Summary

This early phase I trial investigates how well duvelisib exposure before CAR-T cell manufacturing works to enhance immune profiles of T cells in patients with diffuse large B-cell lymphoma that has come back (recurrent) or does not respond to treatment (refractory). Duvelisib, an oral phosphoinositide 3-kinase (PI3K) inhibitor, may favorably change a patient’s T cells to make them more efficient and have a longer duration for manufacturing of CAR-T cells.

Objectives

PRIMARY OBJECTIVE:
I. To assess the increase in CD27+/CD28+ T cells, after 8 to 15 day exposure duvelisib prior to collection of mononuclear cells for chimeric antigen receptor T-cell (CAR-T cell) manufacturing.

SECONDARY OBJECTIVES:
I. To evaluate patient compliance with duvelisib.
II. To evaluate the time required for manufacturing CAR-T using mononuclear cells from duvelisib-treated patients.
III. To describe the frequencies of CD27/28 double positive T cells and CD4/8 double negative T cells.
IV. To evaluate expansion and persistence of CAR-T cells.
V. To evaluate overall response rates following CAR-T therapy.
VI. To evaluate survival rates following CAR-T cell therapy.
VII. To describe the frequency of cytokine release syndrome (CRS) and neurotoxicity requiring intensive care unit (ICU) transfer (for CRS or neurotoxicity) and/or treatment.
VIII. Describe the safety and tolerability profile of duvelisib.

OUTLINE:
Patients receive duvelisib orally (PO) twice daily (BID) for 2 weeks prior to collection of CAR-T cells in the absence of disease progression or unacceptable toxicity. Patients then receive commercial CD19 CAR-T via infusion. Patients also undergo positron emission tomography (PET)/computed tomography (CT) scans between day -14 and day 0 and again on day 90.

Patients are followed for approximately 90 days after CAR-T infusion.

Eligibility

1. Patients must have a biopsy proven diagnosis of relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or relapsed/refractory follicular lymphoma and be eligible to receive commercial CD19 CART (Kymriah, Yescarta, Breyanzi, Tecartus)
2. 18 years of age or older
3. Eastern Cooperative Oncology Group (ECOG) < 2
4. Serum creatinine (Cr) < 2.0 mg/dL
5. Alanine aminotransferase (AST)/aspartate aminotransferase (ALT) < 2 x upper limit of normal (ULN)
6. Total bilirubin < 2.0 mg/dL
7. Hemoglobin > 8 g/dL
8. Platelet count > 50 K/mcl
9. An absolute neutrophil count (ANC) > 1,000/mm^3
10. An absolute lymphocyte count (ALC) > 300/mm^3
11. Completion of all previous therapy (including surgery, radiotherapy, chemotherapy, immunotherapy, or investigational therapy) for the treatment of their DLBCL or relapsed/refractory follicular lymphoma >= 2 weeks before the start of duvelisib. There is no limit on how many previous lines of treatment a patient may have received
12. The effects of duvelisib on the developing human fetus are unknown. For this reason, women of child-bearing potential (WOCBP) must have a negative serum or urine pregnancy test prior to starting therapy. WOCBP and men must agree to use highly effective contraception (hormonal or barrier method of birth control or abstinence) from enrollment into this study until at least 12 months after commercial CD19 CART infusion and until CAR-T cells are no longer present by quantitative polymerase chain reaction (qPCR) on two consecutive tests (qPCR tests will be available upon request). * A woman of childbearing potential (WOCBP) is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months. * WOCBP must have a negative pregnancy test within 24 hours of leukapheresis, lymphodepletion (if performed) and commercial CD19 CART infusion (if lymphodepletion not performed) * Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. * All men treated or enrolled on this protocol must agree to use highly effective contraception from enrollment into this study until at least 12 months after commercial CD19 CART infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests (qPCR tests will be available upon request)
13. The patient must be willing to comply with fertility requirements and contraceptive options below:
14. Female patients identified as WOCBP must be willing to use two adequate barrier methods of contraception to prevent pregnancy or agree to abstain from heterosexual activity (total abstinence)
15. Total abstinence is permitted when this is in line with the usual practice and lifestyle of the patient. Periodic abstinence (i.e., calendar, ovulation, post-ovulation methods) and withdrawals are not acceptable forms of contraception
16. Female sterilization includes having had surgical bilateral oophorectomy and/or bilateral salpingectomy with or without a hysterectomy, a total hysterectomy, or bilateral tubal ligation at least six weeks before taking study treatment. In case of oophorectomy alone, patients are eligible only when the reproductive status of the woman has been confirmed by a follow-up hormone assessment
17. Male sterilization with vasectomy must occur at least 6 months prior to screening. For female patients on the study, the vasectomized male partner should be the sole partner
18. Use of oral (estrogen and progesterone), injected or implanted hormonal methods of contraception, or placement of an intrauterine device (IUD) or intrauterine system (IUS) or other forms of contraception that comparable efficacy (failure rate < 1%). In case of oral contraception, the woman should be stable on the same pill for a minimum of 3 months prior to enrollment on the study
19. Sexually active males must use a condom during intercourse from enrollment into this study until at least 12 months after commercial CD19 CART infusion and until CAR-T cells are no longer present by qPCR on two consecutive tests (qPCR tests will be available upon request). A condom is required of all sexually active male patients to prevent them from fathering a child AND to prevent delivery of study treatment via seminal fluid to their partner
20. The patient must be willing to comply with the following requirements:
21. Patients must agree not to donate blood, sperm/ova or any other organs while taking protocol therapy and for at least 12 months after stopping treatment
22. Willingness and ability of the patient to comply with scheduled visits, drug administration plan, protocol specified laboratory tests, other study procedures and study restrictions
23. Evidence of personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed on the procedures to be followed, the experimental nature of the therapy, alternative, potential risks and discomforts, potential benefits and other pertinent aspects of study participation