EFS) and Overall Survival (OS) | EFS | 0.9 months |
| LAM-003 450 mg QD | Event-Free Survival (EFS) and Overall Survival (OS) | EFS | 1.8 months |
| LAM-003 450 mg QD | Event-Free Survival (EFS) and Overall Survival (OS) | OS | 3.4 months |
| LAM-003 600 mg QD | Event-Free Survival (EFS) and Overall Survival (OS) | EFS | 1.5 months |
| LAM-003 600 mg QD | Event-Free Survival (EFS) and Overall Survival (OS) | OS | 3.1 months |
Secondary
Maximum Plasma Concentration (Cmax)
The pharmacokinetic parameter Cmax was determined in plasma for the active metabolite of LAM-003A and LAM-003 (prodrug)
Time frame: Cycle 1 Days 1, 2 and 8 (1 cycle = 28 days)
Population: The Pharmacokinetic (PK) population included all evaluable participants who were dosed and had sufficient concentration-time data to estimate at least one of the planned PK parameters, as determined by the study pharmacokineticist.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| LAM-003 200 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003A Day 1 | 3550 ng/mL | Standard Deviation 1860 |
| LAM-003 200 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003A Day 8 | 5000 ng/mL | Standard Deviation 576 |
| LAM-003 200 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003 Day 1 | 0.560 ng/mL | Standard Deviation 0.32 |
| LAM-003 200 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003 Day 8 | 0.617 ng/mL | Standard Deviation 0.22 |
| LAM-003 300 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003A Day 8 | 8360 ng/mL | Standard Deviation 1150 |
| LAM-003 300 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003 Day 1 | 1.47 ng/mL | Standard Deviation 1.28 |
| LAM-003 300 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003 Day 8 | 1.08 ng/mL | Standard Deviation 1.36 |
| LAM-003 300 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003A Day 1 | 8360 ng/mL | Standard Deviation 2230 |
| LAM-003 450 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003 Day 1 | 2.71 ng/mL | — |
| LAM-003 450 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003A Day 8 | 8500 ng/mL | — |
| LAM-003 450 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003 Day 8 | 3.60 ng/mL | — |
| LAM-003 450 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003A Day 1 | 9170 ng/mL | — |
| LAM-003 600 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003 Day 8 | 1.45 ng/mL | Standard Deviation 1.43 |
| LAM-003 600 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003A Day 8 | 9620 ng/mL | Standard Deviation 3810 |
| LAM-003 600 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003A Day 1 | 8240 ng/mL | Standard Deviation 3750 |
| LAM-003 600 mg QD | Maximum Plasma Concentration (Cmax) | LAM-003 Day 1 | 1.83 ng/mL | Standard Deviation 1.3 |
Secondary
Objective Response Rate
Tumor response by AML response criteria (Cheson 2003).
Time frame: Every 8 to 12 weeks for up to 48 weeks.
Population: All participants who received ≥1 dose of study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| LAM-003 200 mg QD | Objective Response Rate | Disease Relapse or Progression | 2 Participants |
| LAM-003 200 mg QD | Objective Response Rate | Partial Response | 0 Participants |
| LAM-003 200 mg QD | Objective Response Rate | Nonevaluable | 1 Participants |
| LAM-003 200 mg QD | Objective Response Rate | Treatment Failure | 3 Participants |
| LAM-003 200 mg QD | Objective Response Rate | CRc: Composite complete remission including participants with CR, CRMRD-, and CRi | 0 Participants |
| LAM-003 300 mg QD | Objective Response Rate | Treatment Failure | 1 Participants |
| LAM-003 300 mg QD | Objective Response Rate | Disease Relapse or Progression | 2 Participants |
| LAM-003 300 mg QD | Objective Response Rate | Nonevaluable | 0 Participants |
| LAM-003 300 mg QD | Objective Response Rate | Partial Response | 0 Participants |
| LAM-003 300 mg QD | Objective Response Rate | CRc: Composite complete remission including participants with CR, CRMRD-, and CRi | 0 Participants |
| LAM-003 450 mg QD | Objective Response Rate | Treatment Failure | 2 Participants |
| LAM-003 450 mg QD | Objective Response Rate | CRc: Composite complete remission including participants with CR, CRMRD-, and CRi | 0 Participants |
| LAM-003 450 mg QD | Objective Response Rate | Partial Response | 0 Participants |
| LAM-003 450 mg QD | Objective Response Rate | Disease Relapse or Progression | 2 Participants |
| LAM-003 450 mg QD | Objective Response Rate | Nonevaluable | 0 Participants |
| LAM-003 600 mg QD | Objective Response Rate | Disease Relapse or Progression | 1 Participants |
| LAM-003 600 mg QD | Objective Response Rate | Partial Response | 0 Participants |
| LAM-003 600 mg QD | Objective Response Rate | CRc: Composite complete remission including participants with CR, CRMRD-, and CRi | 0 Participants |
| LAM-003 600 mg QD | Objective Response Rate | Treatment Failure | 3 Participants |
| LAM-003 600 mg QD | Objective Response Rate | Nonevaluable | 0 Participants |
Secondary
Time of Maximum Concentration [Tmax]
The pharmacokinetic parameter Tmax was determined in plasma for the active metabolite of LAM-003A and LAM-003 (prodrug)
Time frame: Cycle 1 Days 1, 2 and 8 (1 cycle = 28 days)
Population: The PK population included all evaluable participants who were dosed and had sufficient concentration-time data to estimate at least one of the planned PK parameters, as determined by the study pharmacokineticist.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| LAM-003 200 mg QD | Time of Maximum Concentration [Tmax] | LAM-003 for Day 8 | 0.75 hours |
| LAM-003 200 mg QD | Time of Maximum Concentration [Tmax] | LAM-003 for Day 1 | 1.00 hours |
| LAM-003 200 mg QD | Time of Maximum Concentration [Tmax] | LAM-003A for Day 1 | 3.80 hours |
| LAM-003 200 mg QD | Time of Maximum Concentration [Tmax] | LAM-003A for Day 8 | 2.00 hours |
| LAM-003 300 mg QD | Time of Maximum Concentration [Tmax] | LAM-003 for Day 8 | 1.10 hours |
| LAM-003 300 mg QD | Time of Maximum Concentration [Tmax] | LAM-003A for Day 8 | 4.00 hours |
| LAM-003 300 mg QD | Time of Maximum Concentration [Tmax] | LAM-003A for Day 1 | 3.80 hours |
| LAM-003 300 mg QD | Time of Maximum Concentration [Tmax] | LAM-003 for Day 1 | 1.80 hours |
| LAM-003 450 mg QD | Time of Maximum Concentration [Tmax] | LAM-003A for Day 8 | 2.10 hours |
| LAM-003 450 mg QD | Time of Maximum Concentration [Tmax] | LAM-003A for Day 1 | 4.10 hours |
| LAM-003 450 mg QD | Time of Maximum Concentration [Tmax] | LAM-003 for Day 1 | 0.50 hours |
| LAM-003 450 mg QD | Time of Maximum Concentration [Tmax] | LAM-003 for Day 8 | 0.50 hours |
| LAM-003 600 mg QD | Time of Maximum Concentration [Tmax] | LAM-003A for Day 1 | 1.95 hours |
| LAM-003 600 mg QD | Time of Maximum Concentration [Tmax] | LAM-003A for Day 8 | 1.95 hours |
| LAM-003 600 mg QD | Time of Maximum Concentration [Tmax] | LAM-003 for Day 8 | 1.10 hours |
| LAM-003 600 mg QD | Time of Maximum Concentration [Tmax] | LAM-003 for Day 1 | 0.50 hours |