| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated | |
| E.1.1.1 | Medical condition in easily understood language |
| B cell malignancies: Chronic lymphocytic leukemia/Small lymphocytic lymphoma; Richters transformation; Mantle cell lymphoma, Marginal zone lymphoma; Follicular lymphoma; Waldenstroms macroglobulinemia |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003899 |
| E.1.2 | Term | B-cell lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10026798 |
| E.1.2 | Term | Mantle cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10054693 |
| E.1.2 | Term | Von Waldenstrom macroglobulinemia |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10076596 |
| E.1.2 | Term | Marginal zone lymphoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
1. Part 1: To determine the safety and tolerability and to establish a recommended Phase 2 dose (RP2D) of MK-1026.
2. Part 2: Cohorts A to C (chronic Lymphocytic Leukemia [CLL]/Small Lymphocytic Lymphoma [SLL]): To evaluate the objective response rate (ORR) following administration with MK-1026 per International Workshop on CLL (iwCLL) criteria 2018 as assessed by independent central review (ICR).
3. Part 2: Cohorts D to G (Richter’s Transformation [RT], Mantle cell Lymphoma [MCL], Marginal zone Lymphoma [MZL], Follicular Lymphoma [FL]): To evaluate the ORR following administration with MK-1026 per the Lugano criteria 2014 as assessed by ICR.
4. Part 2: Cohort H (Waldenström’s Macroglobulinemia [WM]): To evaluate the ORR following administration with MK-1026 per International Workshop on WM (IWWM) 2014 as assessed by ICR.
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| E.2.2 | Secondary objectives of the trial |
1. Part 1: To characterize the pharmacokinetic (PK) profile of MK-1026.
2. Part 1: To evaluate the ORR and duration of response (DOR) following administration with MK-1026 for CLL/SLL participants per iwCLL criteria 2018 as assessed by ICR.
3. Part 2: All Cohorts: To determine the safety and tolerability of MK-1026.
4. Part 2: All Cohorts: To characterize the PK profile of MK-1026.
5. Part 2: Cohorts A to C (CLL/SLL): To evaluate DOR following administration with MK-1026 per iwCLL criteria 2018 as assessed by ICR.
6. Pt 2: Cohorts D to G (RT, MCL, MZL, FL): To evaluate the DOR following administration with MK-1026 per the Lugano criteria 2014 as assessed by ICR.
7. Part 2: Cohort H (WM): To evaluate the DOR of MK-1026 per IWWM 2014 as assessed by ICR
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 the investigator assessment.
6. Have the ability to swallow and retain oral medication.
7. Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization.
8. Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening.
9. Have adequate organ function as defined in Table 7. Specimens must be collected within 7 days prior to the start of study intervention.
10. Is male or female, from 18 years of age inclusive, at the time of signing the informed consent.
11. Male participants are eligible to participate if they agree to the following during the intervention period and for 12 days after the last dose of study intervention:
- Be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent. OR
- Must agree to use contraception unless confirmed to be azoospermic.
12. A female participant is eligible to participate if she is not pregnant or breastfeeding, and:
- Is not a WOCBP
OR
- Is a WOCBP and using a contraceptive method that is highly effective
13. Signed written informed consent granted prior to initiation of any study-specific procedures (or legally acceptable representative if applicable).
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| E.4 | Principal 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.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
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 (Cohorts A to C): Objective Response Rate (ORR) per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria 2018 as assessed by independent central review (ICR)
5. Part 2 (Cohorts D to G): ORR per Lugano criteria 2014 as assessed by ICR
6. Part 2 (Cohort H): ORR per International Workshop on Waldenström’s Macroglobulinemia (IWWM) 2014 as assessed by ICR
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|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to ~56 days (Cycles 1-2, cycle = 28 days)
2. Up to ~78 months
3. Up to ~ 78 months
4. Up to ~ 78 months
5. Up to ~ 78 months
6. Up to ~ 78 months |
|
| E.5.2 | Secondary end point(s) |
1. Part. 1: Area Under the Curve (AUC) of MK-1026
2. Part. 1: Minimum Concentration (Cmin) of MK-1026
3. Part 1: Maximum Concentration (Cmax) of MK-1026
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 (All Cohorts): Number of participants experiencing AEs
7. Part 2 (All Cohorts): Number of participants discontinuing study treatment due to AEs
8. Part. 2 (All Cohorts): AUC of MK-1026
9. Part. 2 (All Cohorts): Cmin of MK-1026
10. Part 2 (All Cohorts): Cmax of MK-1026
11. Part 2 (Cohorts A to C): DOR per iwCLL criteria 2018 as assessed by ICR
12. Part 2 (Cohorts D to G): DOR per Lugano criteria 2014 as assessed by ICR
13. Part 2 (Cohort H): DOR per IWWM 2014 as assessed by ICR
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. At designated time points (up to ~57 days)
2. At designated time points (up to ~57 days)
3. At designated time points (up to ~57 days)
4. Up to ~78 months
5. Up to ~78 months
6. Up to ~78 months
7. Up to ~78 months
8. At designated time points (up to ~57 days)
9. At designated time points (up to ~57 days)
10. At designated time points (up to ~57 days)
11. Up to ~78 months
12. Up to ~78 months
13. Up to ~78 months
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 41 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Brazil |
| Canada |
| Colombia |
| Israel |
| Korea, Republic of |
| Russian Federation |
| Turkey |
| Ukraine |
| United States |
| Czechia |
| Denmark |
| France |
| Germany |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Portugal |
| Romania |
| Spain |
| Sweden |
| Switzerland |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
LVLS - The overall study ends when the last participant completes the last study-related telephone-call or visit, withdraws
from the study, or is lost to follow-up (ie, the participant is unable to be contacted by the investigator). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 1 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 1 |
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