Zandelisib + Tazemetostat in R/R Follicular Lymphoma

Inclusion Criteria:

* Participants must have biopsy-proven relapsed or refractory FL grade 1-2 or 3A by WHO criteria.
* Participants must require therapy based on: symptomatic disease, threatened end-organ dysfunction, compressive disease, cytopenias secondary to lymphoma, bulky disease (defined as any site 7 cm or greater in size, or 3 or more sites 3 cm or greater in size), or progression.
* Participants must have received at least two prior systemic therapies for FL, or have relapsed or refractory FL who have no satisfactory alternative treatment options.
* Age ≥18 years. Because no dosing or adverse event data are currently available on the use of zandelisib in combination with tazemetostat in participants \<18 years of age, children are excluded from this study.
* ECOG performance status ≤2 (Karnofsky ≥60%).
* Participants must have adequate marrow function as defined below (unless abnormalities are considered related to marrow and/or splenic involvement by lymphoma):

  * absolute neutrophil count ≥1,000/mcL
  * platelets ≥75,000/mcL
* Participants must have adequate organ function as defined below (unless abnormalities are considered related to target organ involvement or compression by lymphoma):

  * total bilirubin ≤ 1.5x institutional upper limit of normal (ULN) (Isolated bilirubin ≤3.0x ULN is acceptable if considered secondary to Gilbert's syndrome)
  * AST(SGOT)/ALT(SGPT) ≤2.0 × institutional ULN Creatinine clearance ≥50 mL/min eGFR (Cockcroft-Gault)
* Participants with known history or current symptoms of cardiac disease should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
* The effects of zandelisib and tazemetostat on the developing human fetus are unknown. A female participant is eligible to participate if she is not pregnant or breastfeeding. Women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for at least 4 months after the last dose of study intervention. Women must also agree not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. 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. Nonchildbearing potential is defined as follows (by other than medical reasons):

  * ≥45 years of age and has not had menses for \>1 year
  * Patients who have been amenorrhoeic for \<1 year without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
  * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure.
* Women of childbearing potential must have a negative highly sensitive serum pregnancy test, and agree to repeat the highly sensitive serum pregnancy testing within 72 hours before the first dose of study intervention (if screening pregnancy test was not within 72 hours of dosing).
* Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 6 months after completion of administration. Men must also agree not to donate sperm during this period. Men may agree to remain abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term or persistent basis) OR agree to use a male condom, even if they have undergone a successful vasectomy and female partner to use an additional highly effective contraceptive method with a failure rate of \<1% per year when having sexual intercourse with a WOCBP (including pregnant females).
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Participants who have not recovered from adverse events due to prior anti-cancer therapy (i.e., have residual toxicities \> Grade 1) with the exception of alopecia. At the discretion of the overall PI, participants with residual toxicities \>Grade 1 may be considered eligible if in the opinion of the overall PI the residual toxicity is not likely to interfere with the safety or efficacy assessment of the investigational regimen.
* Participants who are receiving any other investigational agents.
* Participants must not have known central nervous system involvement by lymphoma.
* Participant must not have used an investigational drug or approved systemic lymphoma therapy with 14 days or five half-lives, whichever is shorter, preceding the first dose of study drug. Steroids are permitted.
* Participant must not have received a PI3K inhibitor or EZH2 inhibitor.
* Participants must not have known immediate or delayed hypersensitivity reaction or idiosyncratic reactions to zandelisib, tazemetostat, or drugs chemically related to zandelisib or tazemetostat, or any of the components of the study treatment.
* Participants must not have an uncontrolled intercurrent illness.
* Participants must not have an uncontrolled active infection.
* Participants must not have inflammatory bowel disease.
* Participants must not have active uncontrolled autoimmune disease.
* Participants must not have psychiatric illness/social situations that would limit compliance with study requirements. Participants must not have any serious and/or preexisting medical or other condition (including lab abnormalities) that could interfere with participant's safety in the opinion of the investigator.
* Women who are pregnant are excluded from this study because it is unknown if tazemetostat or zandelisib can cause embryo-fetal harm when administered to a pregnant woman. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with zandelisib and tazemetostat, breastfeeding should be discontinued if the mother is treated with zandelisib and tazemetostat.
* Participants must not have an active malignancy or systemic therapy for another malignancy within 3 years; local/regional therapy with curative intent such as surgical resection or localized radiation within 3 years of treatment is permitted; active prostate cancer that is considered low-risk and appropriate for continued active surveillance strategy is permitted. Additionally, adequately treated basal, squamous cell carcinoma, or non-melanomatous skin cancer, carcinoma in situ of the cervix, or superficial bladder cancer not treated with intravesical chemotherapy or BCG within 6 months, are permitted.
* Participant must be able to swallow pills.
* Participant must not have active uncontrolled HIV infection. Participants with HIV are eligible if disease is adequately controlled, defined by presence of both an undetectable viral load and a CD4 count \>200.
* Participant must not have active hepatitis B infection. Participant with positive HBV core antibody or HBV surface antigen at screening are eligible if HBV viral load is negative by PCR and on appropriate antiviral therapy. Participant must not have active hepatitis C infection. Note: participants with positive Hepatitis C antibody due to prior resolved disease can be enrolled, only if a confirmatory negative Hepatitis C RNA test is obtained. Note: Hepatitis RNA testing is optional and participants with negative Hepatitis C antibody test are not required to also undergo Hepatitis C RNA testing.
* Coadministration of strong or moderate CYP3A inhibitors or inducers is not permitted. If a patient is taking a strong or moderate CYP3A inhibitor or inducer prior to starting treatment, this medication needs to be stopped for 1 week prior to initiation of protocol therapy to allow for a washout period.