Description:
The purpose of this study is to evaluate the safety and efficacy of MK-1026 (formerly ARQ
531) in participants with hematologic malignancies of chronic lymphocytic leukemia (CLL)/
small lymphocytic lymphoma (SLL), Richter's transformation, marginal zone lymphoma (MZL),
mantle cell lymphoma (MCL), follicular lymphoma (FL), and Waldenström's macroglobulinemia
(WM).
Title
- Brief Title: Efficacy and Safety of MK-1026 in Participants With Hematologic Malignancies (MK-1026-003)
- Official Title: A Phase 2 Study to Evaluate the Efficacy and Safety of MK-1026 in Participants With Hematologic Malignancies
Clinical Trial IDs
- ORG STUDY ID:
1026-003
- SECONDARY ID:
2020-002324-36
- SECONDARY ID:
MK-1026-003
- NCT ID:
NCT04728893
Conditions
Interventions
| Drug | Synonyms | Arms |
|---|
| MK-1026 | ARQ 531 | MK-1026 |
Purpose
The purpose of this study is to evaluate the safety and efficacy of MK-1026 (formerly ARQ
531) in participants with hematologic malignancies of chronic lymphocytic leukemia (CLL)/
small lymphocytic lymphoma (SLL), Richter's transformation, marginal zone lymphoma (MZL),
mantle cell lymphoma (MCL), follicular lymphoma (FL), and Waldenström's macroglobulinemia
(WM).
Detailed Description
This study will be performed in 2 parts: Dose Escalation and Confirmation (Part 1) and Cohort
Expansion (Part 2). Following determination of a recommended phase 2 dose (RP2D) in Part 1,
the study plans to proceed with Part 2 using 8 disease-specific expansion cohorts (Cohorts A
to H).
Trial Arms
| Name | Type | Description | Interventions |
|---|
| MK-1026 | Experimental | Participants receive MK-1026 orally once daily (QD) until progressive disease (PD) or discontinuation. | |
Eligibility Criteria
Inclusion Criteria:
- Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7
days prior to allocation
- Has a life expectancy of at least 3 months, based on the investigator assessment
- Has the ability to swallow and retain oral medication
- Participants who are Hepatitis B surface antigen (HBsAg)-positive are eligible if they
have received Hepatitis B virus (HBV) antiviral therapy for at least 4 weeks and have
undetectable HBV viral load prior to randomization
- Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV
viral load is undetectable at screening
- Has adequate organ function
- Male participants agree to refrain from donating sperm and agree to either remain
abstinent from heterosexual intercourse as their preferred and usual lifestyle OR
agree to use contraception, during the intervention period and for 12 days after last
dose of study intervention
- Female participants not pregnant or breastfeeding are eligible to participate if not a
woman of childbearing potential (WOCBP), or if a WOCBP they either use a contraceptive
method that is highly effective OR remain abstinent from heterosexual intercourse as
their preferred and usual lifestyle during the intervention period and for at least 30
days after the last dose of study intervention
Part 1 and Part 2 (Cohorts A to C)
- Has a confirmed diagnosis of CLL/SLL
- Has active disease for CLL/SLL clearly documented to initiate therapy
- Has evaluable core or excisional lymph node biopsy for biomarker analysis from an
archival or newly obtained biopsy at Screening (optional for participants
enrolling in Part 1)
Part 2 (Cohorts D to G)
- Has a confirmed diagnosis of and response to previous treatment of one of the
following:
- Participants with Richter's transformation who are relapsed or refractory
following at least 1 line of prior therapy (Cohort D)
- Participants with pathologically confirmed MCL, documented by either
overexpression of cyclin D1 or t(11;14), who are relapsed or are refractory to
chemoimmunotherapy and a covalent irreversible BTK inhibitor (BTKi) (Cohort E)
- Participants with MZL (including splenic, nodal, and extra nodal MZL) who are
relapsed or refractory to chemoimmunotherapy and a covalent irreversible BTKi
(Cohort F)
- Participants with FL who are relapsed or refractory to chemoimmunotherapy,
immunomodulatory agents (i.e. lenalidomide plus rituximab), and a
phosphoinositide 3-kinase inhibitor (PI3Ki) (Cohort G)
- Have measurable disease defined as at least 1 lesion that can be accurately measured
in at least 2 dimensions with spiral CT scan
- Has an evaluable core or excisional lymph node biopsy for biomarker analysis from an
archival or newly obtained biopsy at Screening
Part 2 (Cohort H): confirmed diagnosis of WM; participants who are relapsed or refractory
to chemoimmunotherapy and a covalent irreversible BTKi
- Has active disease defined as1 of the following: systemic symptoms, physical findings,
laboratory abnormalities, coexisting disease
- Has measurable disease, satisfying any of the following: at least 1 lesion that can be
accurately measured in at least 2 dimensions with spiral CT scan (minimum measurement
must be >15 mm in the longest diameter or >10 mm in the short axis); IgM ≥4500 g/dL;
or bone marrow infiltration of 70%
- Has an evaluable core or excisional lymph node biopsy for biomarker analysis from an
archival or newly obtained biopsy at Screening
Exclusion Criteria:
- Has active HBV/HCV infection (Part 1 and Part 2)
- Has a history of malignancy ≤3 years prior to signing informed consent except for
adequately treated basal cell or squamous cell skin cancer or in situ cervical cancer
- Has active central nervous system (CNS) disease
- Has an active infection requiring systemic therapy
- Has a known history of human immunodeficiency virus (HIV) infection
- Has received prior systemic anti-cancer therapy within 4 weeks prior to allocation
- Is currently participating in or has participated in a study of an investigational
agent or has used an investigational device within 4 weeks prior to the first dose of
study intervention
- Has any clinically significant gastrointestinal abnormalities that might alter
absorption
| Maximum Eligible Age: | N/A |
| Minimum Eligible Age: | 18 Years |
| Eligible Gender: | All |
| Healthy Volunteers: | No |
Primary Outcome Measures
| Measure: | Part 1: Number of participants experiencing dose-limiting toxicities (DLTs) |
| Time Frame: | Up to ~56 days (Cycles 1-2, cycle = 28 days) |
| Safety Issue: | |
| Description: | DLTs will be defined as toxicities observed during the first 2 cycles (8 weeks) of Part 1 and include: Grade ≥3 nonhematologic toxicity (except Grade 3 nausea, vomiting, diarrhea, rash, fatigue, and uncontrolled hypertension which will not be considered a DLT unless lasting ≥72 hours despite optimal supportive care); Grade 4 hematologic toxicity lasting >7 days (except Grade 3 lymphocytosis, Grade 4 platelet count decreased of any duration, or Grade 3 platelet count decreased if associated with bleeding); any Grade 3 or Grade 4 nonhematologic laboratory abnormality if values result in drug-induced liver injury, or medical intervention is required, or the abnormality leads to hospitalization, or the abnormality persists for >1 week (with exceptions); missing >25% of MK-1026 doses as a result of drug-related adverse events (AEs) during the first 2 cycles (8 weeks); Grade 5 toxicity. |
Secondary Outcome Measures
| Measure: | Part 1: Area Under the Curve (AUC) of MK-1026 |
| Time Frame: | At designated time points (up to ~57 days) |
| Safety Issue: | |
| Description: | Blood samples will be obtained at designated time points during Part 1 for the assessment of MK-1026 AUC (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose [up to ~57 days]). Each cycle is 28 days. |
| Measure: | Part 1: Minimum Concentration (Cmin) of MK-1026 |
| Time Frame: | At designated time points (up to ~57 days) |
| Safety Issue: | |
| Description: | Blood samples will be obtained at designated time points during Part 1 for the assessment of MK-1026 Cmin (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose [up to ~57 days]). Each cycle is 28 days. |
| Measure: | Part 1: Maximum Concentration (Cmax) of MK-1026 |
| Time Frame: | At designated time points (up to ~57 days) |
| Safety Issue: | |
| Description: | Blood samples will be obtained at designated time points during Part 1 for the assessment of MK-1026 Cmax (Day 1 of Cycles 1 and 2: Pre-dose, 2, 4, 6, 8, and 24 hours post-dose; Day 1 of Cycle 3: pre-dose and 2, 4, and 6 hours post-dose [up to ~57 days]). Each cycle is 28 days. |
| Measure: | Part 1: ORR per iwCLL criteria 2018 as assessed by ICR |
| Time Frame: | Up to ~78 months |
| Safety Issue: | |
| Description: | ORR per iwCLL 2018 criteria is defined as the percentage of participants achieving a CR, CRi, nPR, or PR. CR is defined as meeting the following criteria: no lymph nodes >1.5 cm, spleen size <13 cm, liver normal; no constitutional symptoms, normal lymphocyte count, platelets ≥100 x 10^9/L; hemoglobin ≥11 g/dL; and normocellular marrow (no CLL cells or B lymphoid nodules). CRi is defined as meeting CR criteria but with hypocellular bone marrow. nPR is defined as having features of CR but with lymphoid nodules in the marrow. PR is defined as ≥50% decrease in ≥2 of the following: lymph nodes, liver and/or spleen size, lymphocytes PLUS ≥1 of the following met: platelets ≥100 x 10^9/L or ≥50% increase from screening, hemoglobin >11 g/dL or ≥50% increase from screening, CLL cells or B lymphoid nodules in marrow. |
| Measure: | Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR |
| Time Frame: | Up to ~78 months |
| Safety Issue: | |
| Description: | For participants with CR, CRi, nPR, or PR per iwCLL 2018 criteria, DOR is defined as the time from the first documented evidence of objective response until PD or death due to any cause, whichever occurs first. CR is defined as meeting the following criteria: no lymph nodes >1.5 cm, spleen size <13 cm, liver normal; no constitutional symptoms, normal lymphocyte count, platelets ≥100 x 10^9/L; hemoglobin ≥11 g/dL; and normocellular marrow (no CLL cells or B lymphoid nodules). CRi is defined as meeting CR criteria but with hypocellular bone marrow. nPR is defined as having features of CR but with lymphoid nodules in the marrow. PR is defined as ≥50% decrease in ≥2 of the following: lymph nodes, liver and/or spleen size, lymphocytes PLUS ≥1 of the following met: platelets ≥100 x 10^9/L or ≥50% increase from screening, hemoglobin >11 g/dL or ≥50% increase from screening, CLL cells or B lymphoid nodules in marrow. |
| Measure: | Part 2: Number of participants experiencing AEs |
| Time Frame: | Up to ~78 months |
| Safety Issue: | |
| Description: | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants experiencing AEs will be reported for Part 2. |
| Measure: | Part 2: Number of participants discontinuing study treatment due to AEs |
| Time Frame: | Up to ~78 months |
| Safety Issue: | |
| Description: | An AE is any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. The number of participants discontinuing study treatment due to an AE will be reported for Part 2. |
| Measure: | Part 2: AUC of MK-1026 |
| Time Frame: | At designated time points (up to ~57 days) |
| Safety Issue: | |
| Description: | Blood samples will be obtained at designated time points during Part 2 for the assessment of MK-1026 AUC (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose [up to ~57 days]). Each cycle is 28 days. |
| Measure: | Part 2: Cmin of MK-1026 |
| Time Frame: | At designated time points (up to ~57 days) |
| Safety Issue: | |
| Description: | Blood samples will be obtained at designated time points during Part 2 for the assessment of MK-1026 Cmin (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose [up to ~57 days]). Each cycle is 28 days. |
| Measure: | Part 2: Cmax of MK-1026 |
| Time Frame: | At designated time points (up to ~57 days) |
| Safety Issue: | |
| Description: | Blood samples will be obtained at designated time points during Part 2 for the assessment of MK-1026 Cmax (Day 1 of Cycles 1, 2, and 3: Pre-dose, 2, 4, 6, hours post-dose [up to ~57 days]). Each cycle is 28 days. |
| Measure: | Part 2: DOR per iwCLL criteria 2018 as assessed by ICR |
| Time Frame: | Up to ~78 months |
| Safety Issue: | |
| Description: | For participants with CR, CRi, nPR, or PR per iwCLL 2018 criteria, DOR is defined as the time from the first documented evidence of objective response until disease progression or death due to any cause, whichever occurs first. CR is defined as meeting the following criteria: no lymph nodes >1.5 cm, spleen size <13 cm, liver normal; no constitutional symptoms, normal lymphocyte count, platelets ≥100 x 10^9/L; hemoglobin ≥11 g/dL; and normocellular marrow (no CLL cells or B lymphoid nodules). CRi is defined as meeting CR criteria but with hypocellular bone marrow. nPR is defined as having features of CR but with lymphoid nodules in the marrow. PR is defined as ≥50% decrease in ≥2 of the following: lymph nodes, liver and/or spleen size, lymphocytes PLUS ≥1 of the following met: platelets ≥100 x 10^9/L or ≥50% increase from screening, hemoglobin >11 g/dL or ≥50% increase from screening, CLL cells or B lymphoid nodules in marrow. |
| Measure: | Part 2: DOR per Lugano criteria 2014 as assessed by ICR |
| Time Frame: | Up to ~78 months |
| Safety Issue: | |
| Description: | For participants with CR or PR per Lugano criteria 2014, DOR is defined as the time from the first documented evidence of objective response until PD or death due to any cause, whichever occurs first. CR defined as EITHER CR by imaging (CT): all lymph nodes normal (none ≥15 mm) and normal liver and spleen OR CMR: score of 1, 2 or 3 on the 5-point scale assessing FDG metabolic activity in lymphomatous lesions (ranging from 1=no uptake above background to 5=uptake markedly higher than liver and/or new lesions) AND BM normal by morphology. PR defined as EITHER PR by imaging (CT) with ≥50% decrease in the SPD of target lesions, no worsening of nontarget lesions, no new lesions and ≥50% spleen abnormal portion OR PMR with score of 4 or 5 on the FDG 5-point scale (with no new lesions) and decreased overall uptake AND residual BM abnormalities; OR CR by imaging with residual BM abnormalities; OR PR by imaging without residual BM abnormalities. |
| Measure: | Part 2: DOR per IWWM criteria 2014 as assessed by ICR |
| Time Frame: | Up to ~78 months |
| Safety Issue: | |
| Description: | For participants with CR, VGPR, or PR per IWWM criteria 2014, DOR defined as the time from first documented evidence of objective response until PD or death due to any cause, whichever occurs first. CR defined as all lymph nodes normal in size (none ≥15 mm), liver and spleen normal in size, serum IgM values in normal range, disappearance of monoclonal protein by immunofixation (confirmation needed with second immunofixation at any subsequent timepoint), and no histological evidence of BM involvement. VGPR defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in abnormal portion of the spleen (if previously abnormal), and ≥90% decrease from baseline in serum IgM, or serum IgM values in normal range. PR is defined as ≥50% decrease from baseline in SPD of lymph nodes (if abnormal at baseline), ≥50% decrease from baseline in serum IgM, and ≥50% decrease from baseline in abnormal portion of the spleen (if previously abnormal). |
Details
| Phase: | Phase 2 |
| Primary Purpose: | Interventional |
| Overall Status: | Recruiting |
| Lead Sponsor: | Merck Sharp & Dohme Corp. |
Last Updated
August 26, 2021
