This study is currently recruiting participants.
Number
000326-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
Yes
Population Exclusion(s)
Children
Keywords
R/R Chronic Lymphocytic Leukemia (CLL); Small Lymphocytic Lymphoma (SLL); study drug treatment; Cancer; Tumors
Recruitment Keyword(s)
None
Condition(s)
Relapsed/Refractory B-cell Malignancies
Investigational Drug(s)
NX-2127
Investigational Device(s)
Intervention(s)
Drug: NX-2127 (BTK degrader)
Supporting Site
National Heart, Lung, and Blood Institute
Blood cancers that affect B cells are often treated with drugs that block or inhibit a protein in cancer cells called BTK. Some tumors become resistant to these drugs. Researchers want to learn if a new drug (NX-2127) that degrades BTK can help.
Objective:
To learn if NX-2127 can be used to treat certain B-cell blood cancers.
Eligibility:
Adults aged 18 and older with certain B-cell blood cancers who have received at least 2 prior treatments that failed (or 1 for people with Waldenstrom macroglobulinemia [WM]). Cancer types include diffuse large B-cell lymphoma, chronic lymphocytic leukemia/small lymphocytic lymphoma, follicular lymphoma, marginal zone lymphoma, mantle cell lymphoma, and WM.
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
PET and/or CT scans
Heart tests
Lymph node biopsy, if needed
Bone marrow biopsy/aspirate, if needed
Participants will take NX-2127 by mouth once daily or every-other day. They will fast for 2 hours before and after taking the drug. On some days, they will fast overnight. They will take the drug until they have bad side effects or their cancer gets worse.
Participants will have weekly study visits for the first 2 months of treatment. Some visits may last 8 hours or more. For the next 2 months, they will have visits every 2 weeks. After that, they will have monthly visits. At visits, they will repeat some screening tests.
Participants will have safety follow-up visits 7 and 30 days after treatment ends. Then they will have follow-up visits in person or by phone every 3 months for 1 year.
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INCLUSION CRITERIA: -Patients must be >= 18 years of age -Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, MCL, FL, MZL, WM, PCNSL, or DLBCL. This includes the following specific subtypes, closely related diagnoses, or synonymous terms: lymphoplasmacytic lymphoma; extranodal mucosa-associated lymphoid tissue (MALT) lymphoma; nodal MZL; FL NOS; testicular FL; FL in situ; duodenal FL; diffuse variant FL; MCL NOS; DLBCL NOS; Tcell histiocytic rich large B-cell lymphoma (LBCL); primary DLBCL of the central nervous system (CNS); Epstein Barr virus (EBV)-positive DLBCL; DLBCL associated with chronic inflammation and fibrin-associated DLBCL; primary mediastinal LBCL; ALK-positive LBCL; and B-cell lymphoma unclassifiable with features intermediate between classical Hodgkin and DLBCL. The criterion is also met when any of these diagnoses occurs as a result of Richter s transformation. Patients with transformed lymphoma are eligible for the study, with the exception of those detailed in Exclusion Criteria -Patients in Phase 1a must meet the following: --Received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL) and have no other therapies known to provide clinical benefit --At least 2 weeks must have elapsed between the last therapy and the first dose of study drug or at least 4 weeks for antibody-containing therapies, except for patients on a small molecule therapy who require at least 5 half-lives or 2 days (whichever is longer) --Must require systemic therapy -Patients in Phase 1b (Dose Optimization) must have 1 of the following histologically documented R/R B-cell malignancies and have failed at least 2 prior treatments (or at least 1 prior therapy for WM or PCNSL) and meet the appropriate criteria listed below: --CLL/SLL whose disease has failed treatment with a BTKi --MCL whose disease has failed treatment with a BTKi and an anti-CD20 mAb-based regimen --FL or MZL whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTKi --PCNSL whose disease has failed at least 1 prior line of treatment --DLBCL whose disease has failed treatment with an anti-CD20 mAb-based regimen and either: an anthracycline-based regimen; or anti-CD19-based regimen; or another regimen or a palliative regimen when the aforementioned regimens (anthracycline based, or CD19-based) were contraindicated or unavailable (see exclusion criteria for prior CAR T-cell therapy) (either progressed post stem cell transplant or transplantineligible), including transformed indolent lymphoma (e.g., grade 3b/transformed FL or MZL), Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements, and high-grade B-cell lymphomas NOS - Patients must have measurable disease. In this context, measurable disease is defined by specific malignancy and includes iwCLL, International Working Group (IWG), Lugano Classification of Lymphoma response criteria, or International PCNSL Collaborative Group response criteria. Measurable by computed tomography (CT), CT/positron emission tomography (CT/PET), or magnetic resonance imaging (MRI) is defined as at least one node >1.5 cm in size or measurable extranodal lesion of >=1.0 cm in longest diameter. Other quantifiable disease (including but not limited to bone marrow infiltration, minimal residual disease [MRD], splenic enlargement, or progressive lymphocytosis) is also allowed. For PCNSL, measurable disease includes the presence of contrast enhancing parenchymal lesions on MRI (CT with contrast is allowed when MRI is medically contra-indicated), cerebrospinal fluid (CSF) cytology positive for lymphomatous involvement, and/or the presence of intra-ocular disease by ophthalmologic examination. Disease evaluation at Screening should be done per disease standard guidelines. Subsequent procedures for the purpose of response assessments may be carried out per institutional standard and as clinically indicated. For WM, measurable abnormal serum monoclonal immunoglobulin M (IgM) protein is considered measurable disease in the context of this protocol - Patients in Phase 1b must have received at least 2 prior lines of systemic therapy for the management of their disease (or at least 1 prior therapy for patients with WM or PCNSL) - Patients with indolent forms of non-Hodgkin lymphoma (NHL) must meet the criteria requiring systemic treatment (i.e., iwCLL, IWG, or Lugano Classification of Lymphoma). Patients with PCNSL should meet the criteria for treatment as per the PCNSL Collaborative Group Criteria - Patients with transformed lymphoma are eligible for the study with the exception of those described in exclusion #1 - Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (non-PCNSL indications) or 0-2 (PCNSL patients) - Adequate organ and bone marrow function as defined by the following laboratory parameters (hematology, hepatic, and renal laboratory parameters are required to be performed 10 days prior to Cycle 1 Day 1 and must meet the criteria below) Laboratory Parameter Value --Hematology ---Hemoglobin > 9 g/dL or > 7 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 (ANC) > 1.0 x 10^9/L unless neutropenia is due to bone marrow involvement per Investigator assessment. Granulocyte colony stimulating factor (G-CSF) is allowed for those with bone marrow involvement of disease. ---Platelets > 75 x 10^9/L or > 50 (SqrRoot) 10^9/L if thrombocytopenia is due to bone marrow or splenic involvement per Investigator assessment. A minimum 5-day transfusion-free interval is required. Use of platelet-derived growth factors are prohibited. ---Coagulation (INR and partial thromboplastin time [PTT] or activated partial thromboplastin time [aPTT]) <= 1.5 (SqrRoot) ULN (Patients undergoing lumbar puncture must have either PTT or aPTT < ULN). --Pancreatic ---Serum amylase <=1.5 (SqrRoot) ULN. ---Serum lipase <=1.5 (SqrRoot) ULN. --Hepatic ---AST and ALT <=2.5 (SqrRoot) ULN. ---Total bilirubin <= 1.5 (SqrRoot) ULN (or < 5 (SqrRoot) ULN for patients with Gilbert s syndrome). --Renal ---Serum creatinine < 1.5 (SqrRoot) ULN or a calculated glomerular filtration rate (GFR) greater than 45mL/min/1.73m^2. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine. --Cardiac ---QT interval corrected (QTc) ECG QTc for heart rate < 475 msec, measured by Fridericia's formula (QTcF = QT/([RR^0.33)]). If the QTc is prolonged in a patient with a pacemaker or bundle branch block, the patient may be enrolled in the study if confirmed by the Medical Monitor. --Pulmonary ---Blood oxygen saturation > 92% on room air. -Women of childbearing potential (WOCBP) must use 2 forms of contraception, of which 1 must be highly effective (defined as < 1% failure rate per year) and 1 must be a barrier method (condom), throughout the study from Screening through 6 months after the final dose of study drug. WOCBP defined as per the 2020 Clinical Trial Facilitation Group recommendations - Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study drug. Men must agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug - A male patient who is sexually active with a WOCBP must agree to use 2 forms of contraception, of which 1 must be highly effective (defined as < 1% failure rate per year) and 1 must be a barrier method (condom with spermicidal foam/gel/film/cream/suppository) throughout the study from Screening through 3 months after the final dose of study drug - Patient must be willing and able to adhere to the prohibitions and restrictions specified in this protocol - Each patient must sign an informed consent form (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 EXCLUSION CRITERIA: Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study: - Prolymphocytic leukemia, MCL with blastoid histology, MCL with pleomorphic morphology, or MCL with known TP53 mutation - Any of the following malignancies: --Prolymphocytic leukemia; hairy cell leukemia; splenic B-cell lymphoma unclassifiable; IgM or immunoglobulin G (IgG) monoclonal gammopathy of undetermined significance; heavy chain disease; plasma cell neoplasms, including plasmacytoma; pediatric type FL; LBCL with IRF4 arrangement; primary cutaneous follicular center lymphoma; EBV-positive mucocutanous ulcer; lymphomatoid granulomatosis; intravascular LBCL, plasmablastic lymphoma; primary effusion lymphoma; HHV-8-associated lymphoproliferative disease, Burkitt lymphoma; mature T-cell and NK cell neoplasms; Hodgkin lymphomas; immunodeficiencyassociated lymphoproliferative diseases; histiocytic and dendritic cell neoplasms; precursor lymphoid neoplasms; blastic plasmacytic dendritic cell neoplasm; AML and related precursors neoplasms; myeloid malignancies; acute leukemias of ambiguous lineage; T-cell PCNSL --Lymphoma or leukemia disease involving the brain stem --Secondary CNS lymphoma/leukemia --For patients with PCNSL only: evidence of disease outside of the CNS - Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia - History of known/suspected other autoimmune disease (exception[s]: patients with alopecia, vitiligo, resolved childhood atopic dermatitis, hypothyroidism, or hyperthyroidism that is clinically euthyroid at Screening are allowed) - 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 - Patient has any of the following: --Uncontrolled intercurrent illness including, but not limited to, persistent, poorly controlled hypertension (defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite optimal medical management) -- Uncontrolled diabetes -- Ongoing significant infection requiring systemic antibiotics, antifungals, or antivirals (with exception of human immunodeficiency virus [HIV] antivirals) in the last 7 days -- Patients who have undergone autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug -- Patients with active graft-versus-host disease (GVHD) or on anti-GVHD treatment or prophylaxis -- History of CAR T-cell therapy within 30 days prior to start of study drug. -- History of known or suspected seizure disorder (non-PCNSL indications) or poorly controlled seizures (PCNSL patients) -- History of prior pneumonitis requiring steroid treatment - Bleeding diathesis, or other known risk for acute blood loss - Patients with known GI lymphoma with history of bleeding within 3 months of planned start of study drug - History of Grade >= 2 hemorrhage within 28 days - Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist and within 7 days prior to first dose of study drug. Exceptions may be permitted after consultation with the Medical Monitor (or delegate) - Prior radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation) - Prior systemic chemotherapy within 2 weeks of planned start of study drug - Prior anti-cancer mAb therapy within 4 weeks of planned start of study drug and prior anti-cancer small molecule therapy within 2 days or 5 half-lives (whichever is longer) - 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) - Patients with a history of significant skin rash secondary to lenalidomide treatment should be discussed with the Medical Monitor to determine eligibility - Active known second malignancy. Exception: patients with non-metastatic, non-melanoma skin cancer are eligible - Any condition requiring hormonal therapy (except for contraception, hormone replacement therapy, and hormonal prophylaxis for a prior malignancy) - Patient has known allergies, hypersensitivity, or intolerance to components of study drug - Patient is 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 (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 - Vaccinated with a live vaccine within 28 days prior to the first dose of study drug or coronavirus-19 (COVID-19) vaccination within 14 days prior to first dose of study drug. Vaccinations of any kind are prohibited during the DLT period - Infection with HIV-1 or HIV-2. Exception: patients with well-controlled HIV (e.g., CD4 > 350/mm^3 and undetectable viral load) are eligible - Current active liver disease from any cause, including hepatitis B (hepatitis B virus surface antigen [HBsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with hepatitis B virus (HBV) who are negative for HBV DNA by quantitative polymerase chain reaction (PCR) are eligible irrespective of serology findings - Active viral reactivation (e.g., cytomegalovirus [CMV] or EBV) - Use of systemic corticosteroids exceeding 20 mg/day prednisone (or equivalent) for non-PCNSL indications within 15 days prior to study start. PCNSL patients may not exceed corticosteroid doses of 40 mg/day prednisone (or equivalent) and should be on a stable or decreasing dose for 7 days prior to study start. One-time corticosteroid doses used as prophylaxis for radio diagnostic contrast reactions are allowed - Use of non-steroidal immunosuppressive drugs within 30 days prior to start of the study - Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 microg (Note: Patients who switch from a high dose to a dose of 30 microg/day or less are eligible for study entry) - Any of the following within 6 months of planned start of study drug: -- Myocardial infarction -- Unstable angina -- Unstable symptomatic ischemic heart disease -- Placement of a coronary arterial stent -- Uncontrolled atrial fibrillation or other clinically significant uncontrolled arrhythmias or conduction abnormalities -- New York Heart Association (NYHA) class III or IV heart failure --Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events) --Stroke or intracranial hemorrhage --Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease) -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 -Administration of any strong inducers or inhibitors of cytochrome P450 3A (CYP3A) for 14 days (or 5 half-lives, whichever is longer) prior to the first dose of study drug, any moderate inducers of CYP3A for 7 days (or 5 half-lives, whichever is longer), and inhibitors of P-glycoprotein for 2 days (or 5 half-lives, whichever is longer) NOTE: Investigators should ensure that all study enrollment criteria have been met at Screening. If a patient's status changes (including laboratory results or receipt of additional medical records) after Screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, supportive treatment may be administered according to local standards of care, if necessary, so that eligibility criteria can be met and laboratory test(s) may be repeated to determine if the patient qualifies for the study. If rescreening occurs within 28 days of the signing of the original informed consent, it is only necessary to perform the procedure(s)/assessment(s) that did not originally meet the eligibility criteria; all other initial Screening procedures/assessments do not need to be repeated. If rescreening is delayed more than 28 days from the signing of the original informed consent, patients must be re-consented and repeat all Screening procedures/assessments that fall outside of a 28-day window prior to Cycle 1 Day 1. Patients may be rescreened more than once with Medical Monitor approval. Be aware that many laboratory tests, including but not limited to cardiovascular diagnostic tests and hormone tests, which use biotin technology are potentially affected, and incorrect test results may be generated if there is biotin in the patient s specimen. Know that biotin is found in multivitamins, including prenatal multivitamins, biotin supplements, and dietary supplements for hair, skin, and nail growth in levels that may interfere with laboratory tests. A threshold high level biotin dose has not yet been defined by the Food and Drug Administration (FDA). Study Investigators should discuss with study patients about any biotin supplements they may be taking. For patients taking biotin supplements at doses > 30 microg/day, the Investigator should assess if it is possible to discontinue use of these supplements. In cases where the Investigator believes a patient is taking high doses of biotin and discontinuation of this supplementation is not in the best interest of the patient, the Investigator should contact the Medical Monitor to assess the potential impact on study laboratory test results.
-Patients must be >= 18 years of age
-Patients in Phase 1a (Dose Escalation) must have histologically confirmed R/R CLL, SLL, MCL, FL, MZL, WM, PCNSL, or DLBCL. This includes the following specific subtypes, closely related diagnoses, or synonymous terms: lymphoplasmacytic lymphoma; extranodal mucosa-associated lymphoid tissue (MALT) lymphoma; nodal MZL; FL NOS; testicular FL; FL in situ; duodenal FL; diffuse variant FL; MCL NOS; DLBCL NOS; Tcell histiocytic rich large B-cell lymphoma (LBCL); primary DLBCL of the central
nervous system (CNS); Epstein Barr virus (EBV)-positive DLBCL; DLBCL associated with chronic inflammation and fibrin-associated DLBCL; primary mediastinal LBCL; ALK-positive LBCL; and B-cell lymphoma unclassifiable with features intermediate between classical Hodgkin and DLBCL. The criterion is also met when any of these diagnoses occurs as a result of Richter s transformation. Patients with transformed lymphoma are eligible for the study, with the exception of those detailed in Exclusion Criteria
-Patients in Phase 1a must meet the following:
--Received at least 2 prior systemic therapies (or at least 1 prior therapy for patients with WM or PCNSL) and have no other therapies known to provide clinical benefit
--At least 2 weeks must have elapsed between the last therapy and the first dose of study drug or at least 4 weeks for antibody-containing therapies, except for patients on a small molecule therapy who require at least 5 half-lives or 2 days (whichever is longer)
--Must require systemic therapy
-Patients in Phase 1b (Dose Optimization) must have 1 of the following histologically documented R/R B-cell malignancies and have failed at least 2 prior treatments (or at least 1 prior therapy for WM or PCNSL) and meet the appropriate criteria listed below:
--CLL/SLL whose disease has failed treatment with a BTKi
--MCL whose disease has failed treatment with a BTKi and an anti-CD20 mAb-based regimen
--FL or MZL whose disease has failed treatment with an anti-CD20 mAb-based regimen; or WM whose disease has failed treatment with a BTKi
--PCNSL whose disease has failed at least 1 prior line of treatment
--DLBCL whose disease has failed treatment with an anti-CD20 mAb-based regimen and either: an anthracycline-based regimen; or anti-CD19-based regimen; or another regimen or a palliative regimen when the aforementioned regimens (anthracycline based, or CD19-based) were contraindicated or unavailable (see exclusion criteria for prior CAR T-cell therapy) (either progressed post stem cell transplant or transplantineligible), including transformed indolent lymphoma (e.g., grade 3b/transformed FL or MZL), Richter-transformed DLBCL, high-grade B-cell lymphoma with MYC and BCL-2 and/or BCL-6 rearrangements, and high-grade B-cell lymphomas NOS
- Patients must have measurable disease. In this context, measurable disease is defined by specific malignancy and includes iwCLL, International Working Group (IWG), Lugano Classification of Lymphoma response criteria, or International PCNSL Collaborative Group response criteria. Measurable by computed tomography (CT), CT/positron emission tomography (CT/PET), or magnetic resonance imaging (MRI) is defined as at least one node >1.5 cm in size or measurable extranodal lesion of >=1.0 cm in longest diameter. Other quantifiable disease (including but not limited to bone marrow infiltration, minimal residual disease [MRD], splenic enlargement, or progressive lymphocytosis) is also allowed. For PCNSL, measurable disease includes the presence of contrast enhancing parenchymal lesions on MRI (CT with contrast is allowed when MRI is medically contra-indicated), cerebrospinal fluid (CSF) cytology positive for lymphomatous involvement, and/or the presence of intra-ocular disease by ophthalmologic examination. Disease evaluation at Screening should be done per disease standard guidelines. Subsequent procedures for the purpose of response assessments may be carried out per institutional standard and as clinically indicated. For WM, measurable abnormal serum monoclonal immunoglobulin M (IgM) protein is considered measurable disease in the context of this protocol
- Patients in Phase 1b must have received at least 2 prior lines of systemic therapy for the management of their disease (or at least 1 prior therapy for patients with WM or PCNSL)
- Patients with indolent forms of non-Hodgkin lymphoma (NHL) must meet the criteria requiring systemic treatment (i.e., iwCLL, IWG, or Lugano Classification of Lymphoma). Patients with PCNSL should meet the criteria for treatment as per the PCNSL Collaborative Group Criteria
- Patients with transformed lymphoma are eligible for the study with the exception of those described in exclusion #1
- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 (non-PCNSL indications) or 0-2 (PCNSL patients)
- Adequate organ and bone marrow function as defined by the following laboratory parameters (hematology, hepatic, and renal laboratory parameters are required to be performed 10 days prior to Cycle 1 Day 1 and must meet the criteria below)
Laboratory Parameter Value
--Hematology
---Hemoglobin > 9 g/dL or > 7 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 (ANC) > 1.0 x 10^9/L unless neutropenia is due to bone marrow involvement per Investigator assessment. Granulocyte colony stimulating factor (G-CSF) is allowed for those with bone marrow involvement of disease.
---Platelets > 75 x 10^9/L or > 50 (SqrRoot) 10^9/L if thrombocytopenia is due to bone marrow or splenic involvement per Investigator assessment. A minimum 5-day transfusion-free interval is required. Use of platelet-derived growth factors are prohibited.
---Coagulation (INR and partial thromboplastin time [PTT] or activated partial thromboplastin time [aPTT]) <= 1.5 (SqrRoot) ULN
(Patients undergoing lumbar puncture must have either PTT or aPTT < ULN).
--Pancreatic
---Serum amylase <=1.5 (SqrRoot) ULN.
---Serum lipase <=1.5 (SqrRoot) ULN.
--Hepatic
---AST and ALT <=2.5 (SqrRoot) ULN.
---Total bilirubin <= 1.5 (SqrRoot) ULN (or < 5 (SqrRoot) ULN for patients with Gilbert s syndrome).
--Renal
---Serum creatinine < 1.5 (SqrRoot) ULN or a calculated glomerular filtration rate (GFR) greater than 45mL/min/1.73m^2. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine.
--Cardiac
---QT interval corrected (QTc) ECG QTc for heart rate < 475 msec, measured by Fridericia's formula (QTcF = QT/([RR^0.33)]). If the QTc is prolonged in a patient with a pacemaker or bundle branch block, the patient may be enrolled in the study if confirmed by the Medical Monitor.
--Pulmonary
---Blood oxygen saturation > 92% on room air.
-Women of childbearing potential (WOCBP) must use 2 forms of contraception, of which 1 must be highly effective (defined as < 1% failure rate per year) and 1 must be a barrier method (condom), throughout the study from Screening through 6 months after the final dose of study drug. WOCBP defined as per the 2020 Clinical Trial Facilitation Group recommendations
- Women must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 6 months after receiving the last dose of study drug. Men must agree not to donate sperm during the study and for 3 months after receiving the last dose of study drug
- A male patient who is sexually active with a WOCBP must agree to use 2 forms of contraception, of which 1 must be highly effective (defined as < 1% failure rate per year) and 1 must be a barrier method (condom with spermicidal foam/gel/film/cream/suppository) throughout the study from Screening through 3 months after the final dose of study drug
- Patient must be willing and able to adhere to the prohibitions and restrictions specified in this protocol
- Each patient must sign an informed consent form (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
EXCLUSION CRITERIA:
Individuals who meet any of the following exclusion criteria will not be eligible to participate in the study:
- Prolymphocytic leukemia, MCL with blastoid histology, MCL with pleomorphic morphology, or MCL with known TP53 mutation
- Any of the following malignancies:
--Prolymphocytic leukemia; hairy cell leukemia; splenic B-cell lymphoma unclassifiable; IgM or immunoglobulin G (IgG) monoclonal gammopathy of undetermined significance; heavy chain disease; plasma cell neoplasms, including plasmacytoma; pediatric type FL; LBCL with IRF4 arrangement; primary cutaneous follicular center lymphoma; EBV-positive mucocutanous ulcer; lymphomatoid granulomatosis; intravascular LBCL, plasmablastic lymphoma; primary effusion lymphoma; HHV-8-associated lymphoproliferative disease, Burkitt lymphoma; mature T-cell and NK cell neoplasms; Hodgkin lymphomas; immunodeficiencyassociated lymphoproliferative diseases; histiocytic and dendritic cell neoplasms; precursor lymphoid neoplasms; blastic plasmacytic dendritic cell neoplasm; AML and related precursors neoplasms; myeloid malignancies; acute leukemias of ambiguous lineage; T-cell PCNSL
--Lymphoma or leukemia disease involving the brain stem
--Secondary CNS lymphoma/leukemia
--For patients with PCNSL only: evidence of disease outside of the CNS
- Active, uncontrolled autoimmune hemolytic anemia or autoimmune thrombocytopenia
- History of known/suspected other autoimmune disease (exception[s]: patients with alopecia, vitiligo, resolved childhood atopic dermatitis, hypothyroidism, or hyperthyroidism that is clinically euthyroid at Screening are allowed)
- 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
- Patient has any of the following:
--Uncontrolled intercurrent illness including, but not limited to, persistent, poorly controlled hypertension (defined as systolic blood pressure > 160 mmHg or diastolic blood pressure > 100 mmHg despite optimal medical management)
-- Uncontrolled diabetes
-- Ongoing significant infection requiring systemic antibiotics, antifungals, or antivirals (with exception of human immunodeficiency virus [HIV] antivirals) in the last 7 days
-- Patients who have undergone autologous or allogeneic stem cell transplant within 100 days prior to planned start of study drug
-- Patients with active graft-versus-host disease (GVHD) or on anti-GVHD treatment or prophylaxis
-- History of CAR T-cell therapy within 30 days prior to start of study drug.
-- History of known or suspected seizure disorder (non-PCNSL indications) or poorly controlled seizures (PCNSL patients)
-- History of prior pneumonitis requiring steroid treatment
- Bleeding diathesis, or other known risk for acute blood loss
- Patients with known GI lymphoma with history of bleeding within 3 months of planned start of study drug
- History of Grade >= 2 hemorrhage within 28 days
- Patients requiring ongoing treatment with warfarin or an equivalent vitamin K antagonist and within 7 days prior to first dose of study drug. Exceptions may be permitted after consultation with the Medical Monitor (or delegate)
- Prior radiotherapy within 2 weeks of planned start of study drug (excluding limited palliative radiation)
- Prior systemic chemotherapy within 2 weeks of planned start of study drug
- Prior anti-cancer mAb therapy within 4 weeks of planned start of study drug and prior anti-cancer small molecule therapy within 2 days or 5 half-lives (whichever is longer)
- 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)
- Patients with a history of significant skin rash secondary to lenalidomide treatment should be discussed with the Medical Monitor to determine eligibility
- Active known second malignancy. Exception: patients with non-metastatic, non-melanoma skin cancer are eligible
- Any condition requiring hormonal therapy (except for contraception, hormone replacement therapy, and hormonal prophylaxis for a prior malignancy)
- Patient has known allergies, hypersensitivity, or intolerance to components of study drug
- Patient is 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 (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
- Vaccinated with a live vaccine within 28 days prior to the first dose of study drug or coronavirus-19 (COVID-19) vaccination within 14 days prior to first dose of study drug. Vaccinations of any kind are prohibited during the DLT period
- Infection with HIV-1 or HIV-2. Exception: patients with well-controlled HIV (e.g., CD4 > 350/mm^3 and undetectable viral load) are eligible
- Current active liver disease from any cause, including hepatitis B (hepatitis B virus surface antigen [HBsAg] positive), or hepatitis C (hepatitis C virus [HCV] antibody positive, confirmed by HCV ribonucleic acid). Patients with HCV with undetectable virus after treatment are eligible. Patients with hepatitis B virus (HBV) who are negative for HBV DNA by quantitative polymerase chain reaction (PCR) are eligible irrespective of serology findings
- Active viral reactivation (e.g., cytomegalovirus [CMV] or EBV)
- Use of systemic corticosteroids exceeding 20 mg/day prednisone (or equivalent) for non-PCNSL indications within 15 days prior to study start. PCNSL patients may not exceed corticosteroid doses of 40 mg/day prednisone (or equivalent) and should be on a stable or decreasing dose for 7 days prior to study start. One-time corticosteroid doses used as prophylaxis for radio diagnostic contrast reactions are allowed
- Use of non-steroidal immunosuppressive drugs within 30 days prior to start of the study
- Use of biotin (i.e., Vitamin B7) or supplements containing biotin higher than the daily adequate intake of 30 microg (Note: Patients who switch from a high dose to a dose of 30 microg/day or less are eligible for study entry)
- Any of the following within 6 months of planned start of study drug:
-- Myocardial infarction
-- Unstable angina
-- Unstable symptomatic ischemic heart disease
-- Placement of a coronary arterial stent
-- Uncontrolled atrial fibrillation or other clinically significant uncontrolled arrhythmias or conduction abnormalities
-- New York Heart Association (NYHA) class III or IV heart failure
--Thromboembolic events (e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular events)
--Stroke or intracranial hemorrhage
--Any other significant cardiac condition (e.g., pericardial effusion, restrictive cardiomyopathy, severe untreated valvular stenosis, or severe congenital heart disease)
-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
-Administration of any strong inducers or inhibitors of cytochrome P450 3A (CYP3A) for 14 days (or 5 half-lives, whichever is longer) prior to the first dose of study drug, any moderate inducers of CYP3A for 7 days (or 5 half-lives, whichever is longer), and inhibitors of P-glycoprotein for 2 days (or 5 half-lives, whichever is longer)
NOTE: Investigators should ensure that all study enrollment criteria have been met at Screening. If a patient's status changes (including laboratory results or receipt of additional medical records) after Screening but before the first dose of study drug is given such that he or she no longer meets all eligibility criteria, supportive treatment may be administered according to local standards of care, if necessary, so that eligibility criteria can be met and laboratory test(s) may be repeated to determine if the patient qualifies for the study. If rescreening occurs within 28 days of the signing of the original informed consent, it is only necessary to perform the procedure(s)/assessment(s) that did not originally meet the eligibility criteria; all other initial Screening procedures/assessments do not need to be repeated. If rescreening is delayed more than 28 days from the signing of the original informed consent, patients must be re-consented and repeat all Screening procedures/assessments that fall outside of a 28-day window prior to Cycle 1 Day 1. Patients may be rescreened more than once with Medical Monitor approval.
Be aware that many laboratory tests, including but not limited to cardiovascular diagnostic tests and hormone tests, which use biotin technology are potentially affected, and incorrect test results may be generated if there is biotin in the patient s specimen. Know that biotin is found in multivitamins, including prenatal multivitamins, biotin supplements, and dietary supplements for hair, skin, and nail growth in levels that may interfere with laboratory tests. A threshold high level biotin dose has not yet been defined by the Food and Drug Administration (FDA).
Study Investigators should discuss with study patients about any biotin supplements they may be taking. For patients taking biotin supplements at doses > 30 microg/day, the Investigator should assess if it is possible to discontinue use of these supplements. In cases where the Investigator believes a patient is taking high doses of biotin and discontinuation of this supplementation is not in the best interest of the patient, the Investigator should contact the Medical Monitor to assess the potential impact on study laboratory test results.
Principal Investigator
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