Summary

This phase II trial tests how well tafasitamab, lenalidomide and venetoclax work in treating patients with mantle cell lymphoma that has come back (after a period of improvement) (relapsed) or that has not responded to previous treatment (refractory). Tafasitamab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Lenalidomide is in a class of medications called immunomodulatory agents. It works by helping the immune system kill cancer cells. Venetoclax is in a class of medications called B-cell lymphoma-2 (Bcl-2) inhibitors. It may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cancer cell survival. Giving tafasitamab, lenalidomide and venetoclax together may kill cancer cells more efficiently in patients with relapsed or refractory mantle cell lymphoma.

Objectives

PRIMARY OBJECTIVE:
I. To evaluate the overall response rate in patients with relapsed/refractory mantle cell lymphoma after treatment with tafasitamab, lenalidomide and venetoclax combination.

SECONDARY OBJECTIVES:
I. To estimate the complete response rate in patients with relapsed/refractory mantle cell lymphoma after treatment with tafasitamab, lenalidomide and venetoclax combination.
II. To estimate the duration of response (DoR) in patients with relapsed/refractory mantle cell lymphoma after treatment with tafasitamab, lenalidomide and venetoclax combination.
III. To estimate the progression free survival (PFS) in patients with relapsed/refractory mantle cell lymphoma after treatment with tafasitamab, lenalidomide and venetoclax combination.
IV. To estimate the overall survival (OS) in patients with relapsed/refractory mantle cell lymphoma after treatment with tafasitamab, lenalidomide and venetoclax combination.
V. To evaluate the safety profile of tafasitamab, lenalidomide and venetoclax combination in patients with relapsed/refractory mantle cell lymphoma.

CORRELATIVE OBJECTIVES:
I. To assess the rate of undetectable minimal residual disease (uMRD) in peripheral blood by multi-color flow cytometry.
II. To assess the correlation between MRD status with clinical outcomes such as DoR, PFS and OS.

OUTLINE: Patients receive tafasitamab intravenously (IV), lenalidomide orally (PO) and venetoclax PO while on study. Patients may undergo lumbar puncture during screening. Patients undergo computed tomography (CT) scan and blood sample collection and may undergo magnetic resonance imaging (MRI) and tumor biopsy on study and during follow-up. Patients undergo positron emission tomography (PET)/CT, bone marrow biopsy, and bone marrow aspirate throughout the study.

After treatment completion, patients follow up every 3 months for 1 year, every 4 months for 1 year and then every 6 months until up to 5 years after entering the trial.

Eligibility

1. Age >= 18 years old
2. Confirmed pathology diagnosis of mantle cell lymphoma (MCL) with t(11;14)(q13;q32) translocation or cyclin D1 overexpression NOTE: Patients with relapsed/refractory MCL after prior anti-CD19 therapy (such as chimeric antigen receptor [CAR] T-cell therapy) should have confirmed preserved expression of CD19, unless a biopsy is not feasible or associated with a high risk of complications in the treating physician’s opinion
3. Relapsed or refractory disease, which is defined as patients with >= 1 line of prior systemic treatment NOTE: Prior exposure to lenalidomide or venetoclax is allowed, provided there was no disease progression on lenalidomide or venetoclax
4. In the view of the treating physician, the patient is in need of treatment, for example, with lymphoma-related symptoms or cytopenia
5. Evaluable disease, which is defined as at least one lymph node or other type of lesion that has a size >= 1.5 cm, or spleen size >= 15 cm or white blood cell (WBC) >= 30,000/mm^3 in leukemic non-nodal MCL patients
6. Eastern Cooperative Oncology Group Performance Status (PS) 0, 1, or 2
7. Absolute neutrophil count (ANC) >= 1500/mm^3 (obtained =< 14 days prior to registration)
8. Platelet count >= 75,000/mm^3 (>= 50,000/mm^3 if there is evidence of bone marrow involvement by MCL or hypersplenism) (obtained =< 14 days prior to registration)
9. Hemoglobin > 8.0 g/dL (obtained =< 14 days prior to registration)
10. Activated partial thromboplastin time (aPTT) or partial thromboplastin time (PTT) =< 1.5 × upper normal limit (ULN) (obtained =< 14 days prior to registration)
11. Prothrombin (PT) or international normalized ratio (INR) =< 1.5 × upper normal limit (ULN) (obtained =< 14 days prior to registration)
12. Total bilirubin =< 1.5 × ULN (or =< 3 × ULN if there is evidence of parenchymal liver involvement with MCL or documented Gilbert’s disease) (obtained =< 14 days prior to registration)
13. Alanine aminotransferase (ALT) and aspartate transaminase (AST) =< 3 × ULN (or =< 5 × ULN if there is evidence of parenchymal liver involvement with MCL) (obtained =< 14 days prior to registration)
14. Calculated creatinine clearance > 60 ml/min using the Cockcroft-Gault formula (obtained =< 14 days prior to registration)
15. Negative pregnancy test done =< 7 days prior to registration, for women of reproductive potential only NOTE: If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required NOTE: Females of reproductive potential include all females who are menstruating, amenorrheic from previous medical treatments, under 50 years of age, and/or perimenopausal, and do not qualify for the females not of reproductive potential category. Females not of reproductive potential include females who have been in natural menopause for at least 24 consecutive months, or who have had a hysterectomy and/or bilateral oophorectomy, or female children who have not started menstruating
16. Agree to use effective contraception during study treatment and for 4 weeks after last dose of lenalidomide and for 3 months after last dose of tafasitamab (whichever is longer) Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously: one highly effective form of contraception – tubal ligation, intrauterine device (IUD), hormonal (birth control pills, injections, hormonal patches, vaginal rings, or implants), or partner's vasectomy, and one additional effective contraceptive method – male latex or synthetic condom, diaphragm, or cervical cap. Contraception should continue during therapy, during dose interruptions, and for 4 weeks following discontinuation of lenalidomide and for 3 months after discontinuation of tafasitamab (whichever is longer). Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. If needed, females of reproductive potential should be referred to a qualified provider of contraceptive methods Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential during trial therapy, during dose interruptions, and for 4 weeks following discontinuation of lenalidomide and for 3 months after discontinuation of tafasitamab (whichever is longer), even if they have undergone a successful vasectomy. Male patients must not donate sperm
17. Willing to be registered into the mandatory REVLIMID REMS (trademark) program, and willing and able to comply with the requirements of the REVLIMID REMS program
18. Able to take low-dose aspirin (81 mg) daily or an alternative form of anticoagulation
19. Subject must voluntarily sign and date an informed consent =< 28 days prior to registration
20. Willing to return to enrolling institution for follow-up during the active monitoring phase (i.e., active treatment and clinical follow-up) of the study
21. Willing to provide mandatory blood specimens for correlative research and banking for future correlative research pertinent to this study

Treatment Sites in Georgia