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

Phase 1

• Conditions: B cell malignancies: Chronic lymphocytic leukemia/Small lymphocytic lymphoma; Richters transformation; Mantle cell lymphoma, Marginal zone lymphoma; Follicular lymphoma; Waldenstroms macroglobulinemia; MedDRA version: 20.0Level: PTClassification code 10003899Term: B-cell lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 21.0Level: LLTClassification code 10008976Term: Chronic lymphocytic leukemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: HLTClassification code 10026798Term: Mantle cell lymphomasSystem Organ Class: 100000004851; MedDRA version: 21.1Level: LLTClassification code 10054693Term: Von Waldenstrom macroglobulinemiaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: PTClassification code 10076596Term: Marginal zone lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

• Registration Number: EUCTR2020-002324-36-IT
• Lead Sponsor: MERCK SHARP & DOHME CORP. UNA SUSSIDIARIA DI MERCK & CO. INC.

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Results First Posted: 1900-01-01
• Study Start: 2021-05-20
• Last Update Posted: 24 August 2021

Recruitment & Eligibility

• Status: Authorised-recruitment may be ongoing or finished
• Sex: All
• Target Recruitment: 400

Inclusion Criteria

1. In Part 1 and Part 2 (Cohorts A to C) has a confirmed diagnosis of CLL/SLL with;
• A response to previous treatment of
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 BTKi, BCL2i and PI3Ki.
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 naïve.
o Part 2 Cohort C: CLL/SLL participants with 17p deletion who are relapsed or refractory following at least 1 line of prior therapy.
• Active disease for CLL/SLL clearly documented to initiate therapy.
• Provision of an evaluable core or excisional lymph node biopsy for biomarker analysis from an archival (<=60 days relative to the date of sample submission to the central laboratory) or newly obtained biopsy at Screening.
2. Part 2 (Cohorts D to G):
• Has a confirmed diagnosis of and response to previous treatment of one of the following:
o Cohort D: participants with Richter’s transformation who are relapsed or refractory following at least 1 line of prior therapy.
o Cohort E: 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 BTKi.
o Cohort F: participants with MZL (including splenic, nodal, and extra nodal MZL) who are relapsed or refractory to chemoimmunotherapy and a covalent irreversible BTKi.
o Cohort G: participants with FL who are relapsed or refractory to chemoimmunotherapy, immunomodulatory agents (i.e. lenalidomide +
rituximab), and a PI3Ki.
• Have measurable disease defined as at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral CT scan. A minimum measurement must be >15 mm in the longest diameter or >10 mm in the short axis.
• Provide an evaluable core or excisional lymph node biopsy for biomarker analysis from an archival (<=60 days relative to the date of sample submission to the central laboratory) or newly obtained biopsy at Screening.
3. Part 2 (Cohort H): confirmed diagnosis of WM; participants who are relapsed or refractory to chemoimmunotherapy and a covalent irreversible BTKi.
• Active disease is defined as 1 of the following:
o Systemic symptoms – Fever, drenching night sweats, fatigue, weight loss, and/or severe neuropathy.
o Physical findings – Symptomatic or bulky (>=5 cm) lymphadenopathy, symptomatic hepatomegaly, and/or symptomatic splenomegaly.
o Laboratory abnormalities – Hemoglobin <=10 g/dL or platelet count <100,000/microL.
o Coexisting disease – Immunoglobulin light chain amyloidosis with organ dysfunction, symptomatic cryoglobulinemia, cold agglutinin anemia, immune hemolytic anemia and/or thrombocytopenia, or nephropathy due to WM.
• Have 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%.
• Provide an evaluable core or excisional lymph node biopsy for biomarker analysis from an archival (<=60 days relative to the date of sample submission to the central laboratory) or newly obtained biopsy at Screening.
4. Have an ECOG performance status of 0 to 2 within 7 days prior to allocation.
5. Have a life expectancy of at least 3 months, based on

Exclusion Criteria

1. Part 1 and Part 2 participants: active HBV/HCV infection. See Inclusion Criteria 7 (HBV) and 8 (HCV) for requirements.
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.
3. Has active CNS disease.
4. Has an active infection requiring systemic therapy.
5. Has a known history of HIV infection. No HIV testing is required unless mandated by local health authority.
6. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the participant's participation for the full duration of the study, or is not in the best interest of the participant to participate, in the opinion of the treating investigator.
7. Has QTc prolongation (defined as a QTcF >450 msecs) or other significant ECG abnormalities including 2nd degree AV block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
8. Has received prior systemic anti-cancer therapy within 4 weeks prior to allocation.
9. Is currently being treated with the following drugs:
•CYP 2C9 substrates with a narrow therapeutic index (such as warfarin, phenytoin)
•CYP 2C8 substrates with a narrow therapeutic index (such as paclitaxel)
•CYP 2C19 substrates with a narrow therapeutic index (such as S-mephenytoin)
•CYP 2D6 substrates with a narrow therapeutic index (such as thioridazine, pimozide)
•P-gp substrates with a narrow therapeutic index (such as digoxin)
10. 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.
11. Prior exposure to non-covalent, reversible BTK inhibitors.
12. Has a known psychiatric or substance abuse disorder that would interfere with the participant’s ability to cooperate with the requirements of the study.
13. Has any clinically significant gastrointestinal abnormalities that might alter absorption.

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified