PLATO -> Glofitamab Combined With Pirtobrutinib in Relapsed/Refractory Patients with Mantle Cell Lymphoma Followed by an Extension in Treatment Naïve Patients
Investigational medicinal products (IMP):
(1) Pirtobrutinib, PO, 200 mg QD continuously from C1D1 until progression or inacceptable toxicity (Cohort A and high risk patients in Cohort B). Standard risk patients in Cohort B will receive Pirtobrutinib from C1D1 through C12D21 in combination with Glofitamab followed by a 24 months maintenance treatment period.
(2) Obinutuzumab, IV, 1000 mg C1D1 (split dosing 100 mg (d1)/900 mg (d2) permitted), 1000 mg C1D2, delayed dosing until C1D7 permitted to mitigate infusion related reactions and tumor lysis syndrome
(3) Glofitamab IV, 2.5 mg C1D8, 10 mg C1D15, 30 mg C2D1, C3D1 through C12D1 30 mg
Cycle duration 21 days (c1 through c12), cycle duration 28 days from c13 onwards
geplant, Rekrutierung startet in Kürze
Herr Prof. Dr. med. Sebastian Böttcher
Sebastian.Boettcher@med.uni-rostock.de
Universitätsmedizin Rostock - Rostock (Prüfzentrum, 11474)
Zentrum für Innere Medizin - Medizinische Klinik III
Ernst-Heydemann-Str. 6
18057 Rostock
Cohort A: To assess safety and efficacy of Glofitamab/Pirtobrutinib in RR MCL patients as compared to a historical control of Ibrutinib treated patients.
Cohort B: To assess efficacy of Glofitamab/Pirtobrutinib in TN elderly MCL patients as compared to a historical control of elderly patients treated with bendamustin, rituximab, and ibrutinib within the scope of the SHINE trial.
(1) for high risk patients according to the CARMAN trial definition
(2) for the remaining standard risk patients.
To further assess efficacy, safety, and tolerability of Glofitamab/Pirtobrutinib by means of secondary and exploratory endpoints in comparison to the standard of care.
Adult patients with relapsed/refractory (rr) stage II-IV mantle cell lymphoma (MCL) after at least one line of previous treatment who have not previously been exposed to Bruton tyrosine kinase inhibitors (BTKi) (Cohort A, 32 patients)
Adult patients with treatment naïve (TN) stage II-IV MCL unsuitable for an intensive, cytarabine and platinum-based induction treatment regimen (Cohort B, 2 x 32 patients, 2 strata according to biological risk)
Statistical Design and Rationale for Sample Size
For each cohort, the null hypothesis of inacceptable efficacy in terms of 24-months PFS from trial registration will be tested by means of a one-sided exact binomial test with 10% significance level. The sample size is chosen to achieve 80% power for rejecting the null hypothesis if the true 24-month PFS is as expected for a suitable promising value.
Cohort A (r/r MCL):
Null hypothesis: 24-month PFS d 45%
Expected promising value giving 80% power to reject the null hypothesis: 65%. This value represents a 10% improvement over results with ibrutinib monotherapy from the RAY trial.
No. of patients necessary (including 10% dropouts): 32
Cohort B (TN MCL, biological standard risk):
Null hypothesis: 24-month PFS d 62%
Expected promising value giving 80% power to reject the null hypothesis: 80%. This value reflects results with BR-I as observed in SHINE trial.
No. of patients necessary (including 10% dropouts): 32
Cohort B (TN MCL, biological high risk):
Null hypothesis: 24-month PFS d 34%
Expected promising value giving 80% power to reject the null hypothesis: 54%. This value reflects results with BR-I as observed in SHINE trial (Wang et al., NEJM , 2022).
No. of patients necessary (including 10% dropouts): 32
All endpoints will be analyzed by cohort (A and B) and within cohort B according to strata (high vs. standard risk).
Primary endpoint: Progression free survival 24 months from trial registration
Secondary endpoints:
• Progression free survival from trial registration
• Complete remission rate (CR) and overall response rate (ORR: CR, PR) 9 months from trial registration (after completion of Glofitamab-treatment, prior to cycle 13) and approximately 24 months (prior to cycle 28) from trial registration
• Rate of PET negative CR (complete metabolic response rate, Lugano criteria) 9 months from trial registration (after completion of Glofitamab-treatment prior to cycle 13) and 24 months (prior to cycle 28) from trial registration
• Time to best response, time to first response from trial registration
• Duration of response
• Duration of CR
• Overall survival (OS) from trial registration
• Safety: adverse events, serious adverse events, toxicities (CTCAE v5.0 and ASTCT 2019 for CRS/ICANS21)
Exploratory endpoints:
• Molecular remission rate in peripheral blood 6 weeks (prior to cycle 3), 4.5 (prior to cycle 7), 9 (prior to cycle 13), 12 (prior to cycle 16), 24 (prior to cycle 28), 36 (prior to cycle 40) months from treatment start (all patients), and additionally 48 and 60 months from treatment start (Cohort B patients)
• Molecular remission rate in bone marrow approximately 9 (after completion of Glofitamab-treatment prior to cycle 13) and 24 months (prior to cycle 28) from treatment start
• In-depth immunophenotype of T-cell, NK-cell, B-cell subpopulations, at baseline, and 1 week, 3 weeks, 6 weeks (prior to cycle 3), 4.5 (prior to cycle 7), 9 (prior to cycle 13), 12 (prior to cycle 16), 24 (prior to cycle 28), 36 (prior to cycle 40) months from treatment start (all patients), and additionally 48 and 60 months from treatment start (Cohort B patients)
• Serological and antigen-specific T-cell response to SARS-COV2 and CMV at base-line, 9 (after completion of Glofitamab-treatment prior to cycle 13) and 24 months (prior to cycle 28) from treatment start
• Prognostic significance of the mutational profile as assessed in cf DNA
• ORR, CR, PFS, OS in biological high risk patients from Cohort B with TP53 mutation and with Ki67 e 30% as individual risk features
Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the study:
Cohort A (R/R MCL):
1. 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 (Therapy in remission after initial induction like intensified chemotherapy for stem cell separation followed by myeloablative therapy or any kind of maintenance therapy is classified as one line of therapy together with the induction therapy.)
2. In the opinion of the investigator not suitable or ineligible for CART-cell therapy
3. Aged 18 years or older
Cohort B (elderly TN MCL):
1. previously untreated
2. Age e 65 years or e 60 years who are in the opinion of the investigator not suited for intensive, cytarabine and platinum-based induction treatment regimens
Cohorts A and B:
1. Histologically confirmed diagnosis of MCL according to WHO classification, with documentation of either overexpression of cyclin D1 or presence of t(11;14)
2. Stage II-IV (Ann Arbor)
3. At least 1 measurable lesion according to the Lugano Response Criteria (>1,5 cm nodal lesion or > 1 cm extranodal lesion).
4. ECOG performance status d 2
5. The following laboratory values at screening (unless related to MCL):
o Absolute neutrophil count (ANC) e 1000 cells/¼L
o Platelets e75,000 cells/¼L (e50,000 cells/¼L required if caused by bone marrow involvement or splenomegaly due to MCL)
o Calculated creatinine clearance e30 mL/min
o Transaminases (AST and ALT) < 3 x ULN
o Total bilirubin d2 x ULN unless other reason known (e.g. Gilbert-Meulengracht-Syndrome)
o aPTT and PT d1.5 x ULN, unless explained by concomitant anticoagulant medication, and in the opinion of the investigator not associated with an increased bleeding risk
6. Adequate cardiopulmonary function (unless related to MCL) defined as: cardiac ejection fraction e 40%, no evidence of pericardial effusion as determined by echocardiography; no clinical significant pleural effusion; baseline oxygen saturation > 92% on room air.
7. No evidence of CNS-disease.
8. Written informed consent form according to ICH/EU GCP and national regulations, ability to follow study instructions and likely to attend and complete all required visits.
9. 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, 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.
10. 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).
11. Availability of tissue samples for central pathology review
1. Subjects not able to give consent
2. Subjects without legal capacity, unable to understand the nature, scope, significance and consequences of this clinical study
3. Known history of hypersensitivity to the investigational drug or to drugs with a similar chemical structure
4. Simultaneously active participation in another clinical study involving an investigational medicinal product within 30 days prior to enrolment
5. 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
6. Known or persistent abuse of medication, drugs, or alcohol
7. 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
8. 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)
9. Severe endocrinological conditions (e.g. severe, not sufficiently controlled diabetes mellitus)
10. Current or planned pregnancy or nursing women
11. History of or active malignancy other than MCL, non-melanoma skin cancer, carcinoma in situ (eg, cervix, bladder, breast) or prostate cancer unless disease-free for at least 3 years (and PSA within normal range in case of prostate cancer).
12. Presence of fungal, bacterial, viral, or other infection that is uncontrolled or requiring intravenous (IV) antimicrobials for management.
13. Positive test results for chronic HBV infection (defined as positive HBsAg serology) (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
14. Positive test results for hepatitis C (mandatory hepatitis C virus [HCV] antibody serology testing). Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA
15. Patients with known HIV positive infection (mandatory test)
16. Known active CMV infection.
17. 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
18. 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
19. Known severe primary immunodeficiency
20. Any medical condition likely to interfere with assessment of safety or efficacy of study treatment
21. Live vaccine d 6 weeks prior to planned start of study treatment
22. Any psychological, familial, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule
23. Previous treatment with an anti-CD20 directed bispecific antibody
24. Previous treatment with a BTKi
25. Previous CART treatment
26. Steroid therapy (prednisolone d100mg daily or equivalent for up to 14 days are permitted during screening for control of lymphoma related symptoms)
27. 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
28. A history of allogeneic transplantation within 6 months of enrolment or ongoing chronic GVHD or use of immunosuppressive therapy within 4 weeks of enrolment
29. 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
30. Requirement of therapeutic anticoagulation with a vitamin K antagonist (warfarin, phenprocoumon) or of treatment with strong CYP3A4 inhibitors or inducers
Study set up: Q2/2023
First subject in: Q2/2024
Last subject in: Q4/2025
Last subject last treatment: Q4/2030
Last subject out: Q1/2031
All sites closed: Q2/2031
Duration of the study approx. 84 months
Duration of recruitment:
Approximately 1 year (cohort A)
Approximately 1 year (cohort B)
International: 30
Germany: 13
Sponsor LMU Munich, financial support provided by Roche and Lilly.
TBD
0
€5000 (cohort A), €6000 (cohort B), plus set-up plus radiology plus pharmacy
Ja
