Phase 2 Study of BTKi-Rituximab Induction Followed by Glofitamab Consolidation in High Risk Untreated MCL Patients - WINDOW-4 Study

Inclusion criteria

• Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative polymerase chain reaction (PCR) and must be willing to undergo DNA PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis B PCR positive will be excluded (unless cleared by hepatology and ID team after discussion with study PI). Subjects who are hepatitis C antibody positive will need to have a negative PCR result to be eligible. Those who are hepatitis C PCR positive will be excluded.
• Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ ca prostate, in situ melanoma (\> 5 mm margins) or other cancer from which the subject has been disease free for ≥ 3 years or which will not limit survival to \< 3 years or not on active systemic chemotherapy.
• Central nervous system involvement with mantle cell lymphoma or with suspected or confirmed progressive multifocal leukoencephalopathy (PML). Magnetic resonance imaging (MRI) of the brain, if performed, showing evidence of central nervous system (CNS) lymphoma or Lumbar puncture with flow cytometry, if performed, with CSF involvement.
• History or presence of uncontrolled CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, cerebral edema, posterior reversible encephalopathy syndrome, or any autoimmune disease with CNS involvement.
• Active bleeding, history of bleeding diathesis (such as Hemophilia or Von-Willebrand disease), Any history of intracranial bleed or stroke within 6 months of first dose of study drug.
• Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura).
• Malabsorption syndrome, disease which is clinically significantly affecting gastrointestinal function, or resection of the stomach or small bowel or active ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of BTKi. These participants may be allowed after discussion, clearance with GI team and discussion with the study PI.
• Presence of a clinically significant gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug.
• Requires anticoagulation with warfarin or equivalent vitamin K antagonist, active treatment for pulmonary embolism (PE)/ deep vein thrombosis (DVT) and persons with mechanical cardiac valves. These participants may be allowed after review with benign hematology and study PI.
• Concomitant use of corticosteroids at \> 20 mg prednisone or equivalent per day longer than 2 weeks.
• Primary immunodeficiency which is clinically active
• History of confirmed autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. Rheumatology clearance and approval by study PI is required for pts with remote history of auto-immune disease.
• The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited.
• Requires treatment with strong CYP3A inhibitors or inducers.
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification. Subjects with controlled, asymptomatic heart failure during screening can enroll on study and/or any of the following cardiac related conditions, unless cleared by cardiology and study PI:
• NYHA Class III and IV heart failure,
• Active/symptomatic coronary artery disease,
• Myocardial infarction in the preceding 6 months,
• Significant conduction abnormalities, including but not limited to:
• Left bundle branch block,
• 2nd degree AV block type II,
• 3rd degree block,
• QT prolongation (QTc \> 500 msec),
• Sick sinus syndrome,
• Ventricular tachycardia,
• Symptomatic bradycardia (heart rate \< 50 bpm),
• Persistent and uncontrolled atrial fibrillation.
• Uncontrolled hypertension
• Uncontrolled Hypotension
• Light headedness and syncope,
• Acute infection requiring systemic anti-infective treatment systemic antibiotics, antivirals, or antifungals, or including subjects with positive cytomegalovirus \[CMV\] DNA polymerase chain reaction \[PCR\] within 14 days prior to initiation of therapy. Participant who exhibit active uncontrolled infection on BTKi-R alone will not be excluded but would await adequate infection control and then get CAR T, as long as they have evidence of disease.
• Vaccinated with live, attenuated vaccines within 6 weeks of first dose of study drug.
• Any other serious medical condition including, but not limited to, clinically significant uncontrolled diabetes mellitus, COPD, renal failure, psychiatric illness or social circumstances that, in the investigator's opinion places the participant at unacceptable risk and would prevent the participant from signing the informed consent form or complying with study procedures.
• Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components. 6\. Concurrent participation in another therapeutic clinical trial. 47. Is unable to swallow any oral medication or has clinically significant gastrointestinal disease thatwould limit absorption of oral medication. 48\. . 49. Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 50\. Participants with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (antiHBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded. Subjects with a history of Hepatitis C who received antiviral treatment are eligible as long as PCR is negative.
• History of severe allergic or anaphylactic reactions or intolerance to anti-CD20 monoclonal antibody therapy or any bispecific antibody.
• History of immunodeficiency (except for hypogammaglobulinemia) or concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc., or chronic administration glucocorticoid equivalent of \>10mg/day of prednisone) within 28 days of the first dose of study drug with exception of steroid used for IV contrast allergy. In addition, use of inhaled, topical, intranasal corticosteroids or local steroid injection (eg, intra- articular injection) is permitted.

Exclusion criteria

• Having radiologically confirmed relapsed/refractory disease.
• Isolated bone marrow or GI only disease MCL participants and/or lack of any measurable disease, except if participants have leukemic phase MCL with any high risk features.
• Pregnant or breast-feeding females.
• Participants who are primary refractory to BTKi-R (No response/progressive disease within first 3 months of BTKi-R)
• Received any investigational drug within 30 days or 5 half-lives (whichever is shorter) before first dose of study drug.
• Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety or put the study at risk.
• Known HIV infection.
• Known history of hemophagocytic lymphohistiocytosis (HLH)
• Known or suspected chronic active Epstein-Barr virus infection (clearance with infectious disease is needed to allow these participants)
• Positive SARS-CoV-2 test within 7 days prior to enrollment. Rapid antigen test result is also acceptable.
• Participants who do not meet high risk features as indicated above in inclusion.
• Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative polymerase chain reaction (PCR) and must be willing to undergo DNA PCR testing during the study to be eligible. Those who are HBsAg positive or hepatitis B PCR positive will be excluded (unless cleared by hepatology and ID team after discussion with study PI). Subjects who are hepatitis C antibody positive will need to have a negative PCR result to be eligible. Those who are hepatitis C PCR positive will be excluded.
• Prior malignancy (or any other malignancy requiring active treatment), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, in situ ca prostate, in situ melanoma (\> 5 mm margins) or other cancer from which the subject has been disease free for ≥ 3 years or which will not limit survival to \< 3 years or not on active systemic chemotherapy.
• Central nervous system involvement with mantle cell lymphoma or with suspected or confirmed progressive multifocal leukoencephalopathy (PML). Magnetic resonance imaging (MRI) of the brain, if performed, showing evidence of central nervous system (CNS) lymphoma or Lumbar puncture with flow cytometry, if performed, with CSF involvement.
• History or presence of uncontrolled CNS disorder, such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, cerebral edema, posterior reversible encephalopathy syndrome, or any autoimmune disease with CNS involvement.
• Active bleeding, history of bleeding diathesis (such as Hemophilia or Von-Willebrand disease), Any history of intracranial bleed or stroke within 6 months of first dose of study drug.
• Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura).
• Malabsorption syndrome, disease which is clinically significantly affecting gastrointestinal function, or resection of the stomach or small bowel or active ulcerative colitis, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction, or any other gastrointestinal condition that could interfere with the absorption and metabolism of BTKi. These participants may be allowed after discussion, clearance with GI team and discussion with the study PI.
• Presence of a clinically significant gastrointestinal ulcer diagnosed by endoscopy within 3 months before first dose of study drug.
• Requires anticoagulation with warfarin or equivalent vitamin K antagonist, active treatment for pulmonary embolism (PE)/ deep vein thrombosis (DVT) and persons with mechanical cardiac valves. These participants may be allowed after review with benign hematology and study PI.
• Concomitant use of corticosteroids at \> 20 mg prednisone or equivalent per day longer than 2 weeks.
• Primary immunodeficiency which is clinically active
• History of confirmed autoimmune disease (e.g. Crohn's disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic disease modifying agents within the last 2 years. Rheumatology clearance and approval by study PI is required for pts with remote history of auto-immune disease.
• The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of study drug is prohibited.
• Requires treatment with strong CYP3A inhibitors or inducers.
• Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification. Subjects with controlled, asymptomatic heart failure during screening can enroll on study and/or any of the following cardiac related conditions, unless cleared by cardiology and study PI:
• NYHA Class III and IV heart failure,
• Active/symptomatic coronary artery disease,
• Myocardial infarction in the preceding 6 months,
• Significant conduction abnormalities, including but not limited to:
• Left bundle branch block,
• 2nd degree AV block type II,
• 3rd degree block,
• QT prolongation (QTc \> 500 msec),
• Sick sinus syndrome,
• Ventricular tachycardia,
• Symptomatic bradycardia (heart rate \< 50 bpm),
• Persistent and uncontrolled atrial fibrillation.
• Uncontrolled hypertension
• Uncontrolled Hypotension
• Light headedness and syncope,
• Acute infection requiring systemic anti-infective treatment systemic antibiotics, antivirals, or antifungals, or including subjects with positive cytomegalovirus \[CMV\] DNA polymerase chain reaction \[PCR\] within 14 days prior to initiation of therapy. Participant who exhibit active uncontrolled infection on BTKi-R alone will not be excluded but would await adequate infection control and then get CAR T, as long as they have evidence of disease.
• Vaccinated with live, attenuated vaccines within 6 weeks of first dose of study drug.
• Any other serious medical condition including, but not limited to, clinically significant uncontrolled diabetes mellitus, COPD, renal failure, psychiatric illness or social circumstances that, in the investigator's opinion places the participant at unacceptable risk and would prevent the participant from signing the informed consent form or complying with study procedures.
• Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components. 6\. Concurrent participation in another therapeutic clinical trial. 47. Is unable to swallow any oral medication or has clinically significant gastrointestinal disease thatwould limit absorption of oral medication. 48\. . 49. Major surgical procedure within 28 days of first dose of study drug. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. 50\. Participants with inactive hepatitis B infection must adhere to hepatitis B reactivation prophylaxis unless contraindicated. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (antiHBc) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result. Those who are hepatitis C PCR positive will be excluded. Subjects with a history of Hepatitis C who received antiviral treatment are eligible as long as PCR is negative.
• History of severe allergic or anaphylactic reactions or intolerance to anti-CD20 monoclonal antibody therapy or any bispecific antibody.
• History of immunodeficiency (except for hypogammaglobulinemia) or concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc., or chronic administration glucocorticoid equivalent of \>10mg/day of prednisone) within 28 days of the first dose of study drug with exception of steroid used for IV contrast allergy. In addition, use of inhaled, topical, intranasal corticosteroids or local steroid injection (eg, intra- articular injection) is permitted.