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Chronic Lymphocytic Leukemia

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Ibrutinib

Tyrosine Kinase Inhibitors

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Tyrosine

Open-label administration of SNX-5422 capsules dosed in the morning once every other day for 21 days (11 doses) followed by a 7 day drug free period and daily with the established ibrutinib dose for 28 days of a 28-days cycle. Subjects will repeat the 28-day schedule for 2 cycles after a CR or until the cancer progresses or the subject is unable to tolerate the therapy

SNX-5422 capsule(s) dosed every other day for 21 days out of a 28-day treatment cycle to a total dose of 56 mg/m2 SNX-5422. Subjects will self-administer daily oral ibrutinib in the afternoon at least 8 hours apart from SNX-5422 for 28 days of each cycle.

SNX-5422 plus ibrutinib

SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in subjects who have residual disease, but have not progressed on ibrutinib after 18 months of monotherapy, and/or prevents or delays disease progression of subjects with CLL.

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults and is not considered curable outside of allogeneic stem cell transplantation. Significant advances have been made in the therapy, notably with the introduction of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib.

While response to ibrutinib has been high with therapy well-tolerated overall, some patients have relapsed while others have been taken off therapy for toxicity or other reasons. In addition, although remissions are durable in many patients, very few patients achieve a complete response (CR), and minimal residual disease (MRD) negativity on single agent ibrutinib has not been reported. Since it is known that for chemoimmunotherapy as well as targeted therapies such as venetoclax that attainment of a CR is associated with longer progression free survival (PFS), it is likely that deepening responses associated with ibrutinib will result in more durable remissions.

Relapse in CLL can be mediated by at least two separate mechanisms. One is by mutations in BTK, the other is through a variety of mutations in the immediate downstream target of BTK, PLCγ2. SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will provide clinical response in subjects who have residual disease, but have not progressed on ibrutinib after 18 months of monotherapy.

Subjects will receive SNX-5422 (56 mg/m2) in the morning once every other day for 21 days (11 doses), followed by a 7-day drug-free period. Subjects will continue to receive daily oral ibrutinib at their established dose level in the afternoon

Efficacy and Safety of SNX-5422 Added to an Established Dose of Ibrutinib in CLL

A Phase 1, Open-label Study of SNX-5422 Added to Ibrutinib in Chronic Lymphocytic Leukemia Subjects With Residual Disease

Change from baseline in percent of CLL cells with Bruton's Tyrosine Kinase mutations at the end of 6 and 12 treatment cycles

Proportion of subjects obtaining a complete response at the end of 6 SNX-5422 treatment cycles

Proportion of subjects obtaining improvement in clinical status (i.e., Stable Disease becoming Partial Response) at the end of 6 SNX-5422 treatment cycles

Elapsed time for each subject from randomization to continued survival up to 52 weeks

Esanex Inc.

Open-label administration of SNX-5422 capsules dosed in the morning once every other day for 21 days (11 doses) followed by a 7 day drug free period and daily with the established ibrutinib dose for 28 days of a 28-days cycle. Subjects will repeat the 28-day schedule until the cancer progresses or the subject is unable to tolerate the therapy

SNX-5422 is a prodrug of SNX-2112, a potent, highly selective, small molecule inhibitor of the molecular chaperone heat shock protein 90 (HSP90). Hsp90 inhibitors may overcome ibrutinib resistance in Mantle cell lymphomas and this study will investigate whether the addition of SNX-5422 to an established dose of ibrutinib will result in the removal of mutated BTK from blood mononuclear cells and/or prevents or delays disease progression of subjects with CLL

Chronic lymphocytic leukemia (CLL) is the most prevalent leukemia in adults and is not considered curable outside of allogeneic stem cell transplantation.

BTK is a critical kinase in the B cell receptor signaling pathway. This pathway is amplified in CLL and results in amplification of proliferation and anti-apoptotic signals. By inhibiting BTK, ibrutinib eliminates the activation of these pro-survival pathways and microenvironment survival signals. While response to ibrutinib has been high with therapy well-tolerated overall, some patients have relapsed while others have been taken off therapy for toxicity or other reasons. Relapse in CLL can be mediated by at least two separate mechanisms. One is by mutations in BTK, which both decrease ibrutinib's affinity for BTK, and also changes the binding from irreversible to reversible. This is a proof of concept study to investigate whether the addition of SNX-5422 to an established dose of ibrutinib will reduce mutated BTK from CLL cells and/or prevents or delays disease progression of subjects with CLL.

This is an open-label study of SNX-5422 combined with ibrutinib. In each 28 day cycle, SNX-5422 will be dosed in the morning once every other day for 21 days, followed by a 7-day drug-free period. Subjects will continue to receive daily oral ibrutinib at their established dose level in the afternoon every day for 28 days. cycle

Safety and Activity of SNX-5422 Plus Ibrutinib in CLL

A Phase 1, Open-label Study of SNX-5422 and Ibrutinib in Chronic Lymphocytic Leukemia Subjects With a Mutation in Bruton's Tyrosine Kinase

Change in percent of mutated BTK in CLL cells

Elapsed time for each subject from randomization to relapse of disease up to 52 weeks

Absolute values and changes from baseline for each subject using standard clinical chemistry, hematology and urinalysis parameters

Digital 12-lead ECG using standard recording methods at trough drug levels. All ECG recordings will be analyzed for PR, RR, QT intervals, and for morphology.

Lymphoma

Neoplasms by Histologic Type

Lymphoproliferative Disorders

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Immunoproliferative Disorders

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Leukemia, B-Cell

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Antineoplastic Agents

Antirheumatic Agents

Venetoclax

Rituximab

Antineoplastic Agents, Immunological

Immunologic Factors

Participants will receive nemtrabrutinib oral tablets at specified doses daily starting at Cycle 1 Day 1 (C1D1) and venetoclax oral tablets at doses of 20 mg up to 400 mg daily starting at Cycle 2 Day 1 (C2D1) up to 2 years post C2D1 or until progressive disease (PD) or discontinuation. A cycle = 4 weeks.

Participants will receive venetoclax oral tablets at doses from 20 mg up to 400 mg daily starting at C1D1 on 4-week cycles up to 2 years and rituximab or biosimilar at 375 mg/m\^2 up to 500 mg/m2 intravenous infusion once per 28-day cycle starting at C2D1, for 6 total cycles. Treatment will continue until progressive disease (PD) or discontinuation.

Nemtabrutinib

100 mg/10 mL, 500 mg/50 mL (10 mg/mL) IV Infusion

Toll Free Number

Study Coordinator

Medical Director

The purpose of this study is to assess the safety and tolerability and to confirm the dose of nemtabrutinib in combination with venetoclax in participants with R/R CLL/SLL. The primary study hypotheses are that the combination of nemtabrutinib plus venetoclax is superior to VR with respect to progression-free survival (PFS) per 2018 International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria as assessed by blinded independent central review (BICR).

In Part 1, Dose Confirmation will be determined by modified toxicity probability interval (mTPI) design, where participants will be assigned to two treatment groups, Nemtabrutinib + Venetoclax in parallel with Nemtabrutinib + Venetoclax. Part 2 will be an Efficacy Expansion where all participants will be randomized 1:1 to Nemtabrutinib Part 1 Dose Selection plus Venetoclax or Venetoclax plus Rituximab (VR) (or Rituximab biosimilar) for the duration of the study.

A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010)

A Phase 3, Open-label, Randomized Study to Compare the Efficacy and Safety of Nemtabrutinib (MK-1026) Plus Venetoclax Versus Venetoclax Plus Rituximab in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Following at Least 1 Prior Therapy (BELLWAVE-010)

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

DLT evaluation period is defined as 8 weeks after the first dose of the combination treatment of nemtabrutinib plus venetoclax Cycle 2 Day 1 in Part 1 + 4 weeks follow up. Each cycle is 4 weeks. DLTs are: 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 nemtabrutinib or venetoclax doses as a result of drug-related adverse events during the first 2 cycles; Grade 5 toxicity.

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 1.

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 AEs will be reported for Part 1.

PFS is defined as the time from randomization to the first documented disease progression per iwCLL criteria 2018 as accessed by BICR, or death due to any cause, whichever occurs first. PFS will be presented.

Undetectable MRD, defined as \<1 leukemic cell per 10,000 cells (MRD \<10-4) in bone marrow. The MRD rate will be presented.

OS, defined as the time from randomization to death due to any cause. OS will be presented.

OR, defined as complete response/remission (CR), complete response with incomplete count recovery (CRi), nodular partial remission (nPR), or partial remission (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. ORR will be presented.

DOR, defined as the time from the first documented evidence of CR, CRi, nPR, or PR that led to 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. DOR will be presented.

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.

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 AEs will be reported for Part 2.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Efficacy and Safety of SNX-5422 Added to an Established Dose of Ibrutinib in CLL	NCT02973399	Cancer	SNX-5422 plus i...	18 Years -	Esanex Inc.
Efficacy and Safety of SNX-5422 Added to an Established Dose of Ibrutinib in CLL	NCT02973399	Cancer	SNX-5422 plus i...	18 Years -	Esanex Inc.
Safety and Activity of SNX-5422 Plus Ibrutinib in CLL	NCT02914327	Cancer	SNX-5422 plus i...	18 Years -	Esanex Inc.
A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010)	NCT05947851	Leukemia, Lymph... Leukemia, Chron... Small-Cell Lymp... Lymphoma, Small... CLL SLL	Nemtabrutinib Venetoclax Rituximab	18 Years -	Merck Sharp & Dohme LLC

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