A Phase 2 Study to Evaluate the Efficacy and Safety of MK-1026 in Participants with Hematologic Malignancies

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Merck Sharp & Dohme LLC

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

6 Apr 2021 → ongoing

Decision date (initial)

2023-12-15

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Merck Sharp & Dohme LLC

External identifiers

EU CT number

2023-504931-42-00

EudraCT number

2020-002324-36

WHO UTN

U1111-1290-4004

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacogenomic, Dose response, Therapy, Pharmacokinetic, Pharmacogenetic, Pharmacodynamic, Safety

1. Part 1: To determine the safety and tolerability and to establish the RP2D of nemtabrutinib

2. Part 2: Cohorts A to C and J (CLL/ SLL): To evaluate the ORR following administration with nemtabrutinib per iwCLL criteria 2018 as assessed by ICR

3. Part 2: Cohorts D to G (RT, MCL, MZL, FL): To evaluate the ORR following administration with nemtabrutinib per the Lugano criteria 2014 as assessed by ICR

4. Part 2: Cohort H (WM): To evaluate the ORR following administration with nemtabrutinib per IWWM 2014 as assessed by ICR

Secondary objectives 6

1. Part 1 and Part 2 (Cohorts A to H and J): To characterize PK profile of nemtabrutinib
2. Part 1: To evaluate the ORR and DOR following administration with nemtabrutinib for CLL/SLL participants per iwCLL criteria 2018 as assessed by ICR
3. Part 2: All Cohorts: To determine the safety and tolerability of nemtabrutinib
4. Part 2: Cohorts A to C and J (CLL/SLL): To evaluate DOR following administration with nemtabrutinib per iwCLL criteria 2018 as assessed by ICR
5. Part 2: Cohorts D to G (RT, MCL, MZL, FL): To evaluate the DOR following administration with nemtabrutinib per the Lugano criteria 2014 as assessed by ICR
6. Part 2: Cohort H (WM): To evaluate the DOR of nemtabrutinib per IWWM 2014 as assessed by ICR

Conditions and MedDRA coding

Chronic lymphocytic leukemia/Small lymphocytic lymphoma; Richters transformation; Mantle cell lymphoma, Marginal zone lymphoma; Follicular lymphoma; Waldenström’s macroglobulinemia

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 within 7 days before C1D1
2. Has a life expectancy of at least 3 months, based on the investigator assessment
3. Has the ability to swallow and retain oral medication
4. 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
5. Participants with history of Hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening
6. Has adequate organ function
7. Male participants agree to refrain from donating sperm and agree to either remain abstinent from penile-vaginal intercourse as their preferred and usual lifestyle OR agree to use contraception, during the intervention period and for at least the time required to eliminate the study intervention after last dose of study intervention
8. Female participants assigned female sex at birth who are not pregnant or breastfeeding are eligible to participate if not a participant of childbearing potential (POCBP), or if a POCBP they either use a contraceptive method that is highly effective OR remain abstinent from penile-vaginal intercourse as their preferred and usual lifestyle during the intervention period and for at least to eliminate the study intervention after the last dose of study intervention
9. Participants with human immunodeficiency virus (HIV) are eligible if they meet all of the following: the cluster of differentiation 4+ (CD4) count is >350 cells/uL at screening, the HIV viral load is below the detectable level, are on a stable antiretroviral therapy (ART) regimen for at least 4 weeks prior to study entry, and are compliant with their ART
10. Part 1 and Part 2 (Cohorts A to C and J) • Has a confirmed diagnosis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) with o At least 2 lines of prior therapy (Part 1 only) o Part 2 Cohort A: CLL/SLL participants who are relapsed or refractory to prior therapy with a covalent, irreversible Bruton's tyrosine kinase inhibitor (BTKi), and a B-cell lymphoma 2 inhibitor (BCL2i). CLL participants must have received and failed, been intolerant to, or determined by their treating physician to be a poor phosphoinositide 3-kinase inhibitor (PI3Ki) candidate or ineligible for a PI3Ki per local guidelines o Part 2 Cohort B: CLL/SLL participants who are relapsed or refractory following at least 1 line of prior therapy and are BTKi treatment naive o Part 2 Cohort C: CLL/SLL participants with 17p deletion or tumor protein p53 (TP53) mutation who are relapsed or refractory following at least 1 line of prior therapy o Part 2 Cohort J: CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi and BCL2i. NOTE: As of Protocol Amendment 09, at least 10 CLL/SLL participants whose disease relapsed or was refractory to prior therapy with a covalent/irreversible BTKi, BCL2i and noncovalent/reversible BTKi (all three classes of therapies are required) will be enrolled into Cohort J. o Has active disease for CLL/SLL clearly documented to initiate therapy o For SLL participants in Part 2: Has evaluable core or excisional lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy or bone marrow aspirate at Screening (optional for participants enrolling in Part 1)
11. Part 2 (Cohorts D to G) • Has a confirmed diagnosis of and meets the following prior therapy requirements: o Participants with Richter's transformation who are relapsed or refractory following at least 1 line of prior therapy (Cohort D) o Participants with pathologically confirmed mantle-cell lymphoma (MCL), documented by either overexpression of cyclin D1 or t(11;14), who are relapsed or are refractory to chemoimmunotherapy and a covalent irreversible BTKi (Cohort E) o Participants with marginal zone lymphoma (MZL) (including splenic, nodal, and extra nodal MZL) who are relapsed or refractory to at least one prior line of systemic therapy including an anti-CD20-based regimen. (Cohort F) o Participants with follicular lymphoma (FL) who are relapsed or refractory to chemoimmunotherapy and immunomodulatory agents (such as lenalidomide based regimen) (Cohort G)Have measurable disease defined as at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral computed tomography (CT) scan o Has a lymph node biopsy for biomarker analysis from an archival or newly obtained biopsy or bone marrow aspirate (Cohort D) at Screening
12. Part 2 (Cohort H): confirmed diagnosis of Waldenström’s macroglobulinemia (WM); participants who are relapsed or refractory to standard therapies for WM including chemoimmunotherapy and a covalent irreversible BTKi • Has active disease defined as 1 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); immunoglobulin M (IgM) ≥450 mg/dL; or bone marrow infiltration of 10% • Has fresh bone marrow aspirate or a lymph node biopsy for biomarker analysis at Screening or a lymph node biopsy from an archival

Exclusion criteria 8

1. Has active HBV/HCV infection (Part 1 and Part 2)
2. Has a history of malignancy ≤3 years before providing documented informed consent. Participants with basal cell carcinoma of skin, squamous cell carcinoma of skin, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potential curative therapy are not excluded. Participants with low-risk, early-stage prostate cancer (T1-T2a, Gleason score ≤6, and prostate-specific antigen <10 ng/mL) either treated with definitive intent or untreated in active surveillance with stable disease (SD) are not excluded
3. Has active central nervous system (CNS) disease
4. Has an active infection requiring systemic therapy
5. Has received prior systemic anti-cancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before C1D1
6. 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
7. Has any clinically significant gastrointestinal abnormalities that might alter absorption
8. History of severe bleeding disorders

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 6

1. Part 1: Number of participants experiencing dose-limiting toxicities (DLTs)
2. Part 1: Number of participants experiencing adverse events (AEs)
3. Part 1: Number of participants discontinuing study treatment due to AEs
4. Part 2: Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR)
5. Part 2: ORR per Lugano criteria 2014 as assessed by ICR
6. Part 2: ORR per International Workshop on Waldenström’s Macroglobulinemia (IWWM) criteria 2014 as assessed by ICR

Secondary endpoints 13

1. Part 1: Area Under the Curve (AUC) of nemtabrutinib
2. Part 1: Minimum Concentration (Cmin) of nemtabrutinib
3. Part 1: Maximum Concentration (Cmax) of nemtabrutinib
4. Part 1: ORR per iwCLL criteria 2018 as assessed by ICR
5. Part 1: Duration of Response (DOR) per iwCLL criteria 2018 as assessed by ICR
6. Part 2: Number of participants experiencing AEs
7. Part 2: Number of participants discontinuing study treatment due to AEs
8. Part 2: AUC of nemtabrutinib
9. Part 2: Cmin of nemtabrutinib
10. Part 2: Cmax of nemtabrutinib
11. Part 2: DOR per iwCLL criteria 2018 as assessed by ICR
12. Part 2: DOR per Lugano criteria 2014 as assessed by ICR
13. Part 2: DOR per IWWM criteria 2014 as assessed by ICR

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 4

Auxiliary 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Merck Sharp & Dohme LLC

Sponsor organisation

Merck Sharp & Dohme LLC

Address

126 East Lincoln Avenue

City

Rahway

Postcode

07065-4607

Country

United States

Scientific contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Jing Yang

Public contact point

Organisation

Merck Sharp & Dohme LLC

Contact name

Jing Yang

Third parties 7

Locations

10 EU/EEA countries · 39 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 104 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

11 submissions — initial application plus substantial / non-substantial modifications