A Study of LAM-003 in Patients With Acute Myeloid Leukemia

Phase 1

Completed

Conditions: Oncology
Acute Myeloid Leukemia

Interventions: Drug: Open Label LAM-003

Registration Number: NCT03426605

Lead Sponsor: OrphAI Therapeutics

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 17

Inclusion Criteria

Men and women of age ≥18 years.
Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
Presence of measurable AML that has progressed during or relapsed after prior therapy
All acute toxic effects of any prior antitumor therapy resolved to Grade 1.
Adequate hepatic profile.
Adequate renal function.
Adequate coagulation profile.
Negative antiviral serology for human immunodeficiency virus (HIV), hepatitis B, and hepatitis C.
For female subjects of childbearing potential, a negative serum pregnancy test.
For both male and female subjects, willingness to use adequate contraception.
Willingness and ability of the subject to comply with study activities.
Evidence of a personally signed informed consent document.

Exclusion Criteria

Leukemic blast cell count >50 × 10^9/L before the start of study therapy and despite the use hydroxyurea, cytarabine, and/or cyclophosphamide.
Presence of known central nervous system (CNS) leukemia.
Presence of another major cancer.
Ongoing Grade >1 proliferative or nonproliferative retinopathy.
Significant cardiovascular disease or ECG abnormalities.
Significant gastrointestinal disease
Uncontrolled ongoing infection.
Pregnancy or breastfeeding.
Major surgery within 4 weeks before the start of study therapy.
Subject was a candidate for hematopoietic stem cell transplantation (HSCT).
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.
Prior solid organ transplantation.
Ongoing immunosuppressive therapy other than corticosteroids.
Use of a strong inhibitor or inducer of cytochrome P450 (CYP) 3A4.
Use of a drug known to prolong the cardiac QT interval.
Concurrent participation in another therapeutic or imaging clinical trial.
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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
LAM-003	Open Label LAM-003	Open label LAM-003 at three sequentially increasing starting dose levels of 200, 300 and 450 mg.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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).
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)
Objective Response Rate	Every 8 to 12 weeks for up to 48 weeks.	Tumor response by AML response criteria (Cheson 2003).
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)
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.

Trial Locations

Locations (6): University of Maryland
🇺🇸
Baltimore, Maryland, United States
Hackensack Meridien Health
🇺🇸
Hackensack, New Jersey, United States
Virginia Cancer Specialists
🇺🇸
Fairfax, Virginia, United States
Weill Cornell Medical College
🇺🇸
New York, New York, United States
Yale University
🇺🇸
New Haven, Connecticut, United States
Dana Farber Cancer Institute
🇺🇸
Boston, Massachusetts, United States