| 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 the RP2D of nemtabrutinib.
2. Part 2: Cohorts A to C (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 International Workshop on WM (IWWM) 2014 as assessed by ICR. |
|
| E.2.2 | Secondary objectives of the trial |
1. Part 1 and Part 2 (Cohorts A to H): To characterize the 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 (CLL/SLL): To evaluate DOR following administration with nemtabrutinib per iwCLL criteria 2018 as assessed by ICR.
5. Pt 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 |
|
| 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:
-At least 2 lines of prior therapy (Part 1 only)
-Part 2 Cohort A: CLL/SLL participants who are relapsed or refractory to prior therapy with a covalent, irreversible BTKi and a BCL2i. CLL participants must have received and failed, been intolerant to, or determined by their treating physician to be a poor PI3Ki candidate or ineligible for a PI3Ki per local (institution) guidelines
-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
-Part 2 Cohort C: CLL/SLL participants with 17p deletion or TP53 mutation (as determined locally) who are relapsed or refractory following at least 1 line of prior therapy
-Active disease for CLL/SLL clearly documented to initiate therapy
-For SLL participants in Part 2: Participants with lymphoma must provide a lymph node biopsy for biomarker analysis from an archival or newly obtained lymph node biopsy or bone marrow aspirate at Screening
2.Part 2 (Cohorts D to G):
-Has a confirmed diagnosis of and response to previous treatment of one of the following:
*Cohort D:participants with RT who are relapsed or refractory following at least 1 line of prior therapy
*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
*Cohort F: participants with MZL (including splenic, nodal, and extranodal MZL) who are relapsed or refractory to chemoimmunotherapy and a covalent irreversible BTKi
*Cohort G: participants with FL who are relapsed or refractory to chemoimmunotherapy, and immunomodulatory agents (i.e. lenalidomide + rituximab)
-Have measurable disease defined as at least 1 lesion that can be accurately measured in at least 2 dimensions with spiral CT scan.
-Provide lymph node biopsy for biomarker analysis from an archival or newly obtained lymph node biopsy at Screening. Cohort D can also submit bone marrow aspirate
3.Part 2 (Cohort H): confirmed diagnosis of WM; participants who are relapsed or refractory to standard therapies for WM including chemoimmunotherapy and a covalent irreversible BTKi
-Active disease is defined as 1 of the following:
*Systemic symptoms – Fever, drenching night sweats, fatigue, weight loss, and/or severe neuropathy
*Physical findings – Symptomatic or bulky (≥5 cm) lymphadenopathy, symptomatic hepatomegaly, and/or symptomatic splenomegaly
*Laboratory abnormalities – Hemoglobin ≤10 g/dL or platelet count <100,000/µL
*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 ≥450 mg/dL; or bone marrow infiltration of 10%
-Provide a fresh bone marrow aspirate for biomarker analysis at Screening. A lymph node biopsy from an archival or newly obtained lymph node biopsy at screening is also acceptable
4.Have an ECOG performance status of 0 to 2 within 7 days before allocation
5.Have a life expectancy of at least 3 months, based on the investigator assessment(all cohorts except D [RT])
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 before randomization
8.Participants with history of HCV infection are eligible if HCV viral load is undetectable at screening
9. Have adequate organ function
10.Is an individual of any sex/ gender, 18 years of age or older at the time of providing documented informed consent
11.If capable of producing sperm, the participant agrees to the following during the intervention period and for at least the time needed to eliminate the study intervention after the last dose:
-Abstains from penile-vaginal intercourse as their preferred and usual lifestyle and agrees to remain abstinent
OR
-Uses contraception unless confirmed to be azoospermic
12.A participant assigned female sex at birth is eligible to participate if not pregnant or breastfeeding, and:
-Is not a POCBP
OR
-Is a POCBP and uses a contraceptive method that is highly effective
13.Documented informed consent granted before initiation of any study-specific procedures
14.Participants with HIV are eligible if they meet ALL of the following criteria:
- The CD4 count is >350 cells/µL at screening
- The HIV viral load is below the detectable level
- Are on a stable ART regimen for at least 4 weeks before study entry
- Are compliant with their ART |
|
| 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 before providing documented informed consent.
3. Has active CNS disease.
4. Has an active infection requiring systemic therapy.
5. Exclusion criterion removed.
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 msec) or other significant ECG abnormalities including second degree AV block type II, third degree AV block, or bradycardia (ventricular rate less than 50 beats/min).
8. Has received prior systemic anticancer therapy within 5 half-lives or 4 weeks (if prior therapy was a monoclonal antibody) before allocation.
9. Currently being treated with the following drugs:
-P-gp substrates with a narrow therapeutic index
-CYP3A strong inducers
-CYP3A strong inhibitors
10. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks before the first dose of study intervention.
11. Prior exposure to noncovalent, 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.
14. Has a known severe hypersensitivity (≥Grade 3) to nemtabrutinib, its active substance and/or any of its excipients. Refer to the IB for a list of excipients.
15. History of severe bleeding disorders |
|
| 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: 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) criteria 2014 as assessed by ICR |
|
| 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 ~34months
3. Up to ~ 34months
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 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 |
|
| 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 ~34months
5. Up to ~34months
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 |
|
| 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 | No |
| 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 | 53 |
| 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 |
| Switzerland |
| Ukraine |
| Australia |
| Brazil |
| Canada |
| China |
| Israel |
| Korea, Republic of |
| Russian Federation |
| Turkey |
| United Kingdom |
| United States |
| Czechia |
| Denmark |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Poland |
| Romania |
| Spain |
|
| 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
|
| The overall study ends when the last participant completes the last study-related contact, withdraws consent, or is lost to follow-up. For purposes of analysis and reporting, the overall study ends when the Sponsor receives the last laboratory test result or at the time of final contact with the last participant, whichever comes last. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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