PIRTOBRUTINIB AND GLOFITAMAB IN MANTLE CELL LYMPHOMA

Prior treatment

• Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure
• Positive test results for chronic HBV/HCV infection (defined as positive HBsAg serology) or HIV (mandatory testing). Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) may be included if HBV DNA is undetectable. Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA.
• Live vaccine ≤ 6 weeks prior to planned start of study treatment.
• Simultaneously active participation in another clinical study involving an investigational medicinal product within 30 days prior to enrolment
• Previous treatment with an anti-CD20 directed bispecific antibody
• Previous treatment with a BTKi
• Previous CART treatment
• Steroid therapy (prednisolone ≤100mg daily or equivalent for up to 14 days are permitted during screening for control of lymphoma related symptoms)
• Targeted agents, investigational agents, therapeutic monoclonal antibodies/antibody drug conjugates or cytotoxic chemotherapy must be completed 5 half-lives or 2 weeks (whichever is longer) prior to study treatment
• Major surgery or significant traumatic injury within 28 days of screening, major surgery does not include uncomplicated lymph node resection/ laparoscopy for the diagnosis of MCL
• Requirement of therapeutic anticoagulation with a vitamin K antagonist (warfarin, phenprocoumon) or of treatment with strong CYP3A4 inhibitors or inducers
• Immunoconjugated antibody treatment within 10 weeks prior to enrolment
• Broad field radiation (≥ 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to treatment start. Palliative limited field radiation must be completed 7 days prior to treatment start.
• Prior treatment-related AEs must have recovered to Grade ≤ 1 with the exception of alopecia and Grade 2 peripheral neuropathy.
• Known or persistent abuse of medication, drugs, or alcohol.
• Serious concomitant disease interfering with a regular therapy according to the study protocol: Clinically significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, unstable angina, myocardial infarction, cardiac angioplasty or stenting within 12 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification

Other illness

• Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management. Known active CMV infection.
• History or presence of 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.
• History of or active autoimmune disease (e.g. Crohn’s disease, rheumatoid arthritis, systemic lupus) resulting in end organ injury or requiring systemic immunosuppression/systemic medication within the last 2 years.
• Any medical condition likely to interfere with assessment of safety or efficacy of study treatment.
• Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule
• Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal absorption of pirtobrutinib.
• History of bleeding diathesis
• History of allogeneic transplantation
• Subjects with a physical or psychiatric condition which at the investigator’s discretion may put the subject at risk, may confound the study results, or may interfere with the subject’s participation in this clinical study
• Severe endocrinological conditions (e.g. severe, not sufficiently controlled diabetes mellitus).
• History of or active malignancy other than MCL, non-melanoma skin cancer, carcinoma in situ (eg, cervix, bladder, breast). History of localized prostate cancer acceptable only if diseasefree and PSA within normal range for at least 3 years

Lab values

• Prolongation of the QT interval corrected for heart rate (QTcF) > 470 msec on at least 2/3 consecutive electrocardiograms (ECGs), and mean QTcF > > 470 msec on all 3 ECGs, during screening. QTcF is calculated using Fridericia’s formula (QTcF): QTcF = QT/(RR*0.33)

Other

• Known severe primary immunodeficiency.
• Current or planned pregnancy (during the study or within 1 month of the last study treatment) or nursing women (within 1 week from the last study treatment)

• Cohort A (R/R MCL): Relapse or progression following at least one prior line of anti-neoplastic standard therapy, which included at least an anti CD20 antibody plus an anthracycline and/or bendamustine and/or fludarabine.
• The following laboratory values at screening (unless related to MCL) : Platelets ≥75,000 cells/μL (≥50,000 cells/μL required if caused by bone marrow involvement or splenomegaly due to MCL), independent of transfusions within 7 days of Screening assessment.Hemoglobin ≥ 8 g/dL or ≥ 6 g/dL in patients with documented bone marrow involvement considered to impair hematopoiesis. Calculated creatinine clearance ≥30 mL/min. Transaminases (AST and ALT) ≤ 3 x ULN. Total Bilirubin ≤ 1.5 x ULN or ≤ 3 x ULN with documented Gilbert-MeulengrachtSyndrome or liver involvement by MCL. aPTT and PT ≤1.5 x ULN, unless explained by concomitant anticoagulant medication, and in the opinion of the investigator not associated with an increased bleeding risk.
• Adequate cardiopulmonary function defined as: cardiac ejection fraction ≥ 45% at all assessments within the last 12 months from screening, no evidence of pericardial effusion as determined by echocardiography; no clinically significant pleural effusion; baseline oxygen saturation > 92% on room air
• No evidence of CNS-disease
• Written informed consent form according to ICH/ E6 (R2) CTR and national regulations, ability to follow study instructions and likely to attend and complete all required visits.
• Sexually active men and women of child-bearing potential must agree to use one of the highly effective contraceptive methods (combined oral contraceptives using two hormones, progestogen-only hormonal contraception associated with inhibition of ovulation, contraceptive implants, injectables, intrauterine devices, sterilized partner) together with one of the barrier methods (latex condoms, diaphragms, contraceptive caps) while on study; this should be maintained for 6 months after the last dose of study drug
• Negative serum or urine pregnancy test (Females of childbearing potential only, females who have undergone surgical sterilization or who have been postmenopausal for at least 2 years are not considered to be of childbearing potential. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient).
• Availability of tissue samples for central pathology review
• Cohort A (R/R MCL): Aged 18 years or older.
• Cohort B (elderly TN MCL): Previously untreated.
• Cohort B (elderly TN MCL): Age ≥ 65 years or ≥ 60 years who are in the opinion of the investigator not suited for intensive, cytarabine and platinum-based induction treatment regimens
• Histologically confirmed diagnosis of MCL according to WHO classification, with documentation of either overexpression of cyclin D1 or presence of t(11;14).
• Stage II-IV (Ann Arbor)
• At least 1 measurable lesion according to the Lugano Response Criteria (>1.5 cm nodal lesion or > 1 cm extranodal lesion)
• ECOG performance status ≤ 2
• The patient is able to take oral medications