None listed
Conditions
Brief summary
The purpose of this study is to evaluate the safety and efficacy of combination pirtobrutinib and glofitmab in patients with relapsed/refractory MCL and prior BTK inhibitor exposure. Who is this study for? You may be eligible to join this study if you are aged 18 or over and have been diagnosed with relapsed/refractory MCL. Study details: This study design involves phases for treatment ramp-up, fixed course combination and maintenance. Treatment Ramp Up 1. Pre-Phase (7 days): Pirtobrutinib 200mg oral daily. 1000mg of Obinutuzumab administered intravenously (IV) on D-7 and a second dose administered between Day 6 and Day 1 2. Cycle 1: Pirtobrutinib 200mg oral daily. An initial dose level of Glofitamab will evaluate step-up dosing. If excessive dose-limiting toxicity is observed, including cytokine release syndrome (CRS), a lower initial dose of 1.25mg of glofitamab will be evaluated at "dose level -1". Dose level 1 (14 days): *Pirtobrutinib 200mg oral daily *2.5mg Glofitamab by IV on Day 1 *10mg Glofitamab by IV on Day 8 Dose level -1 (21 days): *Pirtobrutinib 200mg oral daily *1.25mg Glofitamab by IV on Day 2 *2.5mg Glofitamab by IV on Day 8 *10mg Glofitamab by IV on Day 15 3. Cycle 2 (21 days): 30mg Glofitamab by IV on Day 1 Fixed course combination phase Cycles 3-12 (21 days per cycle): Pirtobrutinib 200mg oral daily, 30mg of Glofitamab by IV on day 1. Maintenance phase Cycles 13+ (28 days per cycle): Pirtobrutinib 200mg oral daily. Glofitamab discontinued. Other testing that will be performed includes physical examination, neurological examination, ECG and monitoring of adverse events. It is hoped that this study will provide evidence for the safety of pirtobrutinib and glofitmab used in combination for relapsed/refractory MCL patients.
Interventions
This study design involves phases for treatment ramp-up, fixed course combination and maintenance.
Pirtobrutinib will be administered by oral tablet at a dosage of 200mg/day for the duration of all phases in this study. In addition, the following treatment regimen will be followed.
Treatment Ramp Up
1. Pre-Phase (7 days): 1000mg of Obinutuzumab administered intravenously (IV) on day 7 and a second dose administered between Day 6 and Day 1
2. Cycle 1: An initial dose level of Glofitamab will e
This study design involves phases for treatment ramp-up, fixed course combination and maintenance. Pirtobrutinib will be administered by oral tablet at a dosage of 200mg/day for the duration of all phases in this study. In addition, the following treatment regimen will be followed. Treatment Ramp Up 1. Pre-Phase (7 days): 1000mg of Obinutuzumab administered intravenously (IV) on day 7 and a second dose administered between Day 6 and Day 1 2. Cycle 1: An initial dose level of Glofitamab will evaluate step-up dosing. If excessive dose-limiting toxicity is observed, including cytokine release syndrome (CRS), a lower initial dose of 1.25mg of glofitamab will be evaluated at "dose level -1". Dose level 1 (14 days): *2.5mg Glofitamab by IV on Day 1 *10mg Glofitamab by IV on Day 8 Dose level -1 (21 days): *1.25mg Glofitamab by IV on Day 2 *2.5mg Glofitamab by IV on Day 8 *10mg Glofitamab by IV on Day 15 3. Cycle 2 (21 days): 30mg Glofitamab by IV on Day 1 Fixed course combination phase Cycles 3-12 (21 days per cycle): 30mg of Glofitamab by IV on day 1 Maintenance phase Cycle 13+ (28 days per cycle): Glofitamab discontinued. Pirtobrutinib 200mg oral daily. Maintenance treatment is planned to continue indefinitely until participants permanently cease study medications for any reason (eg. toxicity, disease progression), followed by End of Treatment assessments and safety follow ups. Patients will only move on to the next consecutive phase once the previous phase is completed. All treatment will be administered by the study team.
Sponsors
Australasian Leukaemia and Lymphoma Group (ALLG)
Study design
Allocation
Non-randomised trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Age >=18 years old 2. A confirmed diagnosis of MCL according to World Health Organization (2016) criteria 3. At least one site of measurable disease not previously irradiated (defined as at least one bi-dimensionally measurable nodal lesion of =1.5cm in longest dimension or extranodal lesion of =1.0cm in longest dimension) 4. Life expectancy (in the opinion of the investigator) of =18 weeks 5. Prior therapy with a BTK inhibitor alone or in combination, and at least one of: a) Progression or relapse post BTK inhibitor and/ or b) Failed to achieve PR following 12 weeks of BTK inhibitor therapy 6. Prior treatment-related AEs (TRAE) must have recovered to Grade = 1 with the exception of alopecia, peripheral neuropathy and lymphopenia. 7. Eastern Cooperative Oncology Group (ECOG) 0-2 8. Adequate washout of prior therapies: a) Broad field radiation (= 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study treatment. b) Palliative limited field radiation must be completed 7 days prior to study treatment. c) Targeted agents, investigational agents, therapeutic monoclonal antibodies/antibody drug conjugates or cytotoxic chemotherapy must be completed 5 half-lives or 2 weeks (whichever is shorter) prior to study treatment (except for BTK inhibitors which may be continued until 1 day prior to planned first therapy with pirtobrutinib) d) Steroids >25mg daily prednisolone (or equivalent) for a condition other than lymphoma must be completed 7 days prior to study treatment (note: prednisolone =100mg daily or equivalent for up to 14 days are permitted during screening for control of lymphoma related symptoms). 9. Ability to take oral medications. 10. Willing and capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in the protocol. 11. Willingness of men and women of reproductive potential, and their partners, to observe barrier and highly effective birth control methods for the duration of treatment and for six months following the last dose of study treatment. When pirtobrutinib is taken with hormonal contraceptives (e.g., birth control pills), pirtobrutinib might affect the birth control. More effective birth control, such as using 2 birth control methods, should be considered. 12. Women of childbearing potential must have a negative serum pregnancy test within seven days of enrolment. 13. Adequate coagulation, defined as aPTT and PT not greater than 1.5xULN, unless laboratory abnormality is explained by concomitant anticoagulant medication, a lupus anticoagulant, or a factor deficiency not associated with an increased bleeding risk, as determined by the investigator. 14. Adequate liver function: a) ALT and AST =3X ULN, or =5X ULN if documented liver involvement b) Total bilirubin =1.5X ULN or =3X ULN if documented liver involvement and/or Gilbert’s Disease 15. Adequate renal function a) Creatinine clearance =30mls/minute according to Cockroft-Gault formula 16. Adequate haematological parameters: a) Haemoglobin =80g/L b) Absolute neutrophil count =1.0x109/L c) Platelets = 75 X 109/L or = 50 X 109/L if documented marrow involvement or splenomegaly (must be platelet transfusion independent for 7 days prior to first dose of obinutuzumab) 17. Sufficient archival tissue is available for central review (or if not available only after discussion with the CPI).
Exclusion criteria
1. Inability to comply with protocol-mandated assessments/ procedures, including hospitalisations. 2. A history of allogeneic transplantation within 6 months of enrolment or ongoing chronic GVHD or use of immunosuppressive therapy within 4 weeks of enrolment. 3. Autologous stem cell transplant (SCT) or chimeric antigen receptor- modified T-cell (CAR-T) therapy within 6 weeks of enrolment, or ongoing need for: a. Anti-cytokine therapy or immunosuppressive therapy (>20mg prednisolone or equivalent daily) for toxicity from CAR-T therapy b. Residual symptoms of neurotoxicity > grade 1 from CAR-T therapy 4. Active central nervous system involvement with MCL Note: Patients with previous treatment for CNS involvement who are neurologically stable and without evidence of disease are eligible 5. Prior treatment with pirtobrutinib or a CD20xCD3 bispecific antibody. 6. Known severe hypersensitivity to any of the excipients of pirtobrutinib, glofitamab, tocilizumab or obinutuzumab. 7. History of stroke or intracranial haemorrhage within six months of enrolment. 8. Live vaccination within 28 days of enrolment. 9. Major surgery or significant traumatic injury within 28 days of study treatment or the anticipation of major surgery during study treatment (surgical procedures for the diagnosis of lymphoma such as lymph node resection/ laparoscopy are allowed provided patient is considered fit for treatment as judged by investigator) 10. Significant cardiovascular disease defined as: a. Unstable angina or acute coronary syndrome within 2 months of registration b. History of myocardial infarction within 3 months prior to registration or c. Documented left ventricular ejection fraction (LVEF) by any method of = 40% during screening d. = Grade 3 New York Heart Association (NYHA) functional classification system of heart failure e. Uncontrolled or symptomatic arrhythmias 11. 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/(RR0.33) Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator’s discretion and only if clinically safe to do so with either discontinuation of the offending drug or switching to another drug not known to be associated with QTcF prolongation. Correction for underlying bundle branch block (BBB) allowed. Patients with pacemakers are eligible if they have no history of fainting or clinically relevant arrhythmias 12. Known human immunodeficiency virus (HIV) infection 13. Known active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection based on criteria below: a. HBV: Patients with positive hepatitis B surface antigen (HBsAg) are excluded. Patients with positive hepatitis B core antibody (antiHBc) and negative HBsAg require negative hepatitis B polymerase chain reaction (PCR) before enrolment and must be treated with antiviral therapy. Patients who are hepatitis B PCR positive will be excluded. b. HCV: If positive hepatitis C antibody, patient will need to have a negative hepatitis C ribonucleic acid (RNA) before enrolment. Patients who are hepatitis C RNA positive will be excluded. 14. Known active cytomegalovirus (CMV) infection. Unknown or negative status are eligible. 15. Pregnancy, lactation or plan to breastfeed during the study or within 6 months of the last dose of study treatment. 16. Clinically significant active malabsorption syndrome or other condition likely to affect gastrointestinal (GI) absorption of pirtobrutinib. 17. Evidence of other clinically significant uncontrolled condition(s) including but not limited to, uncontrolled systemic bacterial, viral, fungal or parasitic infection, or other clinically significant active disease process which in the opinion of the investigator and medical monitor may pose a risk for patient participation. 18. Active uncontrolled auto-immune cytopenia (e.g., autoimmune haemolytic anaemia [AIHA], idiopathic thrombocytopenic purpura [ITP]) for which new therapy was introduced or existing therapy was escalated within the 4 weeks prior to study enrolment to maintain adequate blood counts, unless auto-immune cytopenias are secondary to MCL 19. Active second malignancy unless in remission and with life expectancy > 2 years. 20. Patients requiring therapeutic anticoagulation with warfarin or another vitamin K antagonist. 21. History of bleeding diathesis 22. Patients who experienced a major bleeding event or grade = 3 arrhythmia on prior treatment with a BTK inhibitor. NOTE: Major bleeding is defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise; bleeding associated with a decrease in the hemoglobin level of at least 2g per deciliter; or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome) 23. Any medical condition that in the view of the investigator, or the central study team (if discussed), would render the patient unlikely to medically tolerate a limited duration of grade 3 CRS.
Outcome results
None listed