This study is currently recruiting participants.
Number
001835-H
Sponsoring Institute
National Heart, Lung and Blood Institute (NHLBI)
Recruitment Detail
Type: Participants currently recruited/enrolled Gender: Male & Female Min Age: 18 Years Max Age: 100 Years
Referral Letter Required
No
Population Exclusion(s)
Children
Keywords
BTK Degrader; B-Cell Malignancy; Bruton's Tyrosine Kinase
Recruitment Keyword(s)
None
Condition(s)
Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL); Diffuse Large B Cell Lymphoma (DLBCL); Follicular Lymphoma (FL); Mantle Cell Lymphoma (MCL); Marginal Zone Lymphoma (MZL); Waldenstrom Macroglobulinemia (WM); Primary Central Nervous System Lymphoma (PCNSL); Secondary Central Nervous System Lymphoma
Investigational Drug(s)
NX-5948
Investigational Device(s)
Intervention(s)
Drug: NX-5948
Supporting Site
National Heart, Lung, and Blood Institute
B cells are a type of white blood cell that play a role in immune function. Blood cancers (various leukemias and lymphomas) that affect B cells can be difficult to treat, and they may return after treatment. Better treatments are needed.
Objective:
To test a study drug (NX-5948) in people with B-cell cancers.
Eligibility:
People aged 18 years and older with a B-cell cancer that either did not respond to treatment or returned after treatment.
Design:
Participants will be screened. They will have a physical exam with blood and urine tests. Depending on the specific type of cancer they have, some participants may have additional tests, such as imaging scans; tissue samples collected from their lymph nodes or bone marrow; and lumbar punctures to collect fluid from the area around the spinal cord. These tests will be repeated during the study.
NX-5948 is a capsule taken by mouth daily in 4-week cycles. Participants will take the drug each day at home. They will fast 2 hours before and 2 hours after taking the drug. They will record their doses in a diary.
Participants will visit the clinic once a week during the first 2 months; once every 2 weeks for the next 2 months; and once a month thereafter.
Participants may remain in the study as long as the drug is helping them, up to 5 years.
Participant will have an end-of-treatment visit and 2 more visits at 15 and 30 days after their last treatment. Then they will have long-term follow-up calls every 12 weeks.
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INCLUSION CRITERIA: 1. Each patient must sign an informed consent form (ICF) indicating that he or she understands the purpose of procedures required for the study and is willing to participate in the study. 2. Patients must be >= 18 years of age. 3. Patients in Phase 1a (Dose Escalation) must have 1 of the following histologically confirmed R/R B-cell malignancies: -R/R CLL, SLL -DLBCL of the following subgroups: --DLBCL not otherwise specified (NOS), germinal center B-cell type, activated B-cell type (includes transformed indolent lymphoma [eg, grade 3b/transformed FL] and Richter-transformed DLBCL) --High-grade B-cell lymphoma (HGBL) with MYC and BCL-2 and/or BCL-6 rearrangements, HGBL NOS (note: other subgroups of DLBCL or large B-cell lymphoma (LBCL) from the 2016 WHO classification of lymphoid malignancies [Swerdlow 2016] are excluded) -FL (grade 1-3a; eligibility for systemic treatment as determined by the Groupe d'Etude des Lymphomes Folliculaires [GELF] criteria) -MCL -MZL (eligible subtypes include EMZL, MALT, NMZL, and SMZL) -WM -PCNSL 4. Patients in Phase 1a must meet the following: -For non-PCNSL indications, received at least 2 prior lines of therapy and have no other therapies known to provide clinical benefit. -For PCNSL, received at least 1 prior line of therapy. 5. Patients in Phase 1b (Safety Expansion) must have 1 of the following histologically documented R/R B-cell malignancies, must meet criteria for systemic treatment and must have received the following prior therapies based on indication: -CLL/SLL arm: --CLL or SLL with prior exposure to both a BTKi and BCL-2 inhibitor, unless previously deemed ineligible for those therapies. -MCL arm: --MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemo-immunotherapy regimen. -MZL arm: --MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy. -WM arm: --WM with prior exposure to a BTKi and an additional line of therapy. -DLBCL arm: --DLBCL of the following subgroups with prior exposure to an anthracycline (unless previously deemed ineligible to receive), an anti-CD20 mAb-based chemo-immunotherapy regimen, and an additional line of therapy: ---NOS, germinal center B-cell type, activated B-cell type (includes transformed indolent lymphoma [eg, grade 3b/transformed FL] and Richter-transformed DLBCL) ---HGBL with MYC and BCL-2 and/or BCL-6 rearrangements, and HGBL NOS (note: other subgroups of DLBCL or LBCL from the 2016 WHO classification of lymphoid malignancies [Swerdlow 2016] are excluded). -FL arm: --FL (grade 1-3a; eligibility for systemic treatment as determined by the GELF criteria) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy. -PCNSL/SCNSL arm: --PCNSL patients who have progressed or had no response to at least 1 prior line of therapy. --SCNSL patients meeting criteria for non-CLL/SLL arms above with secondary CNS involvement of lymphoma. 6. Patients must have measurable disease per response criteria specific to the malignancy. For patients with NHL, must have either at least 1 metabolically active lesion defined as fluorodeoxyglucose (FDG)-avid (5PS score of 4 or 5) as assessed by PET-CT or at least 1 target lesion that is >1.5 cm for lymph nodes or >1.0 cm for extranodal lesion(s) in the longest diameter as assessed by CT. For patients with WM, serum monoclonal immunoglobulin M (IgM) paraprotein >0.5 g/dL. 7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (0-2 for patients with PCNSL and SCNSL). 8. Anticipated life expectancy of at least 12 weeks from the time of Screening. 9. Adequate organ and bone marrow function as follows: -Hemoglobin >90 g/dL (or >70 g/dL if anemia is due to bone marrow involvement per Investigator assessment); a minimum 5-day transfusion free interval is required -Absolute neutrophil count >1.0 x 10^9/L unless neutropenia is due to bone marrow involvement per Investigator assessment; G-CSF allowed for bone marrow involvement of disease -Platelet counts: --For patients with CLL/SLL: platelets >50 x 10^9/L (or >30 x 10^9/L if thrombocytopenia is due to bone marrow or splenic involvement. --For patients with NHL/WM: platelets >75 x 10^9/L (or >50 x 10^9/L if thrombocytopenia is due to bone marrow or splenic involvement. For all patients, a minimum 14-day transfusion-free interval is required prior to first dose -Coagulation (international normalized ratio [INR] and partial thromboplastin time [PTT] or activated partial thromboplastin time [aPTT]) <=1.5 x ULN; patients undergoing lumbar puncture must have PTT or aPTT <ULN -Serum amylase and lipase <= 1.5 x ULN -Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 x ULN, total bilirubin <=1.5 x ULN (or <= 5 x ULN for Gilbert s syndrome) -Calculated glomerular filtration rate (GFR) >45 mL/min/1.73 m^2 -QTcF <450 msec (triplicate ECG average); for patients with pacemaker or bundle branch block QTcF <475 msec -SpO2 >92% on room air 10. Women of childbearing potential (WOCBP) must agree to use highly effective contraception (failure rate of < 1% per year) during the study from Screening through 6 months after the last dose of study drug. WOCBP must agree to not donate eggs (ova, oocytes) during the same timeframe. 11. Male patients with WOCBP partners must agree to use highly effective contraception and barrier contraception during the study from Screening through 3 months after the last dose of study drug. Men must agree to not donate sperm during the same timeframe. 12. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol. EXCLUSION CRITERIA: Individuals who meet any of the following exclusion criteria at Screening will not be eligible to participate in the study: 1. Known or suspected prolymphocytic leukemia or Richter s transformation to Hodgkin s lymphoma at any time preceding enrollment. 2. Prior treatment for the indication under study for anti-cancer intent that includes: 2a. Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation). 2b. Prior systemic chemotherapy within 2 weeks of planned start of study drug. Note: Use of intrathecal chemotherapy is allowed per institutional guidelines. 2c. Prior mAb therapy within 4 weeks of planned start of study drug. 2d. Prior small molecule therapy within 5 half-lives or 2 weeks (whichever is shorter) of planned start of study drug. 2e. Autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug. 2f. Chimeric antigen receptor (CAR) T-cell therapy within 100 days prior to start of study drug (within 60 days prior to start of study drug for Phase 1b). 2g. Use of systemic corticosteroids outside of dosing limits described below and within 14 days prior to initiation of study treatment excepting those used as prophylaxis for radio diagnostic contrast. Patients with central nervous system lymphoma (CNSL, including both primary and secondary CNSL): no greater than 40 mg/day prednisone, or equivalent; CNSL patients using greater than 20 mg/day prednisone, or equivalent, must be clinically stable at that dose for 14 days. All other diagnoses: no greater than 20 mg/day prednisone or equivalent. 2h. Use of systemic immunosuppressive drugs other than systemic corticosteroids for any medical condition within 60 days, prior to first dose of study drug. 2i. Previously treated with a BTK degrader. 3. Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia. 4. Unable to swallow capsules or malabsorption syndrome, disease or procedure significantly affecting gastrointestinal function, likely to interfere with the delivery, absorption, or metabolism of study drug. 5. Patients with active graft-versus-host disease (GVHD) or who have required anti-GVHD treatment or prophylaxis within 60 days of planned start of study drug. 6. History of known or suspected uncontrolled seizure disorder not related to CNS involvement of underlying malignancy. 7. Patient has any of the following: 7a. Myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, or placement of a coronary arterial stent within 6 months of planned start of study drug. 7b. Uncontrolled atrial fibrillation or other clinically significant arrhythmias, conduction abnormalities, or New York Heart Association (NYHA) class III or IV heart failure within 6 months of planned start of study drug. 7c. Thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage within 6 months of planned start of study drug. 7d. Any other significant cardiac condition (eg, pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, severe congenital heart disease, or persistent uncontrolled hypertension defined as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg despite optimal medical management) within 6 months of planned start of study drug. 8. Bleeding diathesis, or other known risk for acute blood loss. 9. History of Grade >= 2 hemorrhage within 28 days of planned start of study drug. 10. Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist within 168 hours prior to first dose of study drug. 11. Toxicities from previous anti-cancer therapies must have resolved to baseline levels or to Grade 1. 12. Active known concurrent malignancy or malignancy other than the one under study within the past 3 years. 13. Patient who has known allergies, hypersensitivity, or intolerance to components of study drug. 14. Patient who requires tumor lysis syndrome (TLS) prophylaxis and has known allergy to both xanthine oxidase inhibitors and rasburicase. 15. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study drug. 16. Patient is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug. 17. Patient has had major surgery (eg, requiring general anesthesia) within 4 weeks before the planned first dose of study drug. 18. Active, significant bacterial, fungal, parasitic, or viral infection 19. Active, uncontrolled diabetes (eg, hemoglobin A1c >9%, symptomatic, with or without end organ complications, etc.) as assessed by the Investigator (note: poor glycemic control in the context of disease modifying corticosteroid treatment is not exclusionary) 20. Any other medical or psychiatric condition or social situation that, in the opinion of the Investigator, would compromise patient safety, or interfere with the objectives, the protocol, or completion of treatment per protocol. 21. Vaccinated with a live vaccine within 28 days prior to the first dose of study drug or completion of any vaccinations within 14 days prior to first dose of study drug. For patients in Phase 1a only, vaccinations of any kind are prohibited during the DLT period. 22. Administration of any strong cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days or 5 half-lives, whichever is longer, and moderate CYP3A inhibitors or inducers within 168 hours, or 5 half-lives, whichever is longer, prior to first dose of study drug 23. Administration of any inhibitors of P-glycoprotein or breast cancer resistance protein (BCRP) transporters within 48 hours prior to first dose of study drug. 24. Administration of a proton pump inhibitor (prescription or over-the-counter) within 168 hours prior to first dose of study drug. 25. Use of biotin (ie, vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 microg within 72 hours prior to Screening and during study treatment.
1. Each patient must sign an informed consent form (ICF) indicating that he or she understands the purpose of procedures required for the study and is willing to participate in the study.
2. Patients must be >= 18 years of age.
3. Patients in Phase 1a (Dose Escalation) must have 1 of the following histologically confirmed R/R B-cell malignancies:
-R/R CLL, SLL
-DLBCL of the following subgroups:
--DLBCL not otherwise specified (NOS), germinal center B-cell type, activated B-cell type (includes transformed indolent lymphoma [eg, grade 3b/transformed FL] and Richter-transformed DLBCL)
--High-grade B-cell lymphoma (HGBL) with MYC and BCL-2 and/or BCL-6 rearrangements, HGBL NOS
(note: other subgroups of DLBCL or large B-cell lymphoma (LBCL) from the 2016 WHO classification of lymphoid malignancies [Swerdlow 2016] are excluded)
-FL (grade 1-3a; eligibility for systemic treatment as determined by the Groupe d'Etude des Lymphomes Folliculaires [GELF] criteria)
-MCL
-MZL (eligible subtypes include EMZL, MALT, NMZL, and SMZL)
-WM
-PCNSL
4. Patients in Phase 1a must meet the following:
-For non-PCNSL indications, received at least 2 prior lines of therapy and have no other therapies known to provide clinical benefit.
-For PCNSL, received at least 1 prior line of therapy.
5. Patients in Phase 1b (Safety Expansion) must have 1 of the following histologically documented R/R B-cell malignancies, must meet criteria for systemic treatment and must have received the following prior therapies based on indication:
-CLL/SLL arm:
--CLL or SLL with prior exposure to both a BTKi and BCL-2 inhibitor, unless previously deemed ineligible for those therapies.
-MCL arm:
--MCL with prior exposure to a BTKi and an anti-CD20 monoclonal antibody (mAb)-based chemo-immunotherapy regimen.
-MZL arm:
--MZL (EMZL, MALT, NMZL, SMZL) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy.
-WM arm:
--WM with prior exposure to a BTKi and an additional line of therapy.
-DLBCL arm:
--DLBCL of the following subgroups with prior exposure to an anthracycline (unless previously deemed ineligible to receive), an anti-CD20 mAb-based chemo-immunotherapy regimen, and an additional line of therapy:
---NOS, germinal center B-cell type, activated B-cell type (includes transformed indolent lymphoma [eg, grade 3b/transformed FL] and Richter-transformed DLBCL)
---HGBL with MYC and BCL-2 and/or BCL-6 rearrangements, and HGBL NOS
(note: other subgroups of DLBCL or LBCL from the 2016 WHO classification of lymphoid malignancies [Swerdlow 2016] are excluded).
-FL arm:
--FL (grade 1-3a; eligibility for systemic treatment as determined by the GELF criteria) with prior exposure to an anti-CD20 mAb-based chemo-immunotherapy regimen and an additional line of therapy.
-PCNSL/SCNSL arm:
--PCNSL patients who have progressed or had no response to at least 1 prior line of therapy.
--SCNSL patients meeting criteria for non-CLL/SLL arms above with secondary CNS involvement of lymphoma.
6. Patients must have measurable disease per response criteria specific to the malignancy. For patients with NHL, must have either at least 1 metabolically active lesion defined as fluorodeoxyglucose (FDG)-avid (5PS score of 4 or 5) as assessed by PET-CT or at least 1 target lesion that is >1.5 cm for lymph nodes or >1.0 cm for extranodal lesion(s) in the longest diameter as assessed by CT. For patients with WM, serum monoclonal immunoglobulin M (IgM) paraprotein >0.5 g/dL.
7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (0-2 for patients with PCNSL and SCNSL).
8. Anticipated life expectancy of at least 12 weeks from the time of Screening.
9. Adequate organ and bone marrow function as follows:
-Hemoglobin >90 g/dL (or >70 g/dL if anemia is due to bone marrow involvement per Investigator assessment); a minimum 5-day transfusion free interval is required
-Absolute neutrophil count >1.0 x 10^9/L unless neutropenia is due to bone marrow involvement per Investigator assessment; G-CSF allowed for bone marrow involvement of disease
-Platelet counts:
--For patients with CLL/SLL: platelets >50 x 10^9/L (or >30 x 10^9/L if thrombocytopenia is due to bone marrow or splenic involvement.
--For patients with NHL/WM: platelets >75 x 10^9/L (or >50 x 10^9/L if thrombocytopenia is due to bone marrow or splenic involvement.
For all patients, a minimum 14-day transfusion-free interval is required prior to first dose
-Coagulation (international normalized ratio [INR] and partial thromboplastin time [PTT] or activated partial thromboplastin time [aPTT]) <=1.5 x ULN; patients undergoing lumbar puncture must have PTT or aPTT <ULN
-Serum amylase and lipase <= 1.5 x ULN
-Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 x ULN, total bilirubin <=1.5 x ULN (or <= 5 x ULN for Gilbert s syndrome)
-Calculated glomerular filtration rate (GFR) >45 mL/min/1.73 m^2
-QTcF <450 msec (triplicate ECG average); for patients with pacemaker or bundle branch block QTcF <475 msec
-SpO2 >92% on room air
10. Women of childbearing potential (WOCBP) must agree to use highly effective contraception (failure rate of < 1% per year) during the study from Screening through 6 months after the last dose of study drug. WOCBP must agree to not donate eggs (ova, oocytes) during the same timeframe.
11. Male patients with WOCBP partners must agree to use highly effective contraception and barrier contraception during the study from Screening through 3 months after the last dose of study drug. Men must agree to not donate sperm during the same timeframe.
12. Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
EXCLUSION CRITERIA:
Individuals who meet any of the following exclusion criteria at Screening will not be eligible to participate in the study:
1. Known or suspected prolymphocytic leukemia or Richter s transformation to Hodgkin s lymphoma at any time preceding enrollment.
2. Prior treatment for the indication under study for anti-cancer intent that includes:
2a. Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation).
2b. Prior systemic chemotherapy within 2 weeks of planned start of study drug. Note: Use of intrathecal chemotherapy is allowed per institutional guidelines.
2c. Prior mAb therapy within 4 weeks of planned start of study drug.
2d. Prior small molecule therapy within 5 half-lives or 2 weeks (whichever is shorter) of planned start of study drug.
2e. Autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug.
2f. Chimeric antigen receptor (CAR) T-cell therapy within 100 days prior to start of study drug (within 60 days prior to start of study drug for Phase 1b).
2g. Use of systemic corticosteroids outside of dosing limits described below and within 14 days prior to initiation of study treatment excepting those used as prophylaxis for radio diagnostic contrast. Patients with central nervous system lymphoma (CNSL, including both primary and secondary CNSL): no greater than 40 mg/day prednisone, or equivalent; CNSL patients using greater than 20 mg/day prednisone, or equivalent, must be clinically stable at that dose for 14 days. All other diagnoses: no greater than 20 mg/day prednisone or equivalent.
2h. Use of systemic immunosuppressive drugs other than systemic corticosteroids for any medical condition within 60 days, prior to first dose of study drug.
2i. Previously treated with a BTK degrader.
3. Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia.
4. Unable to swallow capsules or malabsorption syndrome, disease or procedure significantly affecting gastrointestinal function, likely to interfere with the delivery, absorption, or metabolism of study drug.
5. Patients with active graft-versus-host disease (GVHD) or who have required anti-GVHD treatment or prophylaxis within 60 days of planned start of study drug.
6. History of known or suspected uncontrolled seizure disorder not related to CNS involvement of underlying malignancy.
7. Patient has any of the following:
7a. Myocardial infarction, unstable angina, unstable symptomatic ischemic heart disease, or placement of a coronary arterial stent within 6 months of planned start of study drug.
7b. Uncontrolled atrial fibrillation or other clinically significant arrhythmias, conduction abnormalities, or New York Heart Association (NYHA) class III or IV heart failure within 6 months of planned start of study drug.
7c. Thromboembolic events (eg, deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage within 6 months of planned start of study drug.
7d. Any other significant cardiac condition (eg, pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, severe congenital heart disease, or persistent uncontrolled hypertension defined as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg despite optimal medical management) within 6 months of planned start of study drug.
8. Bleeding diathesis, or other known risk for acute blood loss.
9. History of Grade >= 2 hemorrhage within 28 days of planned start of study drug.
10. Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist within 168 hours prior to first dose of study drug.
11. Toxicities from previous anti-cancer therapies must have resolved to baseline levels or to Grade 1.
12. Active known concurrent malignancy or malignancy other than the one under study within the past 3 years.
13. Patient who has known allergies, hypersensitivity, or intolerance to components of study drug.
14. Patient who requires tumor lysis syndrome (TLS) prophylaxis and has known allergy to both xanthine oxidase inhibitors and rasburicase.
15. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study drug.
16. Patient is a man who plans to father a child while enrolled in this study or within 3 months after the last dose of study drug.
17. Patient has had major surgery (eg, requiring general anesthesia) within 4 weeks before the planned first dose of study drug.
18. Active, significant bacterial, fungal, parasitic, or viral infection
19. Active, uncontrolled diabetes (eg, hemoglobin A1c >9%, symptomatic, with or without end organ complications, etc.) as assessed by the Investigator (note: poor glycemic control in the context of disease modifying corticosteroid treatment is not exclusionary)
20. Any other medical or psychiatric condition or social situation that, in the opinion of the Investigator, would compromise patient safety, or interfere with the objectives, the protocol, or completion of treatment per protocol.
21. Vaccinated with a live vaccine within 28 days prior to the first dose of study drug or completion of any vaccinations within 14 days prior to first dose of study drug. For patients in Phase 1a only, vaccinations of any kind are prohibited during the DLT period.
22. Administration of any strong cytochrome P450 3A (CYP3A) inhibitors or inducers within 14 days or 5 half-lives, whichever is longer, and moderate CYP3A inhibitors or inducers within 168 hours, or 5 half-lives, whichever is longer, prior to first dose of study drug
23. Administration of any inhibitors of P-glycoprotein or breast cancer resistance protein (BCRP) transporters within 48 hours prior to first dose of study drug.
24. Administration of a proton pump inhibitor (prescription or over-the-counter) within 168 hours prior to first dose of study drug.
25. Use of biotin (ie, vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 microg within 72 hours prior to Screening and during study treatment.
Principal Investigator
Referral Contact
For more information: