A Phase 1, Dose Escalation, and Cohort Expansion Study Evaluating NX-5948, a Bruton’s Tyrosine Kinase (BTK) Degrader, in Adults with Relapsed/Refractory B-cell Malignancies

Study ID: 50142
Short Title: NX-5948 (BTK degrader) in Relapsed/Refractory B-cell Malignancies
Trust Name: UHS
Recruitment Site: Southampton General Hospital
Disease Area: Haematology
Phase: I
Expected End Date: 15/01/2024
Postcode: SO16 6YD
Contact Name: Amanda Pattie
Contact Email: studysupport1and3.crnwessex@nihr.ac.uk
Active: Yes

Inclusion criteria, exclusion criteria and study summary

1. Each patient must sign an ICF indicating that he or she understands the purpose of procedures required for the study and are willing to participate in the study. Consent is to be obtained prior to the initiation of any study-related tests or procedures that are not part of standard-of-care for the patient’s disease. 2. Patients must be ≥ 18 years of age. 3. Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, DLBCL, FL, MCL, MZL, or WM. 4. Patients in Phase 1a must meet the following: a. Received at least 2 prior systemic therapies (or 1 prior therapy for WM) and have no other therapies known to provide clinical benefit. 5. Patients in Phase 1b (Cohort Expansion) must have one of the following histologically documented R/R B-cell malignancies, must meet criteria for systemic treatment, and must have failed 2 prior lines of therapy (or 1 prior line of therapy for patients with WM, PCNSL, or secondary CNS involvement): a. Cohort A: CLL or SLL without a BTK C481 mutation with disease progression on a BTKi. Patients who stopped BTKi due to side effects must have subsequent progression. b. Cohort B: CLL or SLL with a BTK C481 mutation with disease progression on a BTKi. c. Cohort C: i. DLBCL with disease progression on an anthracycline and an anti-CD20 mAbbased regimen, including transformed indolent lymphoma, Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements, and high-grade B-cell lymphomas NOS, or ii. MCL with disease progression on a BTKi and an anti-CD20 mAb-based regimen. d. Cohort D: i. FL with disease progression on an anti-CD20 mAb-based regimen, or ii. MZL with disease progression on an anti-CD20 mAb-based regimen, or iii. WM with disease progression on a BTKi. e. Cohort E: i. PCNSL with disease progression on 1 prior therapy, or ii. Any of the indications listed above with CNS involvement, with disease progression on 1 prior therapy (see Section 5.1.3 for rationale). 6. Patients must have radiographically measurable disease per response criteria specific to the malignancy (i.e., iwCLL, Lugano Classification of Lymphoma response criteria, WM response criteria, or International PCNSL Collaboration Group criteria) by CT, CT/PET scan, or MRI. Target lymph nodes must be > 1.5 cm and extranodal lesions must be ≥1.0 cm in longest diameter. Evaluable disease in bone marrow or compartment (pleural effusion) is also allowed. 7. ECOG performance status of 0 or 1. 8. Adequate organ and bone marrow function, in the absence of growth factors and without platelet transfusions, as defined by the following laboratory parameters (see table in attachment section) 9. 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. WOCBP and contraception methods are defined as per the 2020 CTFG recommendations (CTFG 2020). 10. Male patients with WOCBP partners must agree to use highly effective contraception and barrier contraception (condom) (defined as per CTFG 2020) 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. 11. Patient must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.

1. Prior treatment for the indication under study that includes: a. Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation). b. Prior chemotherapy within 4 weeks of planned start of study drug. c. Prior monoclonal antibody therapy within 4 weeks of planned start of study drug. d. Prior small molecule therapy within 4 weeks or 5 half-lives (whichever is shorter) of planned start of study drug. e. Autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug. f. CAR-T therapy within 100 days prior to start of study drug (30 days for Phase 1b). Must have evidence of B-cell recovery if patient received prior CAR-T therapy. g. Use of systemic corticosteroids outside of dosing limits described below and within the 14 days prior to initiation of study treatment excepting those used as prophylaxis for radio diagnostic contrast. Patients with 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. h. Use of immunosuppressive drugs other than systemic corticosteroids within 30 days, prior to first dose of study drug. 2. Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia. 3. Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction likely to interfere with the delivery, absorption, or metabolism of study drug. 4. Patients with active GVHD or on anti-GVHD treatment or prophylaxis. 5. History of known or suspected uncontrolled seizure disorder not related to CNSL involvement. 6. Patient has any of the following: a. 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. b. Uncontrolled atrial fibrillation or other clinically significant arrhythmias, conduction abnormalities, or NYHA class III or IV heart failure within 6 months of planned start of study drug. c. Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events), stroke, or intracranial hemorrhage within 6 months of planned start of study drug. d. Any other significant cardiac condition (e.g., 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. 7. Bleeding diathesis, or other known risk for acute blood loss. 8. History of Grade ≥2 hemorrhage within 28 days. 9. Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist within 7 days prior to first dose of study drug or patients treated with dual anti-platelet therapy and vitamin K antagonists. 10. Toxicities from previous anticancer therapies must have resolved to baseline levels or to Grade 1 (except for alopecia, hypothyroidism with adequate replacement therapy, hypopituitarism with adequate replacement therapy, peripheral neuropathy, or hematologic parameters meeting inclusion criteria). 11. Active known second malignancy with the exception of any of the following: a. Adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or in situ cervical cancer. b. Adequately treated Stage I cancer from which the patient has been disease-free for ≥2 years. c. Low-risk prostate cancer with Gleason score < 7 and prostate-specific antigen < 10 ng/mL. 12. Patient has known allergies, hypersensitivity, or intolerance to components of study drug. 13. Pregnant, breastfeeding, or planning to become pregnant while enrolled in this study or within 6 months after the last dose of study drug; for WOCBP, negative pregnancy status must be confirmed by pregnancy test at Screening and within 24 hours of first dose of study drug. 14. 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. 15. Patient has had major surgery (e.g., requiring general anesthesia) within 4 weeks before the planned first dose of study drug, or will not have fully recovered from surgery, or has surgery planned during the time the patient is expected to participate in the study or within 4 weeks after the last dose of study drug. Note: patients with minor planned surgical procedures to be conducted under local anesthesia may participate. 16. Active, significant bacterial, fungal, parasitic, viral, or COVID infection including: a. Current active liver disease from any infectious cause, including hepatitis B (hepatitis B virus surface antigen [HBsAg] positive), and hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by detectable HCV ribonucleic acid). Exceptions: Patients with hepatitis B virus (HBV) who are negative for HBV deoxyribonucleic acid (DNA) by quantitative polymerase chain reaction (PCR) are eligible irrespective of serology findings; as are, patients with a history of Hepatitis C with undetectable viral levels following treatment. b. Infection with HIV-1 or HIV-2. Exception: patients with well-controlled HIV (e.g., CD4 > 350/mm3 and undetectable viral load) are eligible. c. Active viral reactivation (e.g., CMV or EBV) 17. 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 or the protocol or completion of treatment per protocol. 18. Vaccinated with a live vaccine within 28 days prior to the first dose of study drug or completion of COVID-19 vaccinations within 14 days prior to first dose of study drug. Vaccinations of any kind are prohibited during the DLT period. 19. Administration of any strong or moderate CYP3A inhibitors or inducers within 14 days or 5 half-lives, whichever is longer, prior to first dose of study drug (See Section 6.8.2.2). 20. Administration of any sensitive substrates or inhibitors of P-glycoprotein, BCRP, or OATP1B1/1B3 transporters within 14 days or 5 half-lives, whichever is longer, prior to first dose of study drug (see Section 6.8.2.3). 21. Administration of a proton pump inhibitor within 14 days for 5 half-lives, whichever is longer, prior to first dose of study drug. See Section 6.8.2.4 for allowed use of alternative agents. 22. Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg within 3 days prior to Screening and during study treatment (NIH 2020) (Note: Patients who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry).

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