MEN1703 (SEL24) in Participants With Acute Myeloid Leukemia

Menarini Group73 enrolled

Overview

The purpose of the clinical trial is to identify the maximum tolerated dose of MEN1703 and to further investigate its safety profile in participants with acute myeloid leukemia (AML).

Phase I/II, open-label, multi-center, dose escalation study to estimate the maximum tolerated dose of MEN1703 in participants with acute myeloid leukemia. The clinical trial will investigate the safety profile and anti-leukemic activity of MEN1703 in participants with AML and that have no standard therapeutic options available. The clinical trial encompasses 2 parts: * Part 1: Ascending dose levels - the main purpose of this part of the clinical trial is to determine the highest dose of MEN1703 considered to be well tolerated. * Part 2: Expansion cohort - the main purpose of this part of the clinical trial is to assess the safety and anti-leukemia activity of MEN1703 given at the highest tolerated dose in participant with relapsed/refractory acute myeloid leukemia, either all comers as well as harboring isocitrate dehydrogenase (IDH1/IDH2) mutations. Participants participating to the clinical trial will take the study drug as oral capsules once daily for 14 consecutive days over a 21-day treatment cycle.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Acute Myeloid Leukemia

Interventions

MEN1703DRUG

MEN1703 given as oral capsules once daily for 14 consecutive days over a 21-day treatment cycle.

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Participants with diagnosis of AML, all comers or bearing IDH1 or IDH2 mutation (completed) * Participant has no standard therapeutic options available and has either relapsed AML unsuitable for intensive chemotherapy, with no standard therapeutic options and/or not eligible for any approved targeted therapy or primary refractory AML unsuitable for intensive chemotherapy, with no standard therapeutic options and/or not eligible for any approved targeted therapy Exclusion Criteria: * Anti-cancer treatments (including cytotoxic chemotherapy, radiotherapy, hormonal therapy, biologic, immunotherapy or investigational drugs) received within 14 days or 5 half-lives for targeted therapies (whichever is shorter) before first dose of study drug (to be supplemented)

Locations (15)

Northside Hospital

Atlanta, Georgia, United States

Cleveland Clinic, Taussig Cancer Institute

Cleveland, Ohio, United States

Outcomes

Primary Outcomes

Part 1 and Part 2: Number of Participants Experiencing Treatment-emergent Adverse Events

An adverse event (AE) was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a participant or clinical investigation participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavorable and unintended sign (including a clinically significant abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not considered related to the investigational medicinal product. A summary of serious and all other non-serious adverse events regardless of causality is located in the Reported Adverse events module.

Time frame: Up to 21 months

Part 1: Number of Participants Experiencing Dose-limiting Toxicity (DLT)

AEs were graded according to the National Cancer Institute common terminology criteria for adverse events, version 4.03. The following AEs were considered as DLT unless they were clearly and incontrovertibly attributable to the underlying disease or to an extraneous cause: Grade 5 toxicity; Grade 4 neutropenia lasting ≥42 days from the start of the therapy cycle in absence of evidence of active acute myeloid leukemia (AML) (\<5% blasts); Grade 3 or 4 non-hematologic toxicity (with protocol-define exceptions). Only clinically significant abnormalities in laboratory findings, physical examination, vital signs, weight, or electrocardiogram were considered for DLT assessment.

Time frame: Day 1 through Day 21 (first treatment cycle)

Secondary Outcomes

Part 1 and Part 2: Overall Response Rate (ORR)

ORR was defined as the percentage of participants who had a complete remission (CR), complete remission with incomplete hematologic recovery (CRi), complete remission with partial hematologic recovery (CRh), or morphologic leukemia-free state (MLFS) response to therapy.

Time frame: Up to 32 months

Part 1 and Part 2: Partial Remission (PR) Rate

Data from ClinicalTrials.gov

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Oregon Health and Science University

Portland, Oregon, United States

Vanderbilt Ingram Cancer Center

Nashville, Tennessee, United States

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, United States

MD Anderson Cancer Center

Houston, Texas, United States

Fred Hutchinson Cancer Research Center

Seattle, Washington, United States

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori

Meldola, Italy

Istituto Clinico Humanitas

Milan, Italy

ASST Monza - Ospedale San Gerardo

Monza, Italy

...and 5 more locations

PR rate was defined as the percentage of participants who had a partial remission response to therapy.

Time frame: Up to 32 months

Part 1 and Part 2: Duration of Response (DoR)

DoR was defined as the time from the date of first CR, CRi, CRh, CR without minimal residual disease (CRMRD-), MLFS or PR until the date of documented relapse of any type, progressive disease or death due to disease progression for participants who achieve CR, CRi, CRh, CRMRD-, MLFS or PR. Results are reported in days.

Time frame: Up to 32 months

Part 1 and Part 2: Relapse Free Survival (RFS)

RFS was defined as the time from the date of first CR, CRi, CRh, or CRMRD- until the date of documented relapse or death from any cause. Results are reported in days.

Time frame: Up to 32 months

Part 1 and Part 2: Overall Survival (OS)

OS was defined as the number of days between the first study drug administration and death from any cause. Results are reported in days.

Time frame: Up to 32 months

Part 1 and Part 2: Event Free Survival (EFS)

EFS was defined as the time from the date of first study drug intake until the date of documented relapse, treatment failure, or death from any cause. Results are reported in days.

Time frame: Up to 32 months

Part 1 and Part 2: Transfusion Conversion Rate

Transfusion conversion rate was defined as the percentage of participants who were transfusion dependent at baseline but became transfusion independent post-baseline. Participants were classified as baseline transfusion independent if there were no red blood cells (RBC) or platelet transfusions at baseline; otherwise, the participant was considered as baseline transfusion dependent. Participants were classified post-baseline transfusion independent in the event of 56 consecutive days without any RBC or platelet transfusion post-baseline; otherwise, the participant was considered post-baseline transfusion dependent.

Time frame: Up to 21 months

Part 1 and Part 2: Transfusion Maintenance Rate

Transfusion maintenance rate was defined as the percentage of participants who were transfusion independent at baseline and still maintained to be transfusion independent post-baseline. Participants were classified as baseline transfusion independent if there were no RBC or platelet transfusions at baseline; otherwise, the participant was considered as baseline transfusion dependent. Participants were classified post-baseline transfusion independent in the event of 56 consecutive days without any RBC or platelet transfusion post-baseline; otherwise, the participant was considered post-baseline transfusion dependent.

Time frame: Up to 21 months

Part 1 and Part 2: Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Rate

Allogeneic HSCT rate was defined as the percentage of participants undergoing allogeneic stem cell transplant during the study period of each participant.

Time frame: Up to 21 months

Part 1 and Part 2: Percentage of Participants With ≥ 50% Bone Marrow Blast Reduction

Bone marrow aspirates/biopsies were taken at designated timepoints for evaluation of leukemic blast proportion in the bone marrow. A reduction in bone marrow blast proportion indicates increased anti-leukemic activity of the study drug.

Time frame: Up to 20 months

Part 1 and Part 2: Maximum Observed Concentration (Cmax) for MEN1703

Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. Results are reported as nanograms/milliliter (ng/mL). Standard error not reported, arithmetic coefficient of variation (CV%) reported instead.

Time frame: Day 1 and Day 14 of Cycle 1 (pre-dose, up to 120 hours post dose) (21 days/cycle)

Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to the Last Quantifiable Concentration (AUClast) for MEN1703

Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. AUClast was calculated by the linear trapezoidal rule. Results are reported in hour times nanograms/milliliter (h\*ng/mL). Standard error not reported, arithmetic CV% reported instead.

Time frame: Day 1 of Cycle 1 (pre-dose, up to 24 hours post dose) (21 days/cycle)

Part 1 and Part 2: Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours (AUC0-24) for MEN1703

Nominal blood samples were taken at designated timepoints for evaluation of concentration levels of MEN1703 in plasma. AUC0-24 was calculated by the linear trapezoidal rule. Results are reported in h\*ng/mL. Standard error not reported, arithmetic CV% reported instead.

Time frame: Day 14 of Cycle 1 (pre-dose, up to 120 hours post dose) (21 days/cycle)