IRB Study Number 23-312
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objectives
• To evaluate the safety and tolerability of BTK degrader NX-5948, when taken orally, in adult patients with R/R B-cell malignancies.
• To establish the maximum tolerated dose (MTD) and/or recommended Phase 1b dose(s) of NX-5948 in adult patients with R/R B-cell malignancies.
Secondary Objectives
• To characterize the PK profile of NX-5948.
• To characterize the PD profile of NX-5948.
• To assess preliminary anti-tumor activity of NX-5948.
Inclusion Criteria
Each patient must sign an ICF indicating that he or she understands the purpose of procedures required for the study and is 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.
Patients must be ≥ 18 years of age.
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:
o 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)
o High-grade B-cell lymphoma (HGBL) with MYC and BCL-2 and/or BCL-6 rearrangements, high-grade B-cell lymphomas NOS
(note: other subgroups of DLBCL or 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; Section 15.8),
• MCL
• MZL (eligible subtypes include EMZL, MALT, NMZL, and SMZL)
• WM
• PCNSL
- Patients in Phase 1a must meet the following:
a. For non-PCNSL indications, received at least 2 prior lines of therapy and have no other therapies known to provide clinical benefit.
b. For PCNSL, received at least 1 prior line of therapy.
- 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:
o NOS, germinal center B-cell type, activated B-cell type (includes transformed indolent lymphoma [eg, grade 3b/transformed FL] and Richter-transformed DLBCL),
o HGBL with MYC and BCL-2 and/or BCL-6 rearrangements, and HGBL NOS
(note: other subgroups of DLBCL or LBCL from the 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; Section 15.8) 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.
Patients must have measurable disease per response criteria specific to the malignancy (ie, International Workshop on CLL [iwCLL], Lugano Classification of Lymphoma response criteria, WM response criteria, or International PCNSL Collaboration Group criteria; Section 15.4) which may include imaging by computed tomography (CT), CT/positron emission tomography (PET) scan, or magnetic resonance imaging (MRI) as per respective response criteria. For patients with NHL, must have either at least 1 metabolically active lesion defined as 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.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (0-2 for patients with PCNSL and SCNSL).
Anticipated life expectancy of at least 12 weeks from the time of Screening.
Adequate organ and bone marrow function as follows: (See protocol)
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 (see Section 6.6.4). WOCBP must agree to not donate eggs (ova, oocytes) during the same timeframe. WOCBP and contraception methods are defined as per the 2020 Clinical Trial Facilitation Group (CTFG) recommendations (CTFG 2020).
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.
Patients must be willing and able to adhere to the prohibitions and restrictions specified in this protocol.
Exclusion Criteria
Known or suspected prolymphocytic leukemia or Richter’s transformation to Hodgkin’s lymphoma at any time preceding enrollment.
Prior treatment for the indication under study for anti-cancer intent that includes:
a. Radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation).
b. Prior systemic chemotherapy within 2 weeks of planned start of study drug. Note: Use of intrathecal chemotherapy is allowed per institutional guidelines.
c. Prior mAb therapy within 4 weeks of planned start of study drug.
d. Prior small molecule therapy within 5 half-lives or 2 weeks (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. 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).
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 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.
h. Use of systemic immunosuppressive drugs other than systemic corticosteroids for any medical condition within 60 days, prior to first dose of study drug.
i. Previously treated with a BTK degrader.
Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia.
Unable to swallow capsules or malabsorption syndrome, disease or procedure significantly affecting gastrointestinal function, or resection of the stomach or small bowel or ulcerative colitis, inflammatory bowel disease, or partial or complete bowel obstruction likely to interfere with the delivery, absorption, or metabolism of study drug.
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.
History of known or suspected uncontrolled seizure disorder not related to CNS involvement of underlying malignancy.
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 New York Heart Association (NYHA) class III or IV heart failure within 6 months of planned start of study drug.
c. 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.
d. 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.
Bleeding diathesis, or other known risk for acute blood loss.
History of Grade ≥ 2 hemorrhage within 28 days of planned start of study drug.
Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist within 168 hours prior to first dose of study drug.
Toxicities from previous anti-cancer 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).
Active known concurrent malignancy or malignancy other than the one under study within the past 3 years. (Exceptions include patients with more recent history of basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the cervix or breast may enroll if they have undergone curative therapy and have no evidence of disease).
Patient who has known allergies, hypersensitivity, or intolerance to components of study drug.
Patient who requires TLS prophylaxis and has known allergy to both xanthine oxidase inhibitors and rasburicase.
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.
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.
Patient has had major surgery (eg, 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.
Active, significant bacterial, fungal, parasitic, or viral 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 (eg, CD4 >350/mm3 and undetectable viral load) are eligible.
c. Active viral reactivation (eg, cytomegalovirus [CMV] or Epstein-Barr virus [EBV]).
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)
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.
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.
Administration of any strong CYP3A inhibitors or inducers within 14 days or 5 half-lives, whichever is longer, and any moderate CYP3A inhibitors or inducers within 168 hours, or 5 half-lives, whichever is longer, prior to first dose of study drug. (See Section 6.8.2.2).
Administration of any inhibitors of P-glycoprotein or BCRP transporters within 48 hours prior to first dose of study drug (see Section 6.8.2.3).
Administration of a proton pump inhibitor (prescription or over-the-counter) within 168 hours prior to first dose of study drug. See Section 6.8.2.4 for allowed use of alternative agents.
Use of biotin (ie, vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 μg within 72 hours prior to Screening and during study treatment (NIH 2022; Note: Patients who switch from a high dose to a dose of 30 μg/day or less are eligible for study entry).
